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Tanu, Chaturvedi M, Fatima S, Yadav SS, Padhy PK, Tiwari S, Seth K, Chaturvedi RK, Priya S. Expression analysis of molecular chaperones associated with disaggregation complex in rotenone-induced Parkinsonian rat model. Int J Biochem Cell Biol 2025; 181:106752. [PMID: 39952347 DOI: 10.1016/j.biocel.2025.106752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/31/2024] [Revised: 01/30/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the aberrant aggregation and phosphorylation (ser129) of α-synuclein (α-syn, a presynaptic protein) which leads to the formation of pathogenic Lewy bodies. A critical factor in the pathogenesis of PD is the disruption of the cellular protein quality control system, where molecular chaperones and their co-chaperones are integral for mitigating proteotoxic stress. Although the role of molecular chaperones in PD and other protein aggregation diseases has been extensively investigated, the in vivo investigation of disaggregation chaperones, including HSP70, HSP105, and co-chaperone DNAJBs, remains relatively limited. The present study aims to elucidate the expression dynamics of the disaggregation molecular chaperones within the substantia nigra pars compacta of the rotenone-induced Parkinsonian rat model and its association with α-syn aggregation. The rotenone-treated rats exhibited significant behavioural symptoms, α-syn aggregation and degeneration of dopaminergic neurons, confirming the development of Parkinsonism. Significant upregulation of α-syn expression/phosphorylation and co-localization in TH+ve neurons in the SNpc of treated rats was observed. Further, the gene and protein analysis of HSP70, DNAJB6, and HSP105 were found to be upregulated and TH+ve neurons showed their co-localization with p-α-synser129 expression. The total proteomic analysis of SNpc correlated the altered cellular processes with cellular homeostasis imbalance. The observations of the present study provide an in vivo analysis of disaggregation-associated molecular chaperones in Parkinsonian or α-syn related conditions. The study can be helpful for further manipulation in the expression or activity of disaggregation-related chaperones for advanced therapeutic strategies and mechanistic studies in protein aggregation-associated diseases.
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Affiliation(s)
- Tanu
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Minal Chaturvedi
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Siraj Fatima
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Singh Yadav
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Prabeen Kumar Padhy
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Food Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Saurabh Tiwari
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kavita Seth
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Rajnish K Chaturvedi
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Priya
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Acquarone D, Bertero A, Brancaccio M, Sorge M. Chaperone Proteins: The Rising Players in Muscle Atrophy. J Cachexia Sarcopenia Muscle 2025; 16:e13659. [PMID: 39707668 PMCID: PMC11747685 DOI: 10.1002/jcsm.13659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/02/2024] [Revised: 10/18/2024] [Accepted: 10/31/2024] [Indexed: 12/23/2024] Open
Abstract
Despite significant progress in understanding the molecular aetiology of muscle atrophy, there is still a great need for new targets and drugs capable of counteracting muscle wasting. The role of an impaired proteostasis as the underlying causal mechanism of muscle atrophy is a well-established concept. From the earliest work on muscle atrophy and the identification of the first atrogenes, the hyper-activation of the proteolytic systems, such as autophagy and the ubiquitin proteasome system, has been recognized as the major driver of atrophy. However, the role of other key regulators of proteostasis, the chaperone proteins, has been largely overlooked. Chaperone proteins play a pivotal role in protein folding and in preventing the aggregation of misfolded proteins. Indeed, some chaperones, such as αB-crystallin and Hsp25, are involved in compensatory responses aimed at counteracting protein aggregation during sarcopenia. Chaperones also regulate different intracellular signalling pathways crucial for atrogene expression and the control of protein catabolism, such as the AKT and NF-kB pathways, which are regulated by Hsp70 and Hsp90. Furthermore, the downregulation of certain chaperones causes severe muscle wasting per se and experimental strategies aimed at preventing this downregulation have shown promising results in mitigating or reversing muscle atrophy. This highlights the therapeutic potential of targeting chaperones and confirms their crucial anti-atrophic functions. In this review, we summarize the most relevant data showing the modulation and the causative role of chaperone proteins in different types of skeletal muscle atrophies.
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Affiliation(s)
- Davide Acquarone
- Department of Molecular Biotechnology and Health SciencesUniversity of TurinTurinItaly
| | - Alessandro Bertero
- Department of Molecular Biotechnology and Health SciencesUniversity of TurinTurinItaly
| | - Mara Brancaccio
- Department of Molecular Biotechnology and Health SciencesUniversity of TurinTurinItaly
| | - Matteo Sorge
- Department of Molecular Biotechnology and Health SciencesUniversity of TurinTurinItaly
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3
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Zhang L, Zhou Y, Yang Z, Jiang L, Yan X, Zhu W, Shen Y, Wang B, Li J, Song J. Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases. J Neuroinflammation 2025; 22:7. [PMID: 39806503 PMCID: PMC11730833 DOI: 10.1186/s12974-025-03334-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/06/2024] [Accepted: 01/02/2025] [Indexed: 01/16/2025] Open
Abstract
Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within the central nervous system (CNS) can regulate energy metabolism to generate or degrade LDs in response to diverse pathological stimuli. This article provides a comprehensive review on the composition of LDs in CNS, their generation and degradation processes, their interaction mechanisms with mitochondria, the distribution among different cell types, and the roles played by these cells-particularly microglia and astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize the paradoxical role of LDs in post-cerebral ischemia inflammation and explore potential underlying mechanisms, aiming to identify novel therapeutic targets for this disease.
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Affiliation(s)
- Longxiao Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yunfei Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Zhongbo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Liangchao Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xinyang Yan
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Wenkai Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Yi Shen
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Bolong Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Jiaxi Li
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Jinning Song
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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4
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Liao W, Huang M, Du X, Tang L, Li J, Tang Q. Comprehensive analysis of heat shock protein 110, 90, 70, 60 families and tumor immune microenvironment characterization in clear cell renal cell carcinoma. Sci Rep 2025; 15:469. [PMID: 39747468 PMCID: PMC11697189 DOI: 10.1038/s41598-024-84834-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/10/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025] Open
Abstract
Heat shock proteins (HSPs) are a kind of molecular chaperone that helps protein folding, which is closely related to cancer. However, the association between HSPs and clear cell renal clear cell carcinoma (ccRCC) is uncertain. We explored the prognostic value of HSP110, HSP90, HSP70 and HSP60 families in ccRCC and their role in tumor immune microenvironment. The data obtained from the Cancer Genome Atlas (TCGA) were applied to determine the differential expression of HSPs in normal tissues and ccRCC. We comprehensively analyzed the prognostic value of HSPs in ccRCC and constructed a prognostic signature. We further explored the differences of tumor immune microenvironment and targeted therapy based on the signature. Cell proliferation, invasion and metastasis were detected by CCK8 assay, wound healing and transwell. Three clusters were identified with differences in overall survival and tumor stage. 6-gene signature (HSPA8, HSP90B1, HSPA7, HSPA12B, HSPA4L, HSPA1L) was identified to predict ccRCC patients' prognosis. The signature was confirmed in the internal cohort. Survival analysis, receiver operating characteristic (ROC) curve, univariate and multivariate COX regression analysis demonstrated the accuracy and independence of signature. The expression of HSPA7, HSPA8 and HSP90B1 were validated with quantitative real-time PCR. Our signature played a pivotal role in predicting tumor immune microenvironment, immune checkpoint gene expression, drug sensitivity, and tumor mutational burden (TMB) in patients with ccRCC. Our cellular experiments confirmed HSPA7 promotes the proliferation, invasion and metastasis of ccCRC cells. The HSPs signature identified in this study could serve as potential biomarkers for predicting prognosis and treatment response in ccRCC patients. It may provide new ideas for the current research on targeted therapy and immunotherapy strategies for ccRCC patients.
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Affiliation(s)
- Wenjing Liao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mao Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoyi Du
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liangdan Tang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junwu Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qin Tang
- Chongqing Health Center for Women and Children /Women and Children's Hospital of Chongqing Medical University, Chongqing, 401147, China.
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5
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Ncube SM, Nagarajan A, Lang D, Sinkala M, Burmeister CA, Serala K, Blackburn J, Prince S. c-Myc, AKT, Hsc70, and the T-Box Transcription Factor TBX3 Form an Important Oncogenic Signaling Axis in Breast Cancer. Mol Cancer Res 2025; 23:20-32. [PMID: 39264104 DOI: 10.1158/1541-7786.mcr-23-1031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/11/2023] [Revised: 04/17/2024] [Accepted: 08/07/2024] [Indexed: 09/13/2024]
Abstract
Breast cancer is the second leading cause of death in women globally, and it remains a health burden due to poor therapy response, cancer cell drug resistance, and the debilitating side effects associated with most therapies. One approach to addressing the need to improve breast cancer therapies has been to elucidate the mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. The T-box transcription factor, TBX3, is upregulated in breast cancer, in which it contributes to important oncogenic processes, and it has been validated as a potential therapeutic target. Here, we investigated the molecular mechanisms that upregulate TBX3 in breast cancer, and we show that it involves transcriptional activation by c-Myc, post-translational modification by AKT1 and AKT3, and interaction with the molecular chaperone Hsc70. Together, the results from this study provide evidence that c-Myc, AKT, Hsc70, and TBX3 form part of an important oncogenic pathway in breast cancer and thus reveal versatile ways of interfering with the oncogenic activity of TBX3 for the treatment of this neoplasm. Implications: Targeting the c-Myc/AKT/TBX3/Hsc70 signaling axis may be an effective treatment strategy for TBX3-driven breast cancer.
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Affiliation(s)
- Stephanie M Ncube
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - ArulJothi Nagarajan
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, India
| | - Dirk Lang
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Musalula Sinkala
- Division of Computational Biology, Department of Integrated Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Carly A Burmeister
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Karabo Serala
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Jonathan Blackburn
- Division of Chemical and Systems Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Sharon Prince
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Munjal NS, Dey G, Parthasarathi KTS, Chauhan K, Pai K, Patole MS, Pawar H, Sharma J. A Proteogenomic Approach for the Identification of Virulence Factors in Leishmania Parasites. Methods Mol Biol 2025; 2859:279-296. [PMID: 39436608 DOI: 10.1007/978-1-0716-4152-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/23/2024]
Abstract
Identifying new genes involved in virulence and drug resistance may hold the key to a better understanding of parasitic diseases. The proteogenomic profiling of various Leishmania species, the causative agents of leishmaniasis, has identified several novel genes, N- and C-terminal extensions of proteins, and corrections of existing gene models. Various virulence factors (VFs) responsible for leishmaniasis have been previously annotated through a proteogenomic approach, including the C-terminal extension of heat shock protein 70 (HSP70). Furthermore, the diversity of VFs across Leishmania donovani, L. infantum, L. major, and L. mexicana was determined using phylogenetic analysis. Moreover, protein-protein interaction networks (PPINs) of VFs with HSPs aid in making significant biological interpretations. Overall, an integrated omics approach involving proteogenomics was used to identify and study the relationship among VFs with other interacting proteins, including HSPs. This chapter provides a step-by-step guide to the identification of new genes in Leishmania using a proteogenomic approach and their functional assignment using a bioinformatics-based approach.
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Affiliation(s)
| | - Gourav Dey
- Institute of Bioinformatics, Bangalore, India
| | - K T Shreya Parthasarathi
- Institute of Bioinformatics, Bangalore, India
- Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Kshipra Chauhan
- School of Applied Sciences and Technology, Gujarat Technological University, Ahmedabad, India
| | - Kalpana Pai
- Department of Zoology, Savitribai Phule Pune University, Pune, India
| | | | - Harsh Pawar
- Biomedical and Life Sciences Division, Lancaster University, Lancaster, UK
| | - Jyoti Sharma
- Institute of Bioinformatics, Bangalore, India.
- Manipal Academy of Higher Education, Manipal, Karnataka, India.
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Cho Y, Kim Y, Lee H, Kim S, Kang J, Kadam US, Ju Park S, Sik Chung W, Chan Hong J. Cellular and physiological functions of SGR family in gravitropic response in higher plants. J Adv Res 2025; 67:43-60. [PMID: 38295878 PMCID: PMC11725163 DOI: 10.1016/j.jare.2024.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/12/2023] [Revised: 12/29/2023] [Accepted: 01/24/2024] [Indexed: 02/05/2024] Open
Abstract
BACKGROUND In plants, gravity directs bidirectional growth; it specifies upward growth of shoots and downward growth of roots. Due to gravity, roots establish robust anchorage and shoot, which enables to photosynthesize. It sets optimum posture and develops plant architecture to efficiently use resources like water, nutrients, CO2, and gaseous exchange. Hence, gravitropism is crucial for crop productivity as well as for the growth of plants in challenging climate. Some SGR members are known to affect tiller and shoot angle, organ size, and inflorescence stem in plants. AIM OF REVIEW Although the SHOOT GRAVITROPISM (SGR) family plays a key role in regulating the fate of shoot gravitropism, little is known about its function compared to other proteins involved in gravity response in plant cells and tissues. Moreover, less information on the SGR family's physiological activities and biochemical responses in shoot gravitropism is available. This review scrutinizes and highlights the recent developments in shoot gravitropism and provides an outlook for future crop development, multi-application scenarios, and translational research to improve agricultural productivity. KEY SCIENTIFIC CONCEPTS OF REVIEW Plants have evolved multiple gene families specialized in gravitropic responses, of which the SGR family is highly significant. The SGR family regulates the plant's gravity response by regulating specific physiological and biochemical processes such as transcription, cell division, amyloplast sedimentation, endodermis development, and vacuole formation. Here, we analyze the latest discoveries in shoot gravitropism with particular attention to SGR proteins in plant cell biology, cellular physiology, and homeostasis. Plant cells detect gravity signals by sedimentation of amyloplast (starch granules) in the direction of gravity, and the signaling cascade begins. Gravity sensing, signaling, and auxin redistribution (organ curvature) are the three components of plant gravitropism. Eventually, we focus on the role of multiple SGR genes in shoot and present a complete update on the participation of SGR family members in gravity.
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Affiliation(s)
- Yuhan Cho
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Yujeong Kim
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Hyebi Lee
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Sundong Kim
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Jaehee Kang
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Ulhas S Kadam
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea.
| | - Soon Ju Park
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Woo Sik Chung
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea
| | - Jong Chan Hong
- Division of Life Science and Division of Applied Life Science (BK21 Four), Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, Gyeongnam, 52828, Republic of Korea.
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Googins MR, An P, Gauthier CH, Pipas JM. Polyomavirus large T antigens: Unraveling a complex interactome. Tumour Virus Res 2024; 19:200306. [PMID: 39675526 PMCID: PMC11720896 DOI: 10.1016/j.tvr.2024.200306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/13/2024] [Revised: 12/12/2024] [Accepted: 12/12/2024] [Indexed: 12/17/2024] Open
Abstract
All members of the polyomavirus family encode a large T antigen (LT) protein that plays essential roles in viral DNA replication, regulation of viral gene expression, and the manipulation of numerous cellular pathways. Over 100 polyomaviruses have been discovered in hosts ranging from arthropods and fish to mammals, including fourteen that infect humans. LT is among the most studied viral proteins with thousands of articles describing its functions in viral productive infection and tumorigenesis. However, nearly all knowledge of LT activities is based on the studies of simian virus 40 (SV40) and a few other viruses. Comparative studies of LT proteins of different polyomaviruses have revealed a remarkable diversity in the mechanisms by which LT proteins function across different polyomavirus species. This review focuses on human polyomaviruses highlights the similarities and differences between polyomavirus LTs and highlights gaps in our understanding of this protein family. The concentration of knowledge around SV40 LT and the corresponding lack of mechanistic studies on LT proteins encoded by other human and animal polyomaviruses severely constrains our understanding of the biology of this important virus family.
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Affiliation(s)
- Matthew R Googins
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - Ping An
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - Christian H Gauthier
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - James M Pipas
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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Li X, Wang W, Pan S, Cao X, Thomas ER, Xie M, Zhang C, Wu J. Exploring heat shock proteins as therapeutic targets for Parkinson's disease. Biochem Pharmacol 2024; 230:116633. [PMID: 39551273 DOI: 10.1016/j.bcp.2024.116633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/30/2024] [Revised: 11/10/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein (α-syn). Promoting the degradation of misfolded proteins has been shown to be an effective approach to alleviate PD. This review highlights the roles of specific heat shock proteins (HSPs) in modulating α-syn aggregation and neuronal survival. HSP27 prevents glycosylation-induced α-syn aggregation, disrupts copper ion interactions, inhibits mitochondrial apoptosis, and prevents dopaminergic neuronal cell death. HSP70 alleviates dopaminergic neuronal damage by promoting mitophagy and preventing neuronal apoptosis. HSC70 plays a critical role in chaperone-mediated autophagy and facilitates lysosomal degradation. GRP78 mitigates abnormal protein aggregation. The HSP70-HSP40-HSP110 system is capable of degrading α-syn amyloid fibers. Inhibition of HSP90 expression protects neurons. Further research should prioritize developing regulators of HSPs as treatments for PD. While HSPs offer promise in PD management, their complex roles necessitate cautious therapeutic development to harness their potential. Understanding the specific roles of different HSPs will be essential to developing effective therapies for α-syn clearance.
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Affiliation(s)
- Xiang Li
- The Zigong Affiliated Hospital, Southwest Medical University, Zigong Mental Health Center, Zigong Institute of Brain Science, Zigong, Sichuan Province 643020, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Wenjun Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Shi Pan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Xueqin Cao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | | | - Mingyu Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China
| | - Chunxiang Zhang
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
| | - Jianming Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
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10
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Ji M, Li L, Yu J, Wu Z, Sheng Y, Wang F. New insights into the function and therapeutic potential of RNA-binding protein TRBP in viral infection, chronic metabolic diseases, brain disorders and cancer. Life Sci 2024; 358:123159. [PMID: 39447729 DOI: 10.1016/j.lfs.2024.123159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/20/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
RNA-binding proteins (RBPs) and non-coding RNAs are crucial trans-acting factors that bind to specific cis-acting elements in mRNAs, thereby regulating their stability and translation. The trans-activation response (TAR) RNA-binding protein (TRBP) recognizes precursor microRNAs (pre-miRNAs), modulates miRNA maturation, and influences miRNA interference (mi-RNAi) mediated by the RNA-induced silencing complex (RISC). TRBP also directly binds and mediates the degradation of certain mRNAs. Thus, TRBP acts as a hub for regulating gene expression and influences a variety of biological processes, including immune evasion, metabolic abnormalities, stress response, angiogenesis, hypoxia, and metastasis. Aberrant TRBP expression has been proven to be closely related to the initiation and progression of diseases, such as viral infection, chronic metabolic diseases, brain disorders, and cancer. This review summarizes the roles of TRBP in cancer and other diseases, the therapeutic potential of TRBP inhibition, and the current status of drug discovery on TRBP.
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Affiliation(s)
- Minghui Ji
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jialing Yu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Wu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Fei Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
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11
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Takeda T, Her YR, Kim JK, Jha NN, Monani UR. A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1 G86R mouse model of amyotrophic lateral sclerosis. Exp Neurol 2024; 383:115024. [PMID: 39454934 DOI: 10.1016/j.expneurol.2024.115024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/14/2024] [Revised: 10/18/2024] [Accepted: 10/22/2024] [Indexed: 10/28/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.
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Affiliation(s)
- Taishi Takeda
- Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Colleen Giblin Research Laboratories, Columbia University Irving Medical Center, New York, NY 10032, United States of America
| | - Yoon-Ra Her
- Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Colleen Giblin Research Laboratories, Columbia University Irving Medical Center, New York, NY 10032, United States of America
| | - Jeong-Ki Kim
- Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Colleen Giblin Research Laboratories, Columbia University Irving Medical Center, New York, NY 10032, United States of America
| | - Narendra N Jha
- Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Colleen Giblin Research Laboratories, Columbia University Irving Medical Center, New York, NY 10032, United States of America
| | - Umrao R Monani
- Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Colleen Giblin Research Laboratories, Columbia University Irving Medical Center, New York, NY 10032, United States of America; Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, United States of America.
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12
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Gao Z, Zheng J, Wu X, Savinov S, Zhao C, Xiao H. Heat shock cognate 70 protein is a novel target of nobiletin and its colonic metabolites in inhibiting colon carcinogenesis. Food Funct 2024; 15:10447-10458. [PMID: 39329172 DOI: 10.1039/d4fo03211j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 09/28/2024]
Abstract
Nobiletin (NBT) is a unique flavonoid mainly found in citrus fruits and has been reported to inhibit colon carcinogenesis in multiple rodent models. However, the direct molecular targets of NBT are unknown, which greatly limits its utilization in cancer prevention and treatment. In this study, using affinity chromatography, proteomics, computer modeling and various biochemical analyses, for the first time we identified HSC70 as a direct protein target of NBT in colon cancer cells. Moreover, NBT bound to HSC70 at its ATP-binding site and inhibited its ATPase activity. Importantly, our results also demonstrated that the major colonic metabolites of NBT (generated in the colon of NBT-fed mice) produced similar inhibitory effects against HSC70-mediated pro-carcinogenic events to those of NBT. Overall, our results provide a solid basis to further investigate the implication of the interaction between NBT/NBT metabolites and HSC70 in cancer chemoprevention.
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Affiliation(s)
- Zili Gao
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01002, USA.
| | - Jinkai Zheng
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01002, USA.
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, P. R. China
| | - Xian Wu
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01002, USA.
- Department of Kinesiology and Health, Miami University, Oxford, OH 45056, USA
| | - Sergey Savinov
- Division of Arts and Sciences, Rivier University, Nashua, NH, USA
| | - Chengying Zhao
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, P. R. China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, 102 Holdsworth Way, Amherst, MA 01002, USA.
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13
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Chen Q, Chen Y, Bao C, Xiang H, Gao Q, Mao L. Mechanism and complex roles of HSC70/HSPA8 in viral entry. Virus Res 2024; 347:199433. [PMID: 38992806 PMCID: PMC11305274 DOI: 10.1016/j.virusres.2024.199433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2024] [Revised: 07/05/2024] [Accepted: 07/06/2024] [Indexed: 07/13/2024]
Abstract
The process of viruses entering host cells is complex, involving multiple aspects of the molecular organization of the cell membrane, viral proteins, the interaction of receptor molecules, and cellular signaling. Most viruses depend on endocytosis for uptake, when viruses reach the appropriate location, they are released from the vesicles, undergo uncoating, and release their genomes. Heat shock cognate protein 70(HSC70): also known as HSPA8, a protein involved in mediating clathrin-mediated endocytosis (CME), is involved in various viral entry processes. In this mini-review, our goal is to provide a summary of the function of HSC70 in viral entry. Understanding the interaction networks of HSC70 with viral proteins helps to provide new directions for targeted therapeutic strategies against viral infections.
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Affiliation(s)
- Qiaoqiao Chen
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, PR China
| | - Yiwen Chen
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, PR China
| | - Chenxuan Bao
- Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University,Kunshan, Jiangsu, PR China
| | - Huayuan Xiang
- Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University,Kunshan, Jiangsu, PR China
| | - Qing Gao
- Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University,Kunshan, Jiangsu, PR China
| | - Lingxiang Mao
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu, PR China; Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University,Kunshan, Jiangsu, PR China.
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14
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Myrda J, Bremm F, Schaft N, Dörrie J. The Role of the Large T Antigen in the Molecular Pathogenesis of Merkel Cell Carcinoma. Genes (Basel) 2024; 15:1127. [PMID: 39336718 PMCID: PMC11431464 DOI: 10.3390/genes15091127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/29/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
The large T antigen (LT) of the Merkel cell polyomavirus (MCPyV) is crucial for Merkel cell carcinoma (MCC), a rare but very aggressive form of neuroendocrine skin cancer. The clonal integration of MCPyV DNA into the host genome is a signature event of this malignancy. The resulting expression of oncogenes, including the small T (sT) antigen and a truncated form of the LT (truncLT), directly contribute to carcinogenesis. The truncation of the C-terminus of LT prevents the virus from replicating due to the loss of the origin binding domain (OBD) and the helicase domain. This precludes cytopathic effects that would lead to DNA damage and ultimately cell death. At the same time, the LxCxE motif in the N-terminus is retained, allowing truncLT to bind the retinoblastoma protein (pRb), a cellular tumor suppressor. The continuously inactivated pRb promotes cell proliferation and tumor development. truncLT exerts several classical functions of an oncogene: altering the host cell cycle, suppressing innate immune responses to viral DNA, causing immune escape, and shifting metabolism in favor of cancer cells. Given its central role in MCC, the LT is a major target for therapeutic interventions with novel approaches, such as immune checkpoint inhibition, T cell-based immunotherapy, and cancer vaccines.
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Affiliation(s)
- Julia Myrda
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Franziska Bremm
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
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15
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Zhong J, Zhu M, Guo J, Chen X, Long R, Körte F, Wang S, Chen H, Xiong X, Liu Y. Enhancing tumor photodynamic synergistic therapy efficacy through generation of carbon radicals by Prussian blue nanomedicine. Regen Biomater 2024; 11:rbae103. [PMID: 39346686 PMCID: PMC11434160 DOI: 10.1093/rb/rbae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/06/2024] [Revised: 07/11/2024] [Accepted: 07/21/2024] [Indexed: 10/01/2024] Open
Abstract
Significant progress has been achieved in tumor therapies utilizing nano-enzymes which could convert hydrogen peroxide into reactive oxygen species (ROS). However, the ROS generated by these enzymes possess a short half-life and exhibit limited diffusion within cells, making it challenging to inflict substantial damage on major organelles for effective tumor therapy. Therefore, it becomes crucial to develop a novel nanoplatform that could extend radicals half-life. Artesunate (ATS) is a Fe (II)-dependent drug, while the limited availability of iron (II), coupled with the poor aqueous solubility of ATS, limits its application. Here, Prussian blue (PB) was selected as a nano-carrier to release Fe (II), thus constructing a hollow Prussian blue/artesunate/methylene blue (HPB/ATS/MB) nanoplatform. HPB degraded and released iron(III), ATS and MB, under the combined effects of NIR irradiation and the unique tumor microenvironment. Moreover, Fe (III) exploited GSH to formation of Fe (II), disturbing the redox homeostasis of tumor cells and Fe (II) reacted with H2O2 and ATS to generate carbon radicals with a long half-life in situ. Furthermore, MB generates 1O2 under laser irradiation conditions. In vitro and in vivo experiments have demonstrated that the HPB/ATS/MB NPs exhibit a synergistic therapeutic effect through photothermal therapy, photodynamic therapy and radical therapy.
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Affiliation(s)
- Jun Zhong
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Mingzhi Zhu
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Jiaqi Guo
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Xinyu Chen
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Ruimin Long
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Fabian Körte
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen 72770, Germany
| | - Shibin Wang
- College of Materials Science and Engineering, Huaqiao University, Xiamen 361021, China
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, China
- Fujian Provincial Key Laboratory of Biochemical Technology, Xiamen 361021, China
| | - Hao Chen
- Fujian Provincial Key Laboratory of Intelligent Identification and Control of Complex Dynamic System, Haixi Institutes, Chinese Academy of Sciences, Quanzhou 362200, China
| | - Xin Xiong
- NMI Natural and Medical Sciences Institute, University of Tübingen, Reutlingen 72770, Germany
| | - Yuangang Liu
- College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen 361021, China
- Fujian Provincial Key Laboratory of Biochemical Technology, Xiamen 361021, China
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16
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Tao CY, Wu XL, Song SS, Tang Z, Zhou YF, Tian MX, Jiang XF, Fang Y, Zhu GQ, Huang R, Qu WF, Gao J, Chu TH, Yang R, Chen JF, Zhao QF, Ding ZB, Dai Z, Zhou J, Liu WR, Shi YH, Fan J. Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration. Cell Oncol (Dordr) 2024; 47:1391-1403. [PMID: 38607517 PMCID: PMC11322209 DOI: 10.1007/s13402-024-00934-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 03/05/2024] [Indexed: 04/13/2024] Open
Abstract
PURPOSE GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.
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Affiliation(s)
- Chen-Yang Tao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Ling Wu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Shu-Shu Song
- Department of Biochemistry and Molecular, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zheng Tang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Fu Zhou
- Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng-Xin Tian
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Xi-Fei Jiang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan Fang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Gui-Qi Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Run Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei-Feng Qu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jun Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Tian-Hao Chu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jia-Feng Chen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Qian-Fu Zhao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhen-Bin Ding
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhi Dai
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei-Ren Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Ying-Hong Shi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
- Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
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17
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Dong YN, Mercado-Ayón E, Coulman J, Flatley L, Ngaba LV, Adeshina MW, Lynch DR. The Regulation of the Disease-Causing Gene FXN. Cells 2024; 13:1040. [PMID: 38920668 PMCID: PMC11202134 DOI: 10.3390/cells13121040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/15/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/27/2024] Open
Abstract
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease caused in almost all patients by expanded guanine-adenine-adenine (GAA) trinucleotide repeats within intron 1 of the FXN gene. This results in a relative deficiency of frataxin, a small nucleus-encoded mitochondrial protein crucial for iron-sulfur cluster biogenesis. Currently, there is only one medication, omaveloxolone, available for FRDA patients, and it is limited to patients 16 years of age and older. This necessitates the development of new medications. Frataxin restoration is one of the main strategies in potential treatment options as it addresses the root cause of the disease. Comprehending the control of frataxin at the transcriptional, post-transcriptional, and post-translational stages could offer potential therapeutic approaches for addressing the illness. This review aims to provide a general overview of the regulation of frataxin and its implications for a possible therapeutic treatment of FRDA.
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Affiliation(s)
- Yi Na Dong
- Departments of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Jennifer Coulman
- Departments of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Liam Flatley
- The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lucie Vanessa Ngaba
- Departments of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Miniat W. Adeshina
- Departments of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - David R. Lynch
- Departments of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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18
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Yamashima T, Mochly-Rosen D, Wakatsuki S, Mizukoshi E, Seike T, Larus IM, Chen CH, Takemura M, Saito H, Ohashi A. Cleavage of Hsp70.1 causes lysosomal cell death under stress conditions. Front Mol Biosci 2024; 11:1378656. [PMID: 38859931 PMCID: PMC11163108 DOI: 10.3389/fmolb.2024.1378656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2024] [Accepted: 05/03/2024] [Indexed: 06/12/2024] Open
Abstract
Autophagy mediates the degradation of intracellular macromolecules and organelles within lysosomes. There are three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Heat shock protein 70.1 (Hsp70.1) exhibits dual functions as a chaperone protein and a lysosomal membrane stabilizer. Since chaperone-mediated autophagy participates in the recycling of ∼30% cytosolic proteins, its disorder causes cell susceptibility to stress conditions. Cargo proteins destined for degradation such as amyloid precursor protein and tau protein are trafficked by Hsp70.1 from the cytosol into lysosomes. Hsp70.1 is composed of an N-terminal nucleotide-binding domain (NBD) and a C-terminal domain that binds to cargo proteins, termed the substrate-binding domain (SBD). The NBD and SBD are connected by the interdomain linker LL1, which modulates the allosteric structure of Hsp70.1 in response to ADP/ATP binding. After the passage of the Hsp70.1-cargo complex through the lysosomal limiting membrane, high-affinity binding of the positive-charged SBD with negative-charged bis(monoacylglycero)phosphate (BMP) at the internal vesicular membranes activates acid sphingomyelinase to generate ceramide for stabilizing lysosomal membranes. As the integrity of the lysosomal limiting membrane is critical to ensure cargo protein degradation within the acidic lumen, the disintegration of the lysosomal limiting membrane is lethal to cells. After the intake of high-fat diets, however, β-oxidation of fatty acids in the mitochondria generates reactive oxygen species, which enhance the oxidation of membrane linoleic acids to produce 4-hydroxy-2-nonenal (4-HNE). In addition, 4-HNE is produced during the heating of linoleic acid-rich vegetable oils and incorporated into the body via deep-fried foods. This endogenous and exogenous 4-HNE synergically causes an increase in its serum and organ levels to induce carbonylation of Hsp70.1 at Arg469, which facilitates its conformational change and access of activated μ-calpain to LL1. Therefore, the cleavage of Hsp70.1 occurs prior to its influx into the lysosomal lumen, which leads to lysosomal membrane permeabilization/rupture. The resultant leakage of cathepsins is responsible for lysosomal cell death, which would be one of the causative factors of lifestyle-related diseases.
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Affiliation(s)
- Tetsumori Yamashima
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United States
| | - Soichi Wakatsuki
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, United States
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Takuya Seike
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United States
| | - Isabel Maria Larus
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, United States
| | - Che-Hong Chen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United States
| | - Miho Takemura
- Laboratory of Gene Function, Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Nonoichi, Japan
| | - Hisashi Saito
- Division of Collaborative Research and Development, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Akihiro Ohashi
- Division of Collaborative Research and Development, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
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Liu J, Song K, Lin B, Chen Z, Liu Y, Qiu X, He Q, Zuo Z, Yao X, Huang X, Liu Z, Liu Z, Huang Q, Guo X. The suppression of HSPA8 attenuates NLRP3 ubiquitination through SKP2 to promote pyroptosis in sepsis-induced lung injury. Cell Biosci 2024; 14:56. [PMID: 38698431 PMCID: PMC11064404 DOI: 10.1186/s13578-024-01239-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/14/2023] [Accepted: 04/25/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND Acute lung injury (ALI) is strongly associated with hospitalization and mortality in patients with sepsis. Recent evidence suggests that pyroptosis mediated by NLRP3(NOD-, LRR- and pyrin domain-containing 3) inflammasome activation plays a key role in sepsis. However, the mechanism of NLRP3 inflammasome activation in sepsis-induced lung injury remains unclear. RESULTS in this study, we demonstrated that NLRP3 inflammasome was activated by the down-regulation of heat shock protein family A member 8 (HSPA8) in Lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-treated mouse alveolar epithelial cells (AECs). Geranylgeranylacetone (GGA)-induced HSPA8 overexpression in cecum ligation and puncture (CLP) mice could significantly reduce systemic inflammatory response and mortality, effectively protect lung function, whilst HSPA8 inhibitor VER155008 aggravated this effect. The inhibition of HSPA8 was involved in sepsis induced acute lung injury by promoting pyroptosis of AECs. The down-regulation of HSPA8 activated NLRP3 inflammasome to mediate pyroptosis by promoting the degradation of E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2). In addition, when stimulated by LPS and ATP, down-regulated SKP2 promoted pyroptosis of AECs by further attenuating ubiquitination of NLRP3. Adeno-associated virus 9-SKP2(AAV9-SKP2) could promote NLRP3 ubiquitination and degradation, alleviate lung injury and inhibit systemic inflammatory response in vivo. CONCLUSION in summary, our study shows there is strong statistical evidence that the suppression of HSPA8 mediates alveolar epithelial pyroptosis by promoting the degradation of E3 ubiquitin ligase SKP2 and subsequently attenuating the ubiquitination of NLRP3 to activate the NLRP3 inflammasome, which provides a new perspective and therapeutic target for the treatment of sepsis-induced lung injury.
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Affiliation(s)
- Jinlian Liu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ke Song
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Bingqi Lin
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhenfeng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yan Liu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xianshuai Qiu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Qi He
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zirui Zuo
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaodan Yao
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoxia Huang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhuanhua Liu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhifeng Liu
- Department of Medicine intensive care unit , National Clinical Research Center for Geriatric Diseases (Chinese PLA General Hospital), General Hospital of Southern Theatre Command of PLA, Guangdong Branch Center, Guangzhou, Guangdong, China.
| | - Qiaobing Huang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- School of Basic Medical Sciences, Southern Medical University, 1023 Shatai Road, Tonghe, Guangzhou, 510515, China.
| | - Xiaohua Guo
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- School of Basic Medical Sciences, Southern Medical University, 1023 Shatai Road, Tonghe, Guangzhou, 510515, China.
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20
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Butler C, Dunmire M, Choi J, Szalai G, Johnson A, Lei W, Chen X, Liu L, Li W, Walter MJ, Liu T. HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells. Cell Stress Chaperones 2024; 29:300-311. [PMID: 38508444 PMCID: PMC10998001 DOI: 10.1016/j.cstres.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/09/2023] [Revised: 03/16/2024] [Accepted: 03/16/2024] [Indexed: 03/22/2024] Open
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by abnormal hematopoietic cell maturation, increased apoptosis of bone marrow cells, and anemia. They are the most common myeloid blood cancers in American adults. The full complement of gene mutations that contribute to the phenotypes or clinical symptoms in MDS is not fully understood. Around 10%-25% of MDS patients harbor an interstitial heterozygous deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes, including HSPA9. The HSPA9 gene encodes for the protein mortalin, a highly conserved heat shock protein predominantly localized in mitochondria. Our prior study showed that knockdown of HSPA9 induces TP53-dependent apoptosis in human CD34+ hematopoietic progenitor cells. In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that the knockdown of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knockdown, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53.
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Affiliation(s)
- Christopher Butler
- Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA
| | - Morgan Dunmire
- Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA
| | - Jaebok Choi
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gabor Szalai
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, USA
| | - Anissa Johnson
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, USA
| | - Wei Lei
- Department of Pharmaceutical and Graduate Life Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, USA
| | - Xin Chen
- Department of Pharmaceutical and Clinical Sciences, College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC, USA
| | - Liang Liu
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Matthew J Walter
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Tuoen Liu
- Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA.
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21
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Sahu W, Bai T, Das A, Mukherjee S, Prusty A, Mallick NR, Elangovan S, Reddy KS. Plasmodium falciparum J-dot localized J domain protein A8iJp modulates the chaperone activity of human HSPA8. FEBS Lett 2024; 598:818-836. [PMID: 38418371 DOI: 10.1002/1873-3468.14836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/13/2023] [Revised: 01/25/2024] [Accepted: 02/04/2024] [Indexed: 03/01/2024]
Abstract
Plasmodium falciparum renovates the host erythrocyte to survive during intraerythrocytic development. This renovation requires many parasite proteins to unfold and move outside the parasitophorous vacuolar membrane, and chaperone-regulated protein folding becomes essential for the exported proteins to function. We report on a type-IV J domain protein (JDP), PF3D7_1401100, which we found to be processed before export and trafficked inside the lumen of parasite-derived structures known as J-dots. We found this protein to have holdase activity, as well as stimulate the ATPase and aggregation suppression activity of the human HSP70 chaperone HsHSPA8; thus, we named it "HSPA8-interacting J protein" (A8iJp). Moreover, we found a subset of HsHSPA8 to co-localize with A8iJp inside the infected human erythrocyte. Our results suggest that A8iJp modulates HsHSPA8 chaperone activity and may play an important role in host erythrocyte renovation.
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Affiliation(s)
- Welka Sahu
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - Tapaswini Bai
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - Aleena Das
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - Subhadip Mukherjee
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - Aradhana Prusty
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - Nipa Rani Mallick
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - Selvakumar Elangovan
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
| | - K Sony Reddy
- School of Biotechnology, Kalinga Institute of Industrial Technology, Deemed to be University, Bhubaneswar, India
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22
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Dong YN, Ngaba LV, An J, Adeshina MW, Warren N, Wong J, Lynch DR. A peptide derived from TID1S rescues frataxin deficiency and mitochondrial defects in FRDA cellular models. Front Pharmacol 2024; 15:1352311. [PMID: 38495102 PMCID: PMC10940384 DOI: 10.3389/fphar.2024.1352311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/07/2023] [Accepted: 02/02/2024] [Indexed: 03/19/2024] Open
Abstract
Friedreich's ataxia (FRDA), the most common recessive inherited ataxia, results from homozygous guanine-adenine-adenine (GAA) repeat expansions in intron 1 of the FXN gene, which leads to the deficiency of frataxin, a mitochondrial protein essential for iron-sulphur cluster synthesis. The study of frataxin protein regulation might yield new approaches for FRDA treatment. Here, we report tumorous imaginal disc 1 (TID1), a mitochondrial J-protein cochaperone, as a binding partner of frataxin that negatively controls frataxin protein levels. TID1 interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Acute and subacute depletion of frataxin using RNA interference markedly increases TID1 protein levels in multiple cell types. In addition, TID1 overexpression significantly increases frataxin precursor but decreases intermediate and mature frataxin levels in HEK293 cells. In primary cultured human skin fibroblasts, overexpression of TID1S results in decreased levels of mature frataxin and increased fragmentation of mitochondria. This effect is mediated by the last 6 amino acids of TID1S as a peptide made from this sequence rescues frataxin deficiency and mitochondrial defects in FRDA patient-derived cells. Our findings show that TID1 negatively modulates frataxin levels, and thereby suggests a novel therapeutic target for treating FRDA.
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Affiliation(s)
- Yi Na Dong
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Lucie Vanessa Ngaba
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jacob An
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Miniat W. Adeshina
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Nathan Warren
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Johnathan Wong
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - David R. Lynch
- Department of Pediatrics and Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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23
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Tan SY, Liu CL, Han HL, Zhai XD, Jiang H, Wang BJ, Wang JJ, Wei D. Two heat shock cognate 70 genes involved in spermatogenesis regulate the male fertility of Zeugodacus cucurbitae, as potential targets for pest control. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 200:105816. [PMID: 38582574 DOI: 10.1016/j.pestbp.2024.105816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/04/2023] [Revised: 01/29/2024] [Accepted: 02/04/2024] [Indexed: 04/08/2024]
Abstract
The melon fly Zeugodacus cucurbitae Coquillett (Diptera: Tephritidae) is an agricultural quarantine pest threatening fruit and vegetable production. Heat shock cognate 70 (Hsc70), which is a homolog of the heat shock protein 70 (Hsp70), was first discovered in mice testes and plays an important role in spermatogenesis. In this study, we identified and cloned five Hsc70 genes from melon fly, namely ZcHsc70_1/2/3/4/5. Phylogenetic analysis showed that these proteins are closely related to Hsc70s from other Diptera insects. Spatiotemporal expression analysis showed that ZcHsc70_1 and ZcHsc70_2 are highly expressed in Z. cucurbitae testes. Fluorescence in situ hybridization further demonstrated that ZcHsc70_1 and ZcHsc70_2 are expressed in the transformation and maturation regions of testes, respectively. Moreover, RNA interference-based suppression of ZcHsc70_1 or ZcHsc70_2 resulted in a significant decrease of 74.61% and 63.28% in egg hatchability, respectively. Suppression of ZcHsc70_1 expression delayed the transformation of sperm cells to mature sperms. Meanwhile, suppression of ZcHsc70_2 expression decreased both sperm cells and mature sperms by inhibiting the meiosis of spermatocytes. Our findings show that ZcHsc70_1/2 regulates spermatogenesis and further affects the male fertility in the melon fly, showing potential as targets for pest control in sterile insect technique by genetic manipulation of males.
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Affiliation(s)
- Shan-Yuan Tan
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Chuan-Lian Liu
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Hong-Liang Han
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Xiao-Di Zhai
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Hongbo Jiang
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Bao-Jun Wang
- Chongqing Agricultural Technology Extension Station, Chongqing 401121, China
| | - Jin-Jun Wang
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Dong Wei
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; Key Laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River (Ministry of Education), Southwest University, Chongqing 400715, China; Key Laboratory of Surveillance and Management of Invasive Alien Species in Guizhou Education Department, Guiyang University, Guiyang 550005, China.
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24
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Zhang C, Wang Y, Wu G, Sun N, Bai H, Li X, Han S, Zhou H, Qi R, Zhang J. RPL35A promotes the progression of cholangiocarcinoma by mediating HSPA8 ubiquitination. Biol Direct 2024; 19:16. [PMID: 38395908 PMCID: PMC10885515 DOI: 10.1186/s13062-024-00453-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/24/2023] [Accepted: 01/09/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a biliary epithelial malignant tumor with an increasing incidence worldwide. Therefore, further understanding of the molecular mechanisms of CCA progression is required to identify new therapeutic targets. METHODS The expression of RPL35A in CCA and para-carcinoma tissues was detected by immunohistochemical staining. IP-MS combined with Co-IP identified downstream proteins regulated by RPL35A. Western blot and Co-IP of CHX or MG-132 treated CCA cells were used to verify the regulation of HSPA8 protein by RPL35A. Cell experiments and subcutaneous tumorigenesis experiments in nude mice were performed to evaluate the effects of RPL35A and HSPA8 on the proliferation, apoptosis, cell cycle, migration of CCA cells and tumor growth in vivo. RESULTS RPL35A was significantly upregulated in CCA tissues and cells. RPL35A knockdown inhibited the proliferation and migration of HCCC-9810 and HUCCT1 cells, induced apoptosis, and arrested the cell cycle in G1 phase. HSPA8 was a downstream protein of RPL35A and overexpressed in CCA. RPL35A knockdown impaired HSPA8 protein stability and increased HSPA8 protein ubiquitination levels. RPL35A overexpression promoted CCA cell proliferation and migration. HSPA8 knockdown inhibited CCA cell proliferation and migration, and reversed the promoting effect of RPL35A. Furthermore, RPL35A promoted tumor growth in vivo. In contrast, HSPA8 knockdown suppressed tumor growth, while was able to restore the effects of RPL35A overexpression. CONCLUSION RPL35A was upregulated in CCA tissues and promoted the progression of CCA by mediating HSPA8 ubiquitination.
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Affiliation(s)
- Chengshuo Zhang
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Yu Wang
- Department of General Surgery, Anshan Central Hospital, No.51, South Zhonghua Road, Tiedong District, 114008, Anshan, Liaoning Province, China
| | - Gang Wu
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Ning Sun
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Han Bai
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Xuejian Li
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Shuai Han
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Haonan Zhou
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China
| | - Ruizhao Qi
- Senior Department of General Surgery, the First Medical Center of Chinese PLA General Hospital, No.28, Fuxing Road, Haidian District, 100039, Beijing, China.
| | - Jialin Zhang
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei street, 110001, Shenyang, Liaoning Province, P. R. China.
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25
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Hui W, Song T, Yu L, Chen X. The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen-Glucose Deprivation-Induced Fibroblast Senescence. Antioxidants (Basel) 2023; 13:42. [PMID: 38247467 PMCID: PMC10812545 DOI: 10.3390/antiox13010042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/16/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 01/23/2024] Open
Abstract
Cellular senescence refers to the permanent and irreversible cessation of the cell cycle. Recently, it has gained significant interest as a promising target for preventing cardiovascular diseases. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that has been closely linked with an increased risk of cardiovascular diseases. In this study, bioinformatics analysis revealed that the signaling pathway for fibroblast senescence is significantly activated in mice after myocardial infarction (MI), and that ALDH2 might be a crucial molecule responsible for inducing this change. Therefore, we created an NIH3T3 fibroblast cell line oxygen-glucose deprivation (OGD) model to replicate the conditions of MI in vitro. We further revealed that decreased ALDH2 enzyme activity is a critical factor that affects fibroblast senescence after OGD, and the activation of ALDH2 can improve the mitochondrial damage caused by OGD. We identified Heat Shock 70-kDa Protein 8 (HSPA8) as an interacting protein of ALDH2 through co-immunoprecipitation (Co-IP) and mass spectrometry (MS) detection. Subsequently, our studies showed that HSPA8 translocates to the mitochondria after OGD, potentially binding to ALDH2 and inhibiting its enzyme activity. By transfecting siRNA to inhibit HSPA8 expression in cells, it was found that ALDH2 enzyme activity can be significantly increased, and the senescence characteristics induced by OGD in NIH3T3 cells can be improved. In conclusion, the data from this study suggest that HSPA8, in conjunction with ALDH2, could regulate fibroblast senescence after oxygen-glucose deprivation, providing a new direction and foundation for effectively intervening in fibroblast senescence after myocardial infarction.
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Affiliation(s)
- Wenting Hui
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130012, China;
| | - Tongtong Song
- Department of Anatomy, College of Basic Medical Sciences, Jilin University, Changchun 130012, China;
| | - Ling Yu
- Department of Pharmacy, The Second Hospital of Jilin University, Changchun 130022, China;
| | - Xia Chen
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130012, China;
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26
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Li QQ, Zhang J, Wang HY, Niu SF, Wu RX, Tang BG, Wang QH, Liang ZB, Liang YS. Transcriptomic Response of the Liver Tissue in Trachinotus ovatus to Acute Heat Stress. Animals (Basel) 2023; 13:2053. [PMID: 37443851 DOI: 10.3390/ani13132053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/18/2023] [Revised: 06/15/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Trachinotus ovatus is a major economically important cultured marine fish in the South China Sea. However, extreme weather and increased culture density result in uncontrollable problems, such as increases in water temperature and a decline in dissolved oxygen (DO), hindering the high-quality development of aquaculture. In this study, liver transcriptional profiles of T. ovatus were investigated under acute high-temperature stress (31 °C and 34 °C) and normal water temperature (27 °C) using RNA sequencing (RNA-Seq) technology. Differential expression analysis and STEM analysis showed that 1347 differentially expressed genes (DEGs) and four significant profiles (profiles 0, 3, 4, and 7) were screened, respectively. Of these DEGs, some genes involved in heat shock protein (HSPs), hypoxic adaptation, and glycolysis were up-regulated, while some genes involved in the ubiquitin-proteasome system (UPS) and fatty acid metabolism were down-regulated. Our results suggest that protein dynamic balance and function, hypoxia adaptation, and energy metabolism transformation are crucial in response to acute high-temperature stress. Our findings contribute to understanding the molecular response mechanism of T. ovatus under acute heat stress, which may provide some reference for studying the molecular mechanisms of other fish in response to heat stress.
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Affiliation(s)
- Qian-Qian Li
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
| | - Jing Zhang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524025, China
| | - Hong-Yang Wang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
| | - Su-Fang Niu
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524025, China
| | - Ren-Xie Wu
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524025, China
| | - Bao-Gui Tang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang 524025, China
| | - Qing-Hua Wang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
| | - Zhen-Bang Liang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
| | - Yan-Shan Liang
- College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China
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Sanchez-Briñas A, Duran-Ruiz C, Astola A, Arroyo MM, Raposo FG, Valle A, Bolivar J. ZNF330/NOA36 interacts with HSPA1 and HSPA8 and modulates cell cycle and proliferation in response to heat shock in HEK293 cells. Biol Direct 2023; 18:26. [PMID: 37254218 DOI: 10.1186/s13062-023-00384-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/09/2022] [Accepted: 05/20/2023] [Indexed: 06/01/2023] Open
Abstract
BACKGROUND The human genome contains nearly 20.000 protein-coding genes, but there are still more than 6,000 proteins poorly characterized. Among them, ZNF330/NOA36 stand out because it is a highly evolutionarily conserved nucleolar zinc-finger protein found in the genome of ancient animal phyla like sponges or cnidarians, up to humans. Firstly described as a human autoantigen, NOA36 is expressed in all tissues and human cell lines, and it has been related to apoptosis in human cells as well as in muscle morphogenesis and hematopoiesis in Drosophila. Nevertheless, further research is required to better understand the roles of this highly conserved protein. RESULTS Here, we have investigated possible interactors of human ZNF330/NOA36 through affinity-purification mass spectrometry (AP-MS). Among them, NOA36 interaction with HSPA1 and HSPA8 heat shock proteins was disclosed and further validated by co-immunoprecipitation. Also, "Enhancer of Rudimentary Homolog" (ERH), a protein involved in cell cycle regulation, was detected in the AP-MS approach. Furthermore, we developed a NOA36 knockout cell line using CRISPR/Cas9n in HEK293, and we found that the cell cycle profile was modified, and proliferation decreased after heat shock in the knocked-out cells. These differences were not due to a different expression of the HSPs genes detected in the AP-MS after inducing stress. CONCLUSIONS Our results indicate that NOA36 is necessary for proliferation recovery in response to thermal stress to achieve a regular cell cycle profile, likely by interaction with HSPA1 and HSPA8. Further studies would be required to disclose the relevance of NOA36-EHR interaction in this context.
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Affiliation(s)
- Alejandra Sanchez-Briñas
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain
| | - Carmen Duran-Ruiz
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain
- Biomedical Research and Innovation Institute of Cadiz (INiBICA), Cadiz, Spain
| | - Antonio Astola
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain
- Institute of Biomolecules (INBIO), University of Cadiz, Cadiz, Spain
| | - Marta Marina Arroyo
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain
| | - Fátima G Raposo
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain
| | - Antonio Valle
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain
- Institute of Viticulture and Agri-Food Research (IVAGRO) - International Campus of Excellence (ceiA3), University of Cadiz, Cadiz, Spain
| | - Jorge Bolivar
- Department of Biomedicine, Biotechnology and Public Health-Biochemistry and Molecular Biology, Campus Universitario de Puerto Real, University of Cadiz, Puerto Real, Cadiz, 11510, Spain.
- Institute of Biomolecules (INBIO), University of Cadiz, Cadiz, Spain.
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Kim JK, Jha NN, Awano T, Caine C, Gollapalli K, Welby E, Kim SS, Fuentes-Moliz A, Wang X, Feng Z, Sera F, Takeda T, Homma S, Ko CP, Tabares L, Ebert AD, Rich MM, Monani UR. A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses. Neuron 2023; 111:1423-1439.e4. [PMID: 36863345 PMCID: PMC10164130 DOI: 10.1016/j.neuron.2023.02.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/05/2022] [Revised: 12/11/2022] [Accepted: 02/02/2023] [Indexed: 03/04/2023]
Abstract
Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE complex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.
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Affiliation(s)
- Jeong-Ki Kim
- Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA
| | - Narendra N Jha
- Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA
| | - Tomoyuki Awano
- Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA
| | - Charlotte Caine
- Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA
| | - Kishore Gollapalli
- Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA
| | - Emily Welby
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Seung-Soo Kim
- Department of Obstetrics and Gynecology, New York, NY, USA
| | - Andrea Fuentes-Moliz
- Department of Medical Physiology and Biophysics, University of Seville School of Medicine, 41009, Seville, Spain
| | - Xueyong Wang
- Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, USA
| | - Zhihua Feng
- Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Fusako Sera
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Taishi Takeda
- Department of Neurology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA
| | - Shunichi Homma
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Chien-Ping Ko
- Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Lucia Tabares
- Department of Medical Physiology and Biophysics, University of Seville School of Medicine, 41009, Seville, Spain
| | - Allison D Ebert
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Mark M Rich
- Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, USA
| | - Umrao R Monani
- Department of Neurology, New York, NY, USA; Department of Pathology & Cell Biology, New York, NY, USA; Center for Motor Neuron Biology & Disease, New York, NY, USA; Colleen Giblin Research Laboratory, Columbia University Irving Medical Center, New York, NY 10032, USA.
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29
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Zhang S, Ishida Y, Ishigami A, Nosaka M, Kuninaka Y, Yasuda H, Kofuna A, Matsuki J, Osako M, Zhang W, Kimura A, Furukawa F, Kondo T. Forensic application of epidermal expression of HSP27 and HSP70 for the determination of wound vitality in human compressed neck skin. Sci Rep 2023; 13:6692. [PMID: 37095183 PMCID: PMC10126125 DOI: 10.1038/s41598-023-33799-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/22/2022] [Accepted: 04/19/2023] [Indexed: 04/26/2023] Open
Abstract
Estimating the age and vitality of human skin wounds is essential in forensic practice, and the use of immunohistochemical parameters in this regard remains a challenge. Heat shock proteins (HSPs) are evolutionarily conserved universal proteins that protect biological systems from various types of stress. However, its importance in forensic pathology for determining wound activation in neck compression skin remains unclear. The expression of HSP27 and HSP70 in neck skin samples was immunohistochemically examined to understand its forensic applicability in determining wound vitality. Skin samples were obtained from 45 cases of neck compression (hanging, 32 cases; strangulation, 10 cases; manual strangulation, 2 cases; other, 1 case) during forensic autopsies; intact skin from the same individual was used as a control. HSP27 expression was detected in 17.4% of keratinocytes in the intact skin samples. In the compressed region, the frequency of HSP27 expression in keratinocytes was 75.8%, which was significantly higher than that in intact skin. Similarly, HSP70 expression was 24.8% in intact skin samples and 81.9% in compressed skin samples, significantly higher in compressed skin than in intact skin samples. This increase in case compression cases may be due to the cell defence role of HSPs. From a forensic pathology perspective, the immunohistochemical examination of HSP27 and HSP70 expression in neck skin could be considered a valuable marker for diagnosing traces of antemortem compression.
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Affiliation(s)
- Siying Zhang
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
| | - Akiko Ishigami
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Mizuho Nosaka
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Yumi Kuninaka
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Haruki Yasuda
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Ayumi Kofuna
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Jumpei Matsuki
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Miyu Osako
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Wei Zhang
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Akihiko Kimura
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Fukumi Furukawa
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Toshikazu Kondo
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
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Seese SE, Muheisen S, Gath N, Gross JM, Semina EV. Identification of HSPA8 as an interacting partner of MAB21L2 and an important factor in eye development. Dev Dyn 2023; 252:510-526. [PMID: 36576422 PMCID: PMC10947772 DOI: 10.1002/dvdy.560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/19/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Pathogenic variants in human MAB21L2 result in microphthalmia, anophthalmia, and coloboma. The exact molecular function of MAB21L2 is currently unknown. We conducted a series of yeast two-hybrid (Y2H) experiments to determine protein interactomes of normal human and zebrafish MAB21L2/mab21l2 as well as human disease-associated variant MAB21L2-p.(Arg51Gly) using human adult retina and zebrafish embryo libraries. RESULTS These screens identified klhl31, tnpo1, TNPO2/tnpo2, KLC2/klc2, and SPTBN1/sptbn1 as co-factors of MAB21L2/mab21l2. Several factors, including hspa8 and hspa5, were found to interact with MAB21L2-p.Arg51Gly but not wild-type MAB21L2/mab21l2 in Y2H screens. Further analyses via 1-by-1 Y2H assays, co-immunoprecipitation, and mass spectrometry revealed that both normal and variant MAB21L2 interact with HSPA5 and HSPA8. In situ hybridization detected co-expression of hspa5 and hspa8 with mab21l2 during eye development in zebrafish. Examination of zebrafish mutant hspa8hi138Tg identified reduced hspa8 expression associated with severe ocular developmental defects, including small eye, coloboma, and anterior segment dysgenesis. To investigate the effects of hspa8 deficiency on the mab21l2Arg51_Phe52del allele, corresponding zebrafish double mutants were generated and found to be more severely affected than single mutant lines. CONCLUSION This study identifies heat shock proteins as interacting partners of MAB21L2/mab21l2 and suggests a role for this interaction in vertebrate eye development.
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Affiliation(s)
- Sarah E. Seese
- Department of Pediatrics The Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Sanaa Muheisen
- Department of Pediatrics The Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Natalie Gath
- University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Jeffrey M. Gross
- University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Elena V. Semina
- Department of Pediatrics The Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Children’s of Wisconsin, Milwaukee, WI 53226, USA
- Children’s Research Institute, Medical College of Wisconsin, Children’s of Wisconsin, Milwaukee, WI 53226, USA
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31
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Liu Q, Wang Y, Tan L, Ma W, Zhao X, Shao C, Wang Q. The Role of the Heat Shock Cognate Protein 70 Genes in Sex Determination and Differentiation of Chinese Tongue Sole ( Cynoglossus semilaevis). Int J Mol Sci 2023; 24:ijms24043761. [PMID: 36835170 PMCID: PMC9964925 DOI: 10.3390/ijms24043761] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/11/2023] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/16/2023] Open
Abstract
Fish sex determination can be affected by environmental temperature. This process relies on temperature-sensitive proteins such as heat shock proteins (HSPs). Our previous work found that heat shock cognate proteins (HSCs) may participate in high-temperature associated sex reversal of Chinese tongue sole (Cynoglossus semilaevis). However, the role of hsc genes in responding to high temperature and affecting sex determination/differentiation remains unclear. Here, by using C. semilaevis as model, we identified hsc70 and hsc70-like. hsc70 was abundant in the gonads with a testicular-higher expression at all gonadal development stages except for 6 months post fertilization (mpf). Intriguingly, hsc70-like showed higher expression in testes from 6 mpf on. Both long-term heat treatment during the temperature-sensitive sex-determining period and short-term heat stress at the end of this period caused different expression of hsc70/hsc70-like between sexes. The dual-luciferase assay results also suggested that these genes can respond to high temperature rapidly in vitro. Heat treatment of C. semilaevis testis cells overexpressed with hsc70/hsc70-like could affect the expression of sex-related genes sox9a and cyp19a1a. Our results indicated that hsc70 and hsc70-like were key regulators linking external high-temperature signals with sex differentiation in vivo and provide a new idea for understanding the mechanism by which high temperature affects sex determination/differentiation in teleosts.
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Affiliation(s)
- Qian Liu
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
| | - Yue Wang
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
| | - Leilei Tan
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
- Jiangsu Key Laboratory of Marine Biological Resources and Environment/Jiangsu Key Laboratory of Marine Biotechnology, Jiangsu Ocean University, Lianyungang 222000, China
| | - Wenxiu Ma
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
| | - Xiaona Zhao
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
| | - Changwei Shao
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
- Correspondence: (C.S.); (Q.W.); Tel.: +86-139-6962-5483 (C.S.); Tel.: +86-187-6521-7669 (Q.W.)
| | - Qian Wang
- National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Re-search Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
- Correspondence: (C.S.); (Q.W.); Tel.: +86-139-6962-5483 (C.S.); Tel.: +86-187-6521-7669 (Q.W.)
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32
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Heat-Shock Proteins in Leukemia and Lymphoma: Multitargets for Innovative Therapeutic Approaches. Cancers (Basel) 2023; 15:cancers15030984. [PMID: 36765939 PMCID: PMC9913431 DOI: 10.3390/cancers15030984] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/23/2022] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 02/08/2023] Open
Abstract
Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also for the homeostasis of basic cellular machinery. All cancer cells strongly rely on HSPs, as they must continuously adapt to internal but also microenvironmental stresses to survive. In solid tumors, HSPs have been described as helping to correct the folding of misfolded proteins, sustain oncogenic pathways, and prevent apoptosis. Leukemias and lymphomas also overexpress HSPs, which are frequently associated with resistance to therapy. HSPs have therefore been proposed as new therapeutic targets. Given the specific biology of hematological malignancies, it is essential to revise their role in this field, providing a more adaptable and comprehensive picture that would help design future clinical trials. To that end, this review will describe the different pathways and functions regulated by HSP27, HSP70, HSP90, and, not least, HSP110 in leukemias and lymphomas.
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33
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Gao J, Gao Y, Xiao G. The expression of Catsup in escort cells affects Drosophila ovarian stem cell niche establishment and germline stem cells self-renewal via Notch signaling. Biochem Biophys Res Commun 2023; 641:1-9. [PMID: 36516479 DOI: 10.1016/j.bbrc.2022.11.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/20/2022] [Accepted: 11/30/2022] [Indexed: 12/07/2022]
Abstract
Stem cell niche provides extrinsic signals to maintain stem cell renewal or initiate cell differentiation. Drosophila niche is composed of somatic terminal filament cells, cap cells and escort cells. However, the underlying mechanism for the development of stem cell niche remains largely unclear. Here we found that the expression of a zinc transporter Catsup is essential for ovary morphogenesis. Catsup knockdown in escort cells results in defects of niche establishment and germline stem cells self-renewal. These defects could be modified by altered expression of genes involved in zinc metabolism or intervention of dietary zinc levels. Further studies indicated that Catsup RNAi affected adult ovary morphogenesis by suppressing Notch signaling. Lastly, we demonstrated that the defects of Catsup RNAi could be restored by overexpression of heat shock cognate protein 70 (Hsc70). These findings expand our understanding of the mechanisms controlling adult oogenesis and niche establishment in Drosophila.
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Affiliation(s)
- Jiajia Gao
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei, 230009, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Yan Gao
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei, 230009, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Guiran Xiao
- China Light Industry Key Laboratory of Meat Microbial Control and Utilization, Hefei University of Technology, Hefei, 230009, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
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34
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Rahman MF, Billah MM, Kline RJ, Rahman MS. Effects of elevated temperature on 8-OHdG expression in the American oyster ( Crassostrea virginica): Induction of oxidative stress biomarkers, cellular apoptosis, DNA damage and γH2AX signaling pathways. FISH AND SHELLFISH IMMUNOLOGY REPORTS 2022; 4:100079. [PMID: 36589260 PMCID: PMC9798191 DOI: 10.1016/j.fsirep.2022.100079] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/04/2022] [Revised: 12/10/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Global temperature is increasing due to anthropogenic activities and the effects of elevated temperature on DNA lesions are not well documented in marine organisms. The American oyster (Crassostrea virginica, an edible and commercially important marine mollusk) is an ideal shellfish species to study oxidative DNA lesions during heat stress. In this study, we examined the effects of elevated temperatures (24, 28, and 32 °C for one-week exposure) on heat shock protein-70 (HSP70, a biomarker of heat stress), 8‑hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of pro-mutagenic DNA lesion), double-stranded DNA (dsDNA), γ-histone family member X (γH2AX, a molecular biomarker of DNA damage), caspase-3 (CAS-3, a key enzyme of apoptotic pathway) and Bcl-2-associated X (BAX, an apoptosis regulator) protein and/or mRNA expressions in the gills of American oysters. Immunohistochemical and qRT-PCR results showed that HSP70, 8-OHdG, dsDNA, and γH2AX expressions in gills were significantly increased at high temperatures (28 and 32 °C) compared with control (24°C). In situ TUNEL analysis showed that the apoptotic cells in gill tissues were increased in heat-exposed oysters. Interestingly, the enhanced apoptotic cells were associated with increased CAS-3 and BAX mRNA and/or protein expressions, along with 8-OHdG levels in gills after heat exposure. Moreover, the extrapallial (EP) fluid (i.e., extracellular body fluid) protein concentrations were lower; however, the EP glucose levels were higher in heat-exposed oysters. Taken together, these results suggest that heat shock-driven oxidative stress alters extracellular body fluid conditions and induces cellular apoptosis and DNA damage, which may lead to increased 8-OHdG levels in cells/tissues in oysters.
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Key Words
- 8-OHdG, 8‑hydroxy-2′-deoxyguanosine
- BAX, bcl-2-associate X
- BSA, bovine serum albumin
- CAS-3, caspase-3
- Caspase 3
- DSBs, double-stranded breaks
- EP, extrapallial
- Extrapallial fluid
- HSP70
- HSP70, heat shock protein 70
- Heat stress
- Marine mollusks
- PBS, Phosphate buffer saline
- SSBs, single-stranded breaks
- TUNEL, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling
- dsDNA breaks
- dsDNA, double-stranded DNA
- qRT-PCR, quantitative real-time polymerase chain reaction
- ssDNA, single-stranded DNA
- γ-H2AX, γ-histone family member X
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Affiliation(s)
- Md Faizur Rahman
- School of Earth, Environmental, and Marine Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Mohammad Maruf Billah
- School of Earth, Environmental, and Marine Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Richard J. Kline
- School of Earth, Environmental, and Marine Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA,Department of Biology, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Md Saydur Rahman
- School of Earth, Environmental, and Marine Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA,Department of Biology, University of Texas Rio Grande Valley, Brownsville, TX, USA,Corresponding author at: Department of Biology, University of Texas Rio Grande Valley, 1 West University Blvd., Brownsville, Texas 78520, USA.
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35
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Raghawan AK, Radha V, Swarup G. HSC70 as a sensor of low temperature: role in cold-triggered autoinflammatory disorders. FEBS J 2022; 289:8037-8049. [PMID: 34535969 DOI: 10.1111/febs.16203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/22/2021] [Revised: 08/27/2021] [Accepted: 09/16/2021] [Indexed: 01/14/2023]
Abstract
Familial cold autoinflammatory syndrome (FCAS) is a subset of heritable autoinflammatory disorders wherein inflammatory symptoms aggravate upon exposure of the individual to subnormal temperature. In the past two decades, several mutations in various genes such as NLRP3, NLRP12, PLCG2 and NLRC4 have been identified that cause cold-triggered inflammation. However, our understanding of the mechanisms by which cells perceive subnormal temperature, and what keeps the inflammation under check until exposure to low temperature, is very limited. We hypothesise that recognition of FCAS-associated mutants as misfolded polypeptides by temperature-sensitive HSC70 (HSPA8) chaperone determines the FCAS phenotype. At 37 °C, HSC70 would interact with the mutant proteins, keeping them almost inactive, and loss of interaction at low temperature due to a conformational change in HSC70 would lead to their activation. The proposed mechanism of low temperature sensing in the context of FCAS may have wider implications for HSC70 as a cold temperature sensor in various pathological conditions where symptoms get aggravated upon exposure to low temperature.
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Affiliation(s)
| | - Vegesna Radha
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Ghanshyam Swarup
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
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Sîrbulescu RF, Ilieş I, Amelung L, Zupanc GKH. Proteomic characterization of spontaneously regrowing spinal cord following injury in the teleost fish Apteronotus leptorhynchus, a regeneration-competent vertebrate. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2022; 208:671-706. [PMID: 36445471 DOI: 10.1007/s00359-022-01591-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/03/2022] [Revised: 10/30/2022] [Accepted: 11/01/2022] [Indexed: 11/30/2022]
Abstract
In adult mammals, spontaneous repair after spinal cord injury (SCI) is severely limited. By contrast, teleost fish successfully regenerate injured axons and produce new neurons from adult neural stem cells after SCI. The molecular mechanisms underlying this high regenerative capacity are largely unknown. The present study addresses this gap by examining the temporal dynamics of proteome changes in response to SCI in the brown ghost knifefish (Apteronotus leptorhynchus). Two-dimensional difference gel electrophoresis (2D DIGE) was combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) to collect data during early (1 day), mid (10 days), and late (30 days) phases of regeneration following caudal amputation SCI. Forty-two unique proteins with significant differences in abundance between injured and intact control samples were identified. Correlation analysis uncovered six clusters of spots with similar expression patterns over time and strong conditional dependences, typically within functional families or between isoforms. Significantly regulated proteins were associated with axon development and regeneration; proliferation and morphogenesis; neuronal differentiation and re-establishment of neural connections; promotion of neuroprotection, redox homeostasis, and membrane repair; and metabolism or energy supply. Notably, at all three time points examined, significant regulation of proteins involved in inflammatory responses was absent.
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Affiliation(s)
- Ruxandra F Sîrbulescu
- School of Engineering and Science, Jacobs University Bremen, 28725, Bremen, Germany
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA
- Vaccine and Immunotherapy Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA
| | - Iulian Ilieş
- School of Humanities and Social Sciences, Jacobs University Bremen, 28725, Bremen, Germany
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA
| | - Lisa Amelung
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA
| | - Günther K H Zupanc
- School of Engineering and Science, Jacobs University Bremen, 28725, Bremen, Germany.
- Laboratory of Neurobiology, Department of Biology, Northeastern University, Boston, MA, 02115, USA.
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Abstract
Heat-shock proteins (HSPs), or stress proteins, are abundant and highly conserved, present in all organisms and in all cells. Selected HSPs, also known as chaperones, play crucial roles in folding and unfolding of proteins, assembly of multiprotein complexes, transport and sorting of proteins into correct subcellular compartments, cell-cycle control and signaling, and protection of cells against stress and apoptosis. More recently, HSPs have been shown to be key players in immune responses: during antigen presentation as well as cross-priming, they chaperone and transfer antigenic peptides to class I and class II molecules of the major histocompatibility complexes. In addition, extracellular HSPs can stimulate and cause maturation of professional antigen-presenting cells of the immune system, such as macrophages and dendritic cells. They also chaperone several toll-like receptors, which play a central role in innate immune responses. HSPs constitute a large family of proteins that are often classified based on their molecular weight as Hsp10, Hsp40, Hsp60, Hsp70, Hsp90, etc. This unit contains a table that lists common HSPs and summarizes their characteristics including (a) name, (b) subcellular localization, (c) known function, (d) chromosome assignment, (e) brief comments, and (f) references. © 2022 Wiley Periodicals LLC.
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Affiliation(s)
- Adam T Hagymasi
- Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Joseph P Dempsey
- Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Pramod K Srivastava
- Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, Connecticut
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Kim H, Kim HW, Lee JH, Park J, Lee H, Kim S, Shin SC. Gene family expansions in Antarctic winged midge as a strategy for adaptation to cold environments. Sci Rep 2022; 12:18263. [PMID: 36309574 PMCID: PMC9617917 DOI: 10.1038/s41598-022-23268-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/05/2022] [Accepted: 10/27/2022] [Indexed: 12/31/2022] Open
Abstract
Parochlus steinenii is the only flying insect native to Antarctica. To elucidate the molecular mechanisms underlying its adaptation to cold environments, we conducted comparative genomic analyses of P. steinenii and closely related lineages. In an analysis of gene family evolution, 68 rapidly evolving gene families, involved in the innate immune system, unfolded protein response, DNA packaging, protein folding, and unsaturated fatty acid biosynthesis were detected. Some gene families were P. steinenii-specific and showed phylogenetic instability. Acyl-CoA delta desaturase and heat shock cognate protein 70 (Hsc70) were representative gene families, showing signatures of positive selection with multiple gene duplication events. Acyl-CoA delta desaturases may play pivotal roles in membrane fluidity, and expanded Hsc70 genes may function as chaperones or thermal sensors in cold environments. These findings suggest that multiple gene family expansions contributed to the adaptation of P. steinenii to cold environments.
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Affiliation(s)
- Heesoo Kim
- Division of Life Sciences, Korea Polar Research Institute (KOPRI), Incheon, 21990, Republic of Korea
- Animal and Plant Research Department, Nakdonggang National Institute of Biological Resources (NNIBR), Sangju-si, Republic of Korea
| | - Han-Woo Kim
- Research Unit of Cryogenic Novel Material, Korea Polar Research Institute, Incheon, 21990, Republic of Korea
- Department of Polar Sciences, University of Science and Technology, Incheon, 21990, Republic of Korea
| | - Jun Hyuck Lee
- Research Unit of Cryogenic Novel Material, Korea Polar Research Institute, Incheon, 21990, Republic of Korea
- Department of Polar Sciences, University of Science and Technology, Incheon, 21990, Republic of Korea
| | - Joonho Park
- Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Republic of Korea
| | - Hyoungseok Lee
- Division of Life Sciences, Korea Polar Research Institute (KOPRI), Incheon, 21990, Republic of Korea
- Department of Polar Sciences, University of Science and Technology, Incheon, 21990, Republic of Korea
| | - Sanghee Kim
- Division of Life Sciences, Korea Polar Research Institute (KOPRI), Incheon, 21990, Republic of Korea.
| | - Seung Chul Shin
- Division of Life Sciences, Korea Polar Research Institute (KOPRI), Incheon, 21990, Republic of Korea.
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Wang P, Chen B, Zhan Y, Wang L, Luo J, Xu J, Zhan L, Li Z, Liu Y, Wei J. Enhancing the Efficiency of Mild-Temperature Photothermal Therapy for Cancer Assisting with Various Strategies. Pharmaceutics 2022; 14:2279. [PMID: 36365098 PMCID: PMC9695556 DOI: 10.3390/pharmaceutics14112279] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/22/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 11/30/2022] Open
Abstract
Conventional photothermal therapy (PTT) irradiates the tumor tissues by elevating the temperature above 48 °C to exert thermal ablation, killing tumor cells. However, thermal ablation during PTT harmfully damages the surrounding normal tissues, post-treatment inflammatory responses, rapid metastasis due to the short-term mass release of tumor-cellular contents, or other side effects. To circumvent this limitation, mild-temperature photothermal therapy (MTPTT) was introduced to replace PTT as it exerts its activity at a therapeutic temperature of 42-45 °C. However, the significantly low therapeutic effect comes due to the thermoresistance of cancer cells as MTPTT figures out some of the side-effects issues. Herein, our current review suggested the mechanism and various strategies for improving the efficacy of MTPTT. Especially, heat shock proteins (HSPs) are molecular chaperones overexpressed in tumor cells and implicated in several cellular heat shock responses. Therefore, we introduced some methods to inhibit activity, reduce expression levels, and hinder the function of HSPs during MTPTT treatment. Moreover, other strategies also were emphasized, including nucleus damage, energy inhibition, and autophagy mediation. In addition, some therapies, like radiotherapy, chemotherapy, photodynamic therapy, and immunotherapy, exhibited a significant synergistic effect to assist MTPTT. Our current review provides a basis for further studies and a new approach for the clinical application of MTPTT.
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Affiliation(s)
- Pei Wang
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Biaoqi Chen
- Institute of Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Yunyan Zhan
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Lianguo Wang
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Jun Luo
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Jia Xu
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Lilin Zhan
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Zhihua Li
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
| | - Yuangang Liu
- Institute of Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, China
| | - Junchao Wei
- School of Stomatology, Nanchang University, Nanchang 330006, China
- Jiangxi Province Key Laboratory of Oral Biomedicine, Nanchang 330006, China
- Jiangxi Province Clinical Research Center for Oral Diseases, Nanchang 330006, China
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Tan N, Liu T, Wang X, Shao M, Zhang M, Li W, Ling G, Jiang J, Wang Q, Li J, Li C, Wang W, Wang Y. The multi-faced role of FUNDC1 in mitochondrial events and human diseases. Front Cell Dev Biol 2022; 10:918943. [PMID: 35959490 PMCID: PMC9358025 DOI: 10.3389/fcell.2022.918943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/14/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022] Open
Abstract
Mitophagy plays a vital role in the selective elimination of dysfunctional and unwanted mitochondria. As a receptor of mitophagy, FUN14 domain containing 1 (FUNDC1) is attracting considerably critical attention. FUNDC1 is involved in the mitochondria fission, the clearance of unfolded protein, iron metabolism in mitochondria, and the crosstalk between mitochondria and endoplasmic reticulum besides mitophagy. Studies have demonstrated that FUNDC1 is associated with the progression of ischemic disease, cancer, and metabolic disease. In this review, we systematically examine the recent advancements in FUNDC1 and the implications of this protein in health and disease.
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Affiliation(s)
- Nannan Tan
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Tianhua Liu
- Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoping Wang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Mingyan Shao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Miao Zhang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Weili Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Guanjing Ling
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jinchi Jiang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Qiyan Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Jing Li
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Chun Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Chun Li, ; Wei Wang, ; Yong Wang,
| | - Wei Wang
- School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Chun Li, ; Wei Wang, ; Yong Wang,
| | - Yong Wang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Chun Li, ; Wei Wang, ; Yong Wang,
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DİRİCAN E, ÇINAR İ. Gossypin'in farklı kanser hücre dizilerinde HSP60 ve HSP70'in gen ekspresyonu üzerindeki etkisi. CUKUROVA MEDICAL JOURNAL 2022. [DOI: 10.17826/cumj.1052787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/07/2022] Open
Abstract
Amaç: Bu çalışmanın amacı, gossypin'in farklı kanser hücre hatlarında ısı şok proteinleri (HSP) genlerinin ekspresyon seviyesi üzerindeki etkisini incelemektir.
Gereç ve Yöntem: Hücreler, standart kültür koşulları altında büyütüldü. Kanser hücreleri, farklı konsantrasyonlarda (5-100 µg/ml) gossypin ve pozitif kontrol olarak sisplatin (50 µM) ile muamele edildi. Gossypin'in hücre canlılığı ve etkili doz aralığı (5-100 µg/ml), 24, 48 ve 72. saatlerde MTT ile belirlendi. RNA izolasyonu ve cDNA sentezinden sonra, HSP60 ve HSP70 gen ekpresyon seviyesi RT-PCR ile analiz edildi. Gen ekspresyonu için 2-∆∆ct methodu kullanıldı.
Bulgular: MTT sonuçlarına göre kanser hücre hatlarında 25-50-100 µg/ml gossipin dozlarının HSP60 ve HSP70 gen ekspresyon seviyeleri üzerinde etkili olduğu bulundu. Gossypin, üç hücre hattında HSP60 ve HSP70'in ekspresyonunu doza bağımlı olarak etkilemiştir. Üç hücre hattında, 50 µg/ml ve 100 µg/ml gossipin dozları, HSP60 ve HSP70'in ekspresyonunu kontrol grubuna kıyasla önemli ölçüde azalttı.
Sonuç: Sonuçlarımız, farklı hücre dizilerinde çeşitli dozlarda gossypinin antikarsinojenik etkisini güçlü bir şekilde desteklemektedir. Fakat, daha fazla in vivo araştırma ve insan çalışmalarına ihtiyaç olduğuna inanıyoruz. Bulgularımız, gossypin'nin farklı kanser türlerinin önlenmesi ve/veya tedavisi için yeni stratejiler geliştirmek için daha ileri araştırmalar için uygun aday ajan olabileceğini düşündürmektedir.
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Affiliation(s)
- Ebubekir DİRİCAN
- BAYBURT ÜNİVERSİTESİ, BAYBURT SAĞLIK HİZMETLERİ MESLEK YÜKSEKOKULU
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Masoomi‐Aladizgeh F, Kamath KS, Haynes PA, Atwell BJ. Genome survey sequencing of wild cotton (Gossypium robinsonii) reveals insights into proteomic responses of pollen to extreme heat. PLANT, CELL & ENVIRONMENT 2022; 45:1242-1256. [PMID: 35092006 PMCID: PMC9415111 DOI: 10.1111/pce.14268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 12/17/2021] [Accepted: 01/04/2022] [Indexed: 06/14/2023]
Abstract
Heat stress specifically affects fertility by impairing pollen viability but cotton wild relatives successfully reproduce in hot savannas where they evolved. An Australian arid-zone cotton (Gossypium robinsonii) was exposed to heat events during pollen development then mature pollen was subjected to deep proteomic analysis using 57 023 predicted genes from a genomic database we assembled for the same species. Three stages of pollen development, including tetrads (TEs), uninucleate microspores (UNs) and binucleate microspores (BNs) were exposed to 36°C or 40°C for 5 days and the resulting mature pollen was collected at anthesis (p-TE, p-UN and p-BN, respectively). Using the sequential windowed acquisition of all theoretical mass spectra proteomic analysis, 2704 proteins were identified and quantified across all pollen samples analysed. Proteins predominantly decreased in abundance at all stages in response to heat, particularly after exposure of TEs to 40°C. Functional enrichment analyses demonstrated that extreme heat increased the abundance of proteins that contributed to increased messenger RNA splicing via spliceosome, initiation of cytoplasmic translation and protein refolding in p-TE40. However, other functional categories that contributed to intercellular transport were inhibited in p-TE40, linked potentially to Rab proteins. We ascribe the resilience of reproductive processes in G. robinsonii at temperatures up to 40°C, relative to commercial cotton, to a targeted reduction in protein transport.
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Affiliation(s)
| | | | - Paul A. Haynes
- School of Natural SciencesMacquarie UniversityNorth RydeNew South WalesAustralia
| | - Brian J. Atwell
- School of Natural SciencesMacquarie UniversityNorth RydeNew South WalesAustralia
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Neuronal SH2B1 attenuates apoptosis in an MPTP mouse model of Parkinson's disease via promoting PLIN4 degradation. Redox Biol 2022; 52:102308. [PMID: 35390677 PMCID: PMC8987406 DOI: 10.1016/j.redox.2022.102308] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/20/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 11/24/2022] Open
Abstract
The incidence of Parkinson's disease (PD) has increased tremendously, especially in the aged population and people with metabolic dysfunction; however, its underlying molecular mechanisms remain unclear. SH2B1, an intracellular adaptor protein, contributes to the signal transduction of several receptor tyrosine kinases and exerts beneficial metabolic effects for body weight regulation; however, whether SH2B1 plays a major role in pathological neurodegeneration in PD has not yet been investigated. This study aimed to investigate the effects of SH2B1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD mice with Sh2b1 deficiency or neuron-specific Sh2b1 overexpression. Cellular and molecular mechanisms were elucidated using human dopaminergic neuron SH-SY5Y cells analysed. We found that SH2B1 expression was confirmed to be downregulated in the blood samples of PD patients and in the brains of mice with MPTP-induced chronic PD. Sh2b1 deficiency caused marked exacerbation of behavioural defects and increased neuronal apoptosis in MPTP-treated mice, whereas restoration of neuron-specific Sh2b1 expression significantly reversed these effects. Similar results were observed in MPP + -treated SH-SY5Y cells. Mechanistically, upon binding to heat shock cognate 70 (HSC70), SH2B1 promotes HSC70-related recognition and PLIN4 lysosomal translocation and degradation, thus suppressing lipid peroxidation stress in the brains of PD mice. Adeno-associated virus-mediated rescue of neuronal HSC70 expression functionally alleviated the neuropathology of PD in wild-type but not in Sh2b1-deficient mice. This is the first study to examine the molecular underpinnings of SH2B1 against MPTP-induced neurodegeneration through cell autonomous promotion of neuronal survival in an in vivo PD model. Our findings reveal that SH2B1 antagonizes neurodegenerative pathology in PD via the SH2B1–HSC70–PLIN4 axis.
Brain tissues, especially in TH+ neurons, of PD mice showed low SH2B1 expression. SH2B1 suppressed MPTP-induced neurodegeneration by inhibiting neuronal apoptosis. SH2B1 overexpression protected against MPP + -induced cell death via HSC70. SH2B1 interacts with HSC70 to form a complex that regulates PLIN4 degradation.
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Tan SY, Hong F, Ye C, Wang JJ, Wei D. Functional characterization of four Hsp70 genes involved in high-temperature tolerance in Aphis aurantii (Hemiptera: Aphididae). Int J Biol Macromol 2022; 202:141-149. [PMID: 35038465 DOI: 10.1016/j.ijbiomac.2022.01.078] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 01/04/2023]
Abstract
The tea aphid, Aphis aurantii (Boyer de Fonscolombe), is a serious pest that can infest many economically important plants. Tea aphids damage plants by directly sucking phloem sap, transmitting viruses, and secreting honeydew to cause sooty mold. At present, tea aphids has become one of the most important pests in tropical and subtropical tea plants. The heat shock protein 70 (Hsp70) is a key protein involved in heat stress tolerance. In this study, we cloned four Hsp70 genes that are highly expressed in tea aphids after heat shock. Bioinformatic analysis of the deduced amino acid sequences showed that these four AaHsp70s had a close genetic relationship to Hsp70 in Hemiptera insects and shared a conserved ATPase domain. After incubation at low (14 °C) or high (36 °C) temperature, the expression of four AaHsp70s was significantly up-regulated compared to the control (25 °C); however, the up-regulation of the AaHsp70s in the low-temperature treatment was far less than that of the high-temperature treatment. The ATPase activity of the four purified recombinant AaHsp70 proteins after high-temperature treatment was significantly increased compared to the control. In addition, these proteins effectively improved the heat tolerance of Escherichia coli in vivo. Our data indicate that AaHsp701, AaHsp702, AaHsp703, AaHsp704 play important roles in response to the high-temperature tolerance in tea aphids.
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Affiliation(s)
- Shan-Yuan Tan
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; International Joint Laboratory of China-Belgium on Sustainable Crop Pest Control, Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China
| | - Feng Hong
- College of Agriculture, Xinyang Agriculture and Forestry University, Xinyang 464000, China
| | - Chao Ye
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; International Joint Laboratory of China-Belgium on Sustainable Crop Pest Control, Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China
| | - Jin-Jun Wang
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; International Joint Laboratory of China-Belgium on Sustainable Crop Pest Control, Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China
| | - Dong Wei
- Chongqing Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing 400715, China; International Joint Laboratory of China-Belgium on Sustainable Crop Pest Control, Academy of Agricultural Sciences, Southwest University, Chongqing 400715, China.
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Gao H, He C, Hua R, Guo Y, Wang B, Liang C, Gao L, Shang H, Xu JD. Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases. Front Mol Biosci 2022; 9:817392. [PMID: 35402506 PMCID: PMC8988245 DOI: 10.3389/fmolb.2022.817392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 12/21/2022] Open
Abstract
The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.
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Affiliation(s)
- Han Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Chengwei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Rongxuan Hua
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yuexin Guo
- Department of Oral Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Boya Wang
- Undergraduate Student of 2018 Eight Program of Clinical Medicine, Peking University Health Science Center, Beijing, China
| | - Chen Liang
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lei Gao
- Department of Biomedical Informatics, School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Hongwei Shang
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- *Correspondence: Jing-Dong Xu,
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Bona S, Fernandes SA, Moreira ACJ, Rodrigues G, Schemitt EG, Di Naso FC, Marroni CA, Marroni NP. Melatonin restores zinc levels, activates the Keap1/Nrf2 pathway, and modulates endoplasmic reticular stress and HSP in rats with chronic hepatotoxicity. World J Gastrointest Pharmacol Ther 2022; 13:11-22. [PMID: 35433098 PMCID: PMC8968507 DOI: 10.4292/wjgpt.v13.i2.11] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/07/2021] [Revised: 10/18/2021] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Melatonin (MLT) is a potent antioxidant molecule that is shown to have a beneficial effect in various pathological situations, due to its action against free radicals. AIM To evaluate the effect of MLT on carbon tetrachloride (CCl4) induced liver injury in rats in terms of oxidative stress, reticular stress, and cell damage. METHODS Twenty male Wistar rats (230-250 g) were divided into four groups: Control rats, rats treated with MLT alone, rats treated with CCl4 alone, and rats treated with CCl4 plus MLT. CCl4 was administered as follows: Ten doses every 5 d, ten every 4 d, and seven every 3 d. MLT was administered intraperitoneally at a dose of 20 mg/kg from the 10th wk to the end of the experiment (16th wk). RESULTS MLT was able to reduce the release of liver enzymes in the bloodstream and to decrease oxidative stress in CCl4 treated rats by decreasing the level of thiobarbituric acid reactive substances and increasing superoxide dismutase activity, with a lower reduction in serum zinc levels, guaranteeing a reduction in liver damage; additionally, it increased the expression of nuclear factor (erythroid-derived 2)-like 2 and decreased the expression of Kelch-like ECH-associated protein 1. MLT also decreased the expression of the proteins associated with endoplasmic reticulum stress, i.e., glucose-regulated protein 78 and activating transcription factor 6, as well as of heat shock factor 1 and heat shock protein 70. CONCLUSION MLT has a hepatoprotective effect in an experimental model of CCl4-induced liver injury, since it reduces oxidative stress, restores zinc levels, and modulates endoplasmic reticulum stress.
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Affiliation(s)
- Silvia Bona
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Sabrina Alves Fernandes
- Posgraduate Program in Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90040-001, Rio Grande do Sul, Brazil
| | - Andrea C Janz Moreira
- Biological Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Graziella Rodrigues
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Elizângela G Schemitt
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
| | - Fabio Cangeri Di Naso
- Postgraduate Program in Pneumological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90000-000, Rio Grande do Sul, Brazil
| | - Cláudio A Marroni
- Posgraduate Program in Hepatology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre 90040-001, Rio Grande do Sul, Brazil
| | - Norma P Marroni
- Medical Sciences Program, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
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Wadood AA, Pu L, Shahzad Q, Waqas M, Yu L, Liao Y, Rehman SU, Chen D, Huang Z, Lu Y. Proteomic analysis identifies potential markers in small white and small yellow follicle development in chickens. Reprod Fertil Dev 2022; 34:516-525. [PMID: 35296374 DOI: 10.1071/rd21184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/13/2021] [Accepted: 12/21/2021] [Indexed: 11/23/2022] Open
Abstract
Extensive knowledge of follicular development is imperative for improving egg production in chickens. The functional role of follicles to produce oocytes (eggs) is well recognised; however, specific markers associated with follicle development have been poorly explored. Therefore, a tandem mass tag based proteomic technique was used to identify the status of the proteome of small white follicles (1-4mm) and small yellow follicles (6-8mm). Analysis of differentially expressed proteins (DEP, Fold Change>1.2, P -value<0.05) demonstrated a total of 92 proteins (n =92), of which 35 (n =35) were upregulated and 57 were downregulated. DEP were further used for gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathways. The GO analysis found that DEP were mainly associated with the RNA metabolic process, cellular component organisation, peptide biosynthetic process and protein folding, thereby suggesting a key role in the follicle development process. Kyoto Encyclopedia of Genes and Genomes enrichment pathway analysis of the DEP substantiated the findings of GO analysis and described that DEP are involved in regulation of the cytoskeleton, carbon metabolism and amino acid biosynthesis. The validation of proteomic data through real-time quantitative polymerase chain reaction suggested HSPA8, HSPA2, SOD1 and FKPB3 as potential markers of small white and small yellow follicle development. This study demonstrates an understanding of proteome dynamics and represents the most comprehensive information on the entire Guangxi Ma chicken follicular proteome.
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Affiliation(s)
- Armughan Ahmed Wadood
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Liping Pu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Qaisar Shahzad
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Muhammad Waqas
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Lintian Yu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Yuying Liao
- Guangxi Veterinary Research Institute, Nanning, Guangxi, China
| | - Saif Ur Rehman
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Dongyang Chen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Zhenwen Huang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Yangqing Lu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
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Xie J, Sun Y, Cao Y, Han L, Li Y, Ding B, Gao C, Hao P, Jin X, Chang Y, Song J, Yin D, Ding J. Transcriptomic and Metabolomic Analyses Provide Insights into the Growth and Development Advantages of Triploid Apostichopus japonicus. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2022; 24:151-162. [PMID: 35122573 PMCID: PMC8940865 DOI: 10.1007/s10126-022-10093-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 10/21/2021] [Accepted: 01/17/2022] [Indexed: 06/14/2023]
Abstract
Polyploid breeding is widely used in aquaculture as an important area of new research. We have previously grown Apostichopus japonicus triploids with a growth advantage. The body length, body weight, and aestivation time of triploid and diploid A. japonicus were measured in this study, and the transcriptome and metabolome were used to examine the growth advantage of triploids A. japonicus. The results showed that the proportion of triploid A. japonicus with a body length of 6-12 cm and 12-18 cm was significantly higher than that of diploid A. japonicus, and triploid A. japonicus had a shorter aestivation time (39 days) than diploid (63 days). We discovered 3296 differentially expressed genes (DEGs); 13 DEGs (for example, cyclin-dependent kinase 2) related to growth advantage, immune regulation, and energy storage were screened as potential candidates. According to Gene Ontology (GO) enrichment analysis, DEGs were significantly enriched in the cytoplasm (cellular component), ATP binding process (molecular function), oxidation-reduction process (biological process), and other pathways. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment data, DEGs were significantly enriched in ribosome production and other areas. We discovered 414 significant differential metabolites (SDMs), with 11 important SDMs (for example, nocodazole) linked to a growth advantage. SDMs are significantly enriched in metabolic pathways, as well as other pathways, according to the KEGG enrichment results. According to a combined transcriptome and metabolome analysis, 6 DEGs have regulatory relationships with 11 SDMs, which act on 11 metabolic pathways together. Our results further enrich the biological data of triploid A. japonicus and provide useful resources for genetic improvement of this species.
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Affiliation(s)
- Jiahui Xie
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Yi Sun
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Yue Cao
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Lingshu Han
- Ningbo University, Ningbo, Zhejiang, People's Republic of China, 315211
| | - Yuanxin Li
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Beichen Ding
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Chuang Gao
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Pengfei Hao
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Xin Jin
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Yaqing Chang
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Jian Song
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Donghong Yin
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023
| | - Jun Ding
- Key Laboratory of Mariculture & Stock Enhancement in, Ministry of Agriculture and Rural Affairs, North China's Sea, Dalian Ocean University, Dalian, Liaoning, People's Republic of China, 116023.
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Benbrook DM. SHetA2 Attack on Mortalin and Colleagues in Cancer Therapy and Prevention. Front Cell Dev Biol 2022; 10:848682. [PMID: 35281109 PMCID: PMC8906462 DOI: 10.3389/fcell.2022.848682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/04/2022] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Heat Shock Proteins of the 70-kDa family (HSP70s) do not cause cancer by themselves, but instead protect cells as they transform into cancer. These molecular chaperones bind numerous client proteins and utilize ATP hydrolysis to facilitate proper protein folding, formation of functional complexes and cellular localizations, or degradation of irreparably damaged proteins. Their transient upregulation by stressful situations avoids induction of programmed cell death. Continued upregulation of the mortalin, heat shock cognate (hsc70) and glucose regulated protein 78 (Grp78) support cancer development and progression by supporting pro-proliferative and metabolic functions and repressing pro-death functions of oncoproteins and tumor suppressor proteins. This review describes the discovery and development of a lead anti-cancer compound, sulfur heteroarotinoid A2 (SHetA2, NSC726189), which was originally developed to bind retinoic acid receptors, but was subsequently found to work independently of these receptors. The discovery and validation of mortalin, hsc70 and Grp78 as SHetA2 target proteins is summarized. The documented and hypothesized roles of these HSP70 proteins and their clients in the mechanism of SHetA2 inhibition of cancer without toxicity are discussed. Use of this mechanistic data to evaluate drug action in a cancer clinical trial and develop synergistic drug combinations is explained. Knowledge needed to optimize SHetA2 analogs for use in cancer therapy and prevention is proposed as future directions.
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Yang Q, Sun K, Xia W, Li Y, Zhong M, Lei K. Autophagy-related prognostic signature for survival prediction of triple negative breast cancer. PeerJ 2022; 10:e12878. [PMID: 35186475 PMCID: PMC8840057 DOI: 10.7717/peerj.12878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/14/2020] [Accepted: 01/12/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a highly aggressive type of cancer with few available treatment methods. The aim of the current study was to provide a prognostic autophagy-related gene (ARG) model to predict the outcomes for TNBC patients using bioinformatic analysis. METHODS mRNA expression data and its clinical information for TNBC samples obtained from The Cancer Genome Atlas (TCGA) and Metabric databases were extracted for bioinformatic analysis. Differentially expressed autophagy genes were identified using the Wilcoxon rank sum test in R software. ARGs were downloaded from the Human Autophagy Database. The Kaplan-Meier plotter was employed to determine the prognostic significance of the ARGs. The sample splitting method and Cox regression analysis were employed to establish the risk model and to demonstrate the association between the ARGs and the survival duration. The corresponding ARG-transcription factor interaction network was visualized using the Cytoscape software. RESULTS A signature-based risk score model was established for eight genes (ITGA3, HSPA8, CTSD, ATG12, CLN3, ATG7, MAP1LC3C, and WIPI1) using the TCGA data and the model was validated with the GSE38959 and Metabric datasets, respectively. Patients with high risk scores had worse survival outcomes than those with low risk scores. Of note, amplification of ATG12 and reduction of WIPI were confirmed to be significantly correlated with the clinical stage of TNBC. CONCLUSION An eight-gene autophagic signature model was developed in this study to predict the survival risk for TNBC. The genes identified in the study may favor the design of target agents for autophagy control in advanced TNBC.
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Affiliation(s)
- Qiong Yang
- Department of General Surgery, Cancer Center, Division of Breast Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Kewang Sun
- Department of General Surgery, Cancer Center, Division of Breast Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Wenjie Xia
- Department of General Surgery, Cancer Center, Division of Breast Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ying Li
- Department of General Surgery, Cancer Center, Division of Breast Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Miaochun Zhong
- Department of General Surgery, Cancer Center, Division of Breast Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Kefeng Lei
- Department of General Surgery, Cancer Center, Division of Breast Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China,Department of General Surgery, The 7th Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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