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Gebert JT, Scribano FJ, Engevik KA, Huleatt EM, Eledge MR, Dorn LE, Philip AA, Kawagishi T, Greenberg HB, Patton JT, Hyser JM. Viroporin activity is necessary for intercellular calcium signals that contribute to viral pathogenesis. SCIENCE ADVANCES 2025; 11:eadq8115. [PMID: 39823322 PMCID: PMC11740935 DOI: 10.1126/sciadv.adq8115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 06/06/2024] [Accepted: 12/18/2024] [Indexed: 01/19/2025]
Abstract
Viruses engage in a variety of processes to subvert host defenses and create an environment amenable to replication. Here, using rotavirus as a prototype, we show that calcium conductance out of the endoplasmic reticulum by the virus encoded ion channel, NSP4, induces intercellular calcium waves that extend beyond the infected cell and contribute to pathogenesis. Viruses that lack the ability to induce this signaling show diminished viral shedding and attenuated disease in a mouse model of rotavirus diarrhea. This implicates nonstructural protein 4 (NSP4) as a virulence factor and provides mechanistic insight into its mode of action. Critically, this signaling induces a transcriptional signature characteristic of interferon-independent innate immune activation, which is not observed in response to a mutant NSP4 that does not conduct calcium. This implicates calcium dysregulation as a means of pathogen recognition, a theme broadly applicable to calcium-altering pathogens beyond rotavirus.
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Affiliation(s)
- J. Thomas Gebert
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
| | - Francesca J. Scribano
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kristen A. Engevik
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ethan M. Huleatt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
| | - Michael R. Eledge
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lauren E. Dorn
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
| | - Asha A. Philip
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Takahiro Kawagishi
- Departments of Medicine and Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Harry B. Greenberg
- Departments of Medicine and Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - John T. Patton
- Department of Biology, Indiana University, Bloomington, IN 47405, USA
| | - Joseph M. Hyser
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA
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Li Q, Zheng JW, Wang ZY, Liao SP, Zhu L, Wang X, Wan LH. Protective Effect of Rosmarinic Acid on Endotoxin-Induced Neuronal Damage Through Modulating GRP78/PERK/MANF Pathway. Drug Des Devel Ther 2025; 19:39-50. [PMID: 39816847 PMCID: PMC11733956 DOI: 10.2147/dddt.s481646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/13/2024] [Accepted: 11/08/2024] [Indexed: 01/18/2025] Open
Abstract
Objective Neuronal damage is criminal to cognitive dysfunction, closely related to endoplasmic reticulum stress (ERS). However, due to the pathogenesis of endotoxin-induced long-term cognitive dysfunction is not fully clarified, there is still a lack of effective treatment. This study was conducted to explore the protective effects and mechanism of rosmarinic acid (RA) against ERS in endotoxin-induced cognitive dysfunction in mice and neuronal injury in cells. Methods The efficacy of RA was evaluated using an endotoxin-induced cognitive dysfunction mice model and an in vitro neuronal injury model. Brain injury was assessed using behavioral tests and hematoxylin and eosin (HE) staining. Western blotting and Immunohistochemistry (IHC) were performed to determine NeuN, GRP78, PERK, ATF6, IRE1α, and MANF expression levels. Molecular docking was used to assess the associated mechanisms. Results Behavioral tests indicated that 20 and 40 mg/kg RA significantly improve endotoxin-induced cognitive dysfunction without dose differences. Histological analysis revealed no significant alterations in the number, morphology, and arrangement of neurons in the hippocampus and amygdala. However, 40 mg/kg RA treatment significantly decreased the hippocampal level of PERK protein and increased MANF in CA1 and DG in mice. Furthermore, our data showed that 120 μM RA pretreatment significantly inhibited LPS-conditioned culture-induced GRP78, PERK, and MANF upregulation in vitro. Finally, molecular docking studies suggested that RA could directly interact with GRP78, PERK, and IRE1, but not with MANF. Conclusion RA plays a protective role in improving cognitive function against endotoxemia-associated encephalopathy in mice via inhibiting the GRP78/PERK/MANF pathway.
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Affiliation(s)
- Qian Li
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Jing-Wen Zheng
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Zi-Yao Wang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Shi-Ping Liao
- Functional Laboratory, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Ling Zhu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Xia Wang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
| | - Li-Hong Wan
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
- NHC Key Laboratory of Chronobiology (Sichuan University), West China School of Basic Medical Sciences & Forensic Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China
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3
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Shukla S, Comerci CJ, Süel GM, Jahed Z. Bioelectronic tools for understanding the universal language of electrical signaling across species and kingdoms. Biosens Bioelectron 2025; 267:116843. [PMID: 39426280 DOI: 10.1016/j.bios.2024.116843] [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: 07/24/2023] [Revised: 09/10/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024]
Abstract
Modern bioelectronic tools are rapidly advancing to detect electric potentials within networks of electrogenic cells, such as cardiomyocytes, neurons, and pancreatic beta cells. However, it is becoming evident that electrical signaling is not limited to the animal kingdom but may be a universal form of cell-cell communication. In this review, we discuss the existing evidence of, and tools used to collect, subcellular, single-cell and network-level electrical signals across kingdoms, including bacteria, plants, fungi, and even viruses. We discuss how cellular networks employ altered electrical "circuitry" and intercellular mechanisms across kingdoms, and we assess the functionality and scalability of cutting-edge nanobioelectronics to collect electrical signatures regardless of cell size, shape, or function. Researchers today aim to design micro- and nano-topographic structures which harness mechanosensitive membrane and cytoskeletal pathways that enable tight electrical coupling to subcellular compartments within high-throughput recording systems. Finally, we identify gaps in current knowledge of inter-species and inter-kingdom electrical signaling and propose critical milestones needed to create a central theory of electrical signaling across kingdoms. Our discussion demonstrates the need for high resolution, high throughput tools which can probe multiple, diverse cell types at once in their native or experimentally-modeled environments. These advancements will not only reveal the underlying biophysical laws governing the universal language of electrical communication, but can enable bidirectional electrical communication and manipulation of biological systems.
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Affiliation(s)
- Shivani Shukla
- Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, United States; Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California San Diego, La Jolla, CA, United States
| | - Colin J Comerci
- Department of Molecular Biology, University of California San Diego, La Jolla, CA, United States
| | - Gürol M Süel
- Department of Molecular Biology, University of California San Diego, La Jolla, CA, United States
| | - Zeinab Jahed
- Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, United States; Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California San Diego, La Jolla, CA, United States.
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4
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Roy S, Pokharel P, Piganelli JD. Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes. Mol Metab 2024; 88:101998. [PMID: 39069156 PMCID: PMC11342121 DOI: 10.1016/j.molmet.2024.101998] [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: 05/11/2024] [Revised: 07/12/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by the specific destruction of insulin-producing beta cells in the pancreas by the immune system, including CD4 cells which orchestrate the attack and CD8 cells which directly destroy the beta cells, resulting in the loss of glucose homeostasis. SCOPE OF REVIEW This comprehensive document delves into the complex interplay between the immune system and beta cells, aiming to shed light on the mechanisms driving their destruction in T1D. Insights into the genetic predisposition, environmental triggers, and autoimmune responses provide a foundation for understanding the autoimmune attack on beta cells. From the role of viral infections as potential triggers to the inflammatory response of beta cells, an intricate puzzle starts to unfold. This exploration highlights the importance of beta cells in breaking immune tolerance and the factors contributing to their targeted destruction. Furthermore, it examines the potential role of autophagy and the impact of cytokine signaling on beta cell function and survival. MAJOR CONCLUSIONS This review collectively represents current research findings on T1D which offers valuable perspectives on novel therapeutic approaches for preserving beta cell mass, restoring immune tolerance, and ultimately preventing or halting the progression of T1D. By unraveling the complex dynamics between the immune system and beta cells, we inch closer to a comprehensive understanding of T1D pathogenesis, paving the way for more effective treatments and ultimately a cure.
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Affiliation(s)
- Saptarshi Roy
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Pravil Pokharel
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Jon D Piganelli
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
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5
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Chen L, Wei M, Zhou B, Wang K, Zhu E, Cheng Z. The roles and mechanisms of endoplasmic reticulum stress-mediated autophagy in animal viral infections. Vet Res 2024; 55:107. [PMID: 39227990 PMCID: PMC11373180 DOI: 10.1186/s13567-024-01360-4] [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: 02/08/2024] [Accepted: 06/28/2024] [Indexed: 09/05/2024] Open
Abstract
The endoplasmic reticulum (ER) is a unique organelle responsible for protein synthesis and processing, lipid synthesis in eukaryotic cells, and the replication of many animal viruses is closely related to ER. A considerable number of viral proteins are synthesised during viral infection, resulting in the accumulation of unfolded and misfolded proteins in ER, which in turn induces endoplasmic reticulum stress (ERS). ERS further drives three signalling pathways (PERK, IRE1, and ATF6) of the cellular unfolded protein response (UPR) to respond to the ERS. In numerous studies, ERS has been shown to mediate autophagy, a highly conserved cellular degradation mechanism to maintain cellular homeostasis in eukaryotic cells, through the UPR to restore ER homeostasis. ERS-mediated autophagy is closely linked to the occurrence and development of numerous viral diseases in animals. Host cells can inhibit viral replication by regulating ERS-mediated autophagy, restoring the ER's normal physiological process. Conversely, many viruses have evolved strategies to exploit ERS-mediated autophagy to achieve immune escape. These strategies include the regulation of PERK-eIF2α-Beclin1, PERK-eIF2α-ATF4-ATG12, IRE1α-JNK-Beclin1, and other signalling pathways, which provide favourable conditions for the replication of animal viruses in host cells. The ERS-mediated autophagy pathway has become a hot topic in animal virological research. This article reviews the most recent research regarding the regulatory functions of ERS-mediated autophagy pathways in animal viral infections, emphasising the underlying mechanisms in the context of different viral infections. Furthermore, it considers the future direction and challenges in the development of ERS-mediated autophagy targeting strategies for combating animal viral diseases, which will contribute to unveiling their pathogenic mechanism from a new perspective and provide a scientific reference for the discovery and development of new antiviral drugs and preventive strategies.
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Affiliation(s)
- Lan Chen
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Miaozhan Wei
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Bijun Zhou
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Kaigong Wang
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China
| | - Erpeng Zhu
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China.
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China.
| | - Zhentao Cheng
- Department of Veterinary Medicine, College of Animal Science, Guizhou University, Guiyang, 550025, China.
- Key Laboratory of Animal Disease and Veterinary Public Health of Guizhou Province, College of Animal Science, Guizhou University, Guiyang, 550025, China.
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6
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Macauslane KL, Pegg CL, Short KR, Schulz BL. Modulation of endoplasmic reticulum stress response pathways by respiratory viruses. Crit Rev Microbiol 2024; 50:750-768. [PMID: 37934111 DOI: 10.1080/1040841x.2023.2274840] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/04/2023] [Revised: 10/04/2023] [Accepted: 10/15/2023] [Indexed: 11/08/2023]
Abstract
Acute respiratory infections (ARIs) are amongst the leading causes of death and disability, and the greatest burden of disease impacts children, pregnant women, and the elderly. Respiratory viruses account for the majority of ARIs. The unfolded protein response (UPR) is a host homeostatic defence mechanism primarily activated in response to aberrant endoplasmic reticulum (ER) resident protein accumulation in cell stresses including viral infection. The UPR has been implicated in the pathogenesis of several respiratory diseases, as the respiratory system is particularly vulnerable to chronic and acute activation of the ER stress response pathway. Many respiratory viruses therefore employ strategies to modulate the UPR during infection, with varying effects on the host and the pathogens. Here, we review the specific means by which respiratory viruses affect the host UPR, particularly in association with the high production of viral glycoproteins, and the impact of UPR activation and subversion on viral replication and disease pathogenesis. We further review the activation of UPR in common co-morbidities of ARIs and discuss the therapeutic potential of modulating the UPR in virally induced respiratory diseases.
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Affiliation(s)
- Kyle L Macauslane
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia
| | - Cassandra L Pegg
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia
| | - Kirsty R Short
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia
| | - Benjamin L Schulz
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia
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Lan Z, Zhao L, Peng L, Wan L, Liu D, Tang C, Chen G, Liu Y, Liu H. EIF2α/ATF4 pathway enhances proliferation of mesangial cell via cyclin D1 during endoplasmic reticulum stress in IgA nephropathy. Clin Immunol 2023; 257:109840. [PMID: 37939913 DOI: 10.1016/j.clim.2023.109840] [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: 09/04/2022] [Revised: 03/30/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023]
Abstract
IgA nephropathy (IgAN) is an essential cause of kidney failure and end-stage kidney disease worldwide. Mesangial hypercellularity is an important characteristic of IgAN, but the underlying mechanism remains unclear. Endoplasmic reticulum (ER) stress is a series of stress responses to restore the function of endoplasmic reticulum. We aimed to explore how ER stress functioned in kidneys of IgAN. We first examined ER stress in IgAN kidneys in vivo and in vitro, by testing the levels of ER stress associated proteins (BIP, p-eIF2α and ATF4). Our results showed that ER stress was activated in IgAN patients, mice and cell model. ER stress activation was related to the distribution of IgA deposition and the degree of mesangial proliferation. To determine the role of ER stress in mesangial cell (MC) proliferation of IgAN, we then tested the levels of ER stress and MC proliferation (cyclin D1, cell viability and cell cycle) through inhibiting ER stress associated proteins. After inhibiting ER stress associated proteins, ER stress was inactivated and cell proliferation was inhibited in MCs. We also explored the correlation between ER stress in the glomerulus and the clinical outcomes of IgAN patients in a prospective study. Patients with lower expression of p-eIF2α or ATF4 had higher rates of hematuria remission, proteinuria remission and clinical remission. In summary, our work outlines that in IgAN, ER stress mediated by eIF2α/ATF4 pathway promotes MC proliferation via up-regulating the expression of cyclin D1. Furthermore, p-eIF2α and ATF4 in the glomerulus negatively correlate with the clinical remission of IgAN patients.
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Affiliation(s)
- Zhixin Lan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lu Zhao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Liang Peng
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lili Wan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Di Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chengyuan Tang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Guochun Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yu Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
| | - Hong Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
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Zhang P, Fu HJ, Lv LX, Liu CF, Han C, Zhao XF, Wang JX. WSSV exploits AMPK to activate mTORC2 signaling for proliferation by enhancing aerobic glycolysis. Commun Biol 2023; 6:361. [PMID: 37012372 PMCID: PMC10070494 DOI: 10.1038/s42003-023-04735-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: 01/13/2022] [Accepted: 03/20/2023] [Indexed: 04/05/2023] Open
Abstract
AMPK plays significant roles in the modulation of metabolic reprogramming and viral infection. However, the detailed mechanism by which AMPK affects viral infection is unclear. The present study aims to determine how AMPK influences white spot syndrome virus (WSSV) infection in shrimp (Marsupenaeus japonicus). Here, we find that AMPK expression and phosphorylation are significantly upregulated in WSSV-infected shrimp. WSSV replication decreases remarkably after knockdown of Ampkα and the shrimp survival rate of AMPK-inhibitor injection shrimp increases significantly, suggesting that AMPK is beneficial for WSSV proliferation. Mechanistically, WSSV infection increases intracellular Ca2+ level, and activates CaMKK, which result in AMPK phosphorylation and partial nuclear translocation. AMPK directly activates mTORC2-AKT signaling pathway to phosphorylate key enzymes of glycolysis in the cytosol and promotes expression of Hif1α to mediate transcription of key glycolytic enzyme genes, both of which lead to increased glycolysis to provide energy for WSSV proliferation. Our findings reveal a novel mechanism by which WSSV exploits the host CaMKK-AMPK-mTORC2 pathway for its proliferation, and suggest that AMPK might be a target for WSSV control in shrimp aquaculture.
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Affiliation(s)
- Peng Zhang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China
| | - Hai-Jing Fu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China
| | - Li-Xia Lv
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China
| | - Chen-Fei Liu
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China
| | - Chang Han
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China
| | - Xiao-Fan Zhao
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China
| | - Jin-Xing Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, 266237, Qingdao, Shandong, China.
- State Key Laboratory of Microbial Technology, Shandong University, 266237, Qingdao, Shandong, China.
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9
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Zeng T, Zhou Y, Yu Y, Wang JW, Wu Y, Wang X, Zhu L, Zhou LM, Wan LH. rmMANF prevents sepsis-associated lung injury via inhibiting endoplasmic reticulum stress-induced ferroptosis in mice. Int Immunopharmacol 2023; 114:109608. [PMID: 36700778 DOI: 10.1016/j.intimp.2022.109608] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/30/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022]
Abstract
Ferroptosis plays a critical role in LPS-induced acute lung injury and is modulated by endoplasmic reticulum stress (ERS). As a typical ER stress-responsive protein, recently mesencephalic astrocyte-derived neurotrophic factor (MANF) has been demonstrated to attenuate LPS-induced acute lung injury (ALI) through repressing macrophage activation. However, whether MANF exerts a preventive role on ferroptosis and excess ER stress remains unclear. Here, we first built a protein-protein interaction (PPI) network to obtain potential interacting proteins related to MANF through STRING and GeneMANIA. Then, male C57BL/6J mice were used to build a model of LPS-induced lung injury. Two days before LPS injection, the tail vein injected recombinant murine MANF (rmMANF) at 750 μg/kg. Twenty-four hours after the LPS injection, the histopathological changes and damage in the lung tissues were detected and scored by HE staining and TUNEL assay, respectively. Endogenous MANF levels, oxidative stress markers (GSH, SOD, CAT, and MDA), ERS markers (GRP78, PERK, and ATF4), and the ferroptosis markers (iron, GPX4, and 4-HNE) in the lung tissues were measured by IHC, western blotting, and commercial kits. Our results showed that LPS induced significant lung injury to the increase in MPO, MDA, and 4-HNE, a decrease in GPX4 and GSH, SOD, CAT, and total iron accumulation in LPS-exposed mice. Simultaneously, GRP78/PERK/ATF4 pathway was notably activated by LPS, accompanied by the down-regulation of MANF. Furthermore, rmMANF pretreatment markedly prevented LPS-induced lung tissue injury and ferroptosis characteristics with the increased GPX4 level in sepsis mice. Finally, we found that LPS-induced oxidative stress and activation of the GRP78/PERK/ATF4 pathway were significantly restrained by rmMANF pretreatment, except for endogenous MANF level. Overall, rmMANF pretreatment can prevent sepsis-associated lung injury by inhibiting ER stress-induced ferroptosis in mice.
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Affiliation(s)
- Tao Zeng
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Yan Zhou
- Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Yang Yu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Jian-Wen Wang
- Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Yao Wu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xin Wang
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Ling Zhu
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Li-Ming Zhou
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Li-Hong Wan
- Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China.
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10
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Chen L, Ni M, Ahmed W, Xu Y, Bao X, Zhuang T, Feng L, Guo M. Pseudorabies virus infection induces endoplasmic reticulum stress and unfolded protein response in suspension-cultured BHK-21 cells. J Gen Virol 2022; 103. [PMID: 36748498 DOI: 10.1099/jgv.0.001818] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/24/2022] Open
Abstract
Viral infections cause endoplasmic reticulum (ER) stress and subsequently unfolded protein response (UPR) which restores ER homeostasis. In this study, levels of proteins or transcription of three UPR pathways were examined in suspension-cultured BHK-21 cells to investigate Pseudorabies virus (PRV) infection-induced ER stress, in which glucose-related proteins 78 kD and 94 kD (GRP78 and GRP94) were upregulated. The downstream double-stranded RNA-activated protein kinase-like ER kinase (PERK) pathway was activated with upregulation of ATF4, CHOP, and GADD34, and the inositol requiring kinase 1 (IRE1) pathway was triggered by the splicing of X box-binding protein 1 (XBP1) mRNA and the enhanced expression of p58IPK and EDEM. Furthermore, our results showed that the ER stress, induced by 0.005 µM thapsigargin, promoted PRV replication in suspension-cultured BHK-21 cells, and that PRV glycoprotein B (gB) overexpression triggered the PERK and IRE1 pathways.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, PR China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, PR China
| | - Minshu Ni
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, PR China
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, PR China
| | - Waqas Ahmed
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China
| | - Yue Xu
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, PR China
| | - Xi Bao
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, PR China
| | - Tenghan Zhuang
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, PR China
| | - Lei Feng
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, PR China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, PR China
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, PR China
| | - Meijin Guo
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, PR China
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11
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Li Q, Wu Y, Chen XS, Zeng T, Liu LL, Feng ZQ, Liu DY, Zhu L, Wan LH. Ascorbic acid 6-palmitate modulates microglia M1/M2 polarization in lipopolysaccharide-stimulated BV-2 cells via PERK/elF2α mediated endoplasmic reticulum stress. BMC Complement Med Ther 2022; 22:302. [PMID: 36401257 PMCID: PMC9675226 DOI: 10.1186/s12906-022-03780-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/12/2022] [Accepted: 11/04/2022] [Indexed: 11/19/2022] Open
Abstract
Background Neuroinflammation-mediated microglia polarization is a major process in various central nervous system (CNS) diseases. Endoplasmic reticulum (ER) stress contributes to the inflammatory signals as well as to microglia polarization in lipopolysaccharide (LPS) induced neuroinflammation. Ascorbic acid 6-palmitate (L-AP) has been broadly used as a dietary antioxidant in foods and demonstrated a strong inhibitory effect on 5-LOX; however, the specific anti-inflammation mechanisms remain unclear. In this study, we investigated the effects and possible mechanisms of L-AP on LPS-induced neuroinflammation in BV-2 cells. Methods Immortalized murine microglia cell line BV-2 cells were employed to assess the effect of L-AP to modulate microglia M1/M2 polarization in vivo, and the molecular mechanism was evaluated by qRT-PCR and Western blotting analysis. Molecular docking was used to predict the binding activity of L-AP with protein kinase R-like ER kinase (PERK). Results L-AP at 62.5 µM significantly modulated LPS-induced microglia M1/M2 polarization (increases of interleukin (IL)-10 and arginase-1 (Arg-1) transcriptions) independent of cell growth. Besides, L-AP at 62.5 µM significantly down-regulated glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding homologous protein (CHOP) mRNA levels. Similar data were shown in the tunicamycin (TM) induced ER stress cells model. Moreover, the protective effect of L-AP on TM-induced microglia M1/M2 polarization was similar to that of 4-phenyl butyric acid (4-PBA), the ER stress inhibitor. Molecular docking results indicated L-AP might directly bind with PERK, with a binding affinity of -7.7 kcal/mol. A further study unveiled that L-AP notably inhibited LPS-induced PERK/ eukaryotic initiation factor 2α (elf2α) activation. Conclusion Together, this study revealed that L-AP possessed its effect on the reconstruction of microglia M1/M2 polarization balance in LPS-stimulated BV-2 cells via modulating PERK/elF2α mediated ER stress. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-022-03780-1.
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12
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Ju J, Su Y, Zhou Y, Wei H, Xu Q. The SARS-CoV-2 envelope protein disrupts barrier function in an in vitro human blood-brain barrier model. Front Cell Neurosci 2022; 16:897564. [PMID: 36082238 PMCID: PMC9445123 DOI: 10.3389/fncel.2022.897564] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/16/2022] [Accepted: 07/26/2022] [Indexed: 12/02/2022] Open
Abstract
Patients with coronavirus disease 2019 (COVID-19) have been frequently reported to exhibit neurological manifestations and disruption of the blood-brain barrier (BBB). Among the risk factors for BBB breakdown, the loss of endothelial cells and pericytes has caused widespread concern. Recent studies have revealed that severe acute respiratory syndrome coronavirus 2 envelope (S2E) protein caused cell death. We tested the hypothesis that the S2E protein alone could induce BBB dysfunction. The S2E protein bound to human BBB-related cells and inhibited cell viability in a dose- and time-dependent manner. Importantly, the S2E protein disrupted barrier function in an in vitro BBB model composed of HCMEC/D3 (brain endothelial cell line), HBVP (brain vascular pericyte), and U87MG (astrocyte cell line) cells and suppressed the expression of major genes involved in maintaining endothelial permeability and function. In addition, the S2E protein crossed the HCMEC/D3 monolayer. The S2E protein triggered inflammatory responses in HCMEC/D3 and U87MG cells. Taken together, these results show for the first time that the S2E protein has a negative impact on the BBB. Therapies targeting the S2E protein could protect against and treat central nervous system manifestations in COVID-19 patients.
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Affiliation(s)
- Jiahang Ju
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuwen Su
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - You Zhou
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui Wei
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Xu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Qi Xu
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13
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Zhang L, Zhou J, Feng Z, Jiang B, Li C, Zhou L, Zhou X. Qingluo Tongbi Formula Alleviates Hepatotoxicity Induced by Tripterygium wilfordii Hook. F. by Regulating Excessive Mitophagy Through the PERK-ATF4 Pathway. Front Pharmacol 2022; 13:918466. [PMID: 35873540 PMCID: PMC9301126 DOI: 10.3389/fphar.2022.918466] [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: 04/12/2022] [Accepted: 06/17/2022] [Indexed: 12/23/2022] Open
Abstract
Qingluo Tongbi Formula (QTF) is an empirical formula of Chinese medicine master Zhongying Zhou for the treatment of rheumatoid arthritis. Although including Tripterygium wilfordii Hook. F. (TW), it has not shown liver toxicity in clinical application for many years. Our previous studies have shown that QTF can significantly reduce TW-caused hepatotoxicity, but the mechanism is still unclear. This study aimed to explore the important roles of mitophagy and endoplasmic reticulum stress (ERS) and the relationship between them in QTF in alleviating TW-induced hepatotoxicity. In vivo, C57BL/6J female mice were used to build a model of TW-induced liver toxicity; Then mice were randomly divided into control, TW, TW + RG, TW + PN, TW + SA, TW + BM, and QTF groups. After intragastric administration for 7 days, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in serum were detected; H and E staining, Oil Red O staining, transmission electron microscopy, Western blotting, and RT-qPCR were used to detect the pathological changes in liver tissue, the levels of ERS and mitophagy related proteins and genes, including GRP78, PERK, DRP1, LC3, etc., In vitro, triptolide (TP), catalpol (CAT), and panax notoginseng saponins (PNS), the main active ingredients of QTF, were selected. The mitophagy inhibitor, ERS inhibitor, and PERK inhibitor were used to further study the relationship between TW-induced ERS and mitophagy in HepaRG cells. The results showed that, QTF reduced excessive mitophagy and ERS in TW-induced hepatotoxicity in C57BL/6J mice, and the attenuating effects of RG and PN in QTF were most obvious, and they also significantly restrained the TW-induced ERS and mitophagy by the PERK-ATF4 pathway. Furthermore, PNS was superior to CAT in inhibiting the expression levels of GRP78, PERK, and ATF4, while CAT was superior to PNS in reversing the expression levels of DRP1, P62, and LC3. The combination of CAT and PNS had the best attenuating effect and the most significant regulation on ERS and mitophagy. In conclusion, QTF can alleviate TW-induced hepatotoxicity by differentially downregulating the PERK-ATF4 pathway and excessive mitophagy by different components.
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Affiliation(s)
- Linluo Zhang
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jie Zhou
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhe Feng
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Baoping Jiang
- Jiangsu Provincial Key Laboratory of Pharmacology and Safety Evaluation of Material Medical, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Changqing Li
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lingling Zhou
- Jiangsu Provincial Key Laboratory of Pharmacology and Safety Evaluation of Material Medical, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Lingling Zhou, ; Xueping Zhou,
| | - Xueping Zhou
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Lingling Zhou, ; Xueping Zhou,
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14
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Wu Y, Zhang Z, Li Y, Li Y. The Regulation of Integrated Stress Response Signaling Pathway on Viral Infection and Viral Antagonism. Front Microbiol 2022; 12:814635. [PMID: 35222313 PMCID: PMC8874136 DOI: 10.3389/fmicb.2021.814635] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/14/2021] [Accepted: 12/15/2021] [Indexed: 12/13/2022] Open
Abstract
The integrated stress response (ISR) is an adaptational signaling pathway induced in response to different stimuli, such as accumulation of unfolded and misfolded proteins, hypoxia, amino acid deprivation, viral infection, and ultraviolet light. It has been known that viral infection can activate the ISR, but the role of the ISR during viral infection is still unclear. In some cases, the ISR is a protective mechanism of host cells against viral infection, while viruses may hijack the ISR for facilitating their replication. This review highlighted recent advances on the induction of the ISR upon viral infection and the downstream responses, such as autophagy, apoptosis, formation of stress granules, and innate immunity response. We then discussed the molecular mechanism of the ISR regulating viral replication and how viruses antagonize this cellular stress response resulting from the ISR.
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Affiliation(s)
- Yongshu Wu
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Zhidong Zhang
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
| | - Yanmin Li
- College of Animal Husbandry and Veterinary Medicine, Southwest Minzu University, Chengdu, China
- *Correspondence: Yanmin Li,
| | - Yijing Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
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15
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Zhang L, Li C, Fu L, Yu Z, Xu G, Zhou J, Shen M, Feng Z, Zhu H, Xie T, Zhou L, Zhou X. Protection of catalpol against triptolide-induced hepatotoxicity by inhibiting excessive autophagy via the PERK-ATF4-CHOP pathway. PeerJ 2022; 10:e12759. [PMID: 35036109 PMCID: PMC8742543 DOI: 10.7717/peerj.12759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/06/2021] [Accepted: 12/16/2021] [Indexed: 01/07/2023] Open
Abstract
Catalpol significantly reduces triptolide-induced hepatotoxicity, which is closely related to autophagy. The aim of this study was to explore the unclear protective mechanism of catalpol against triptolide. The detoxification effect of catalpol on triptolide was investigated in HepaRG cell line. The detoxification effects were assessed by measuring cell viability, autophagy, and apoptosis, as well as the endoplasmic reticulum stress protein and mRNA expression levels. We found that 5-20 µg/L triptolide treatments increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), as well as the expression of autophagy proteins including LC3 and Beclin1. The expression of P62 was downregulated and the production of autophagosomes was increased, as determined by transmission electron microscope and monodansylcadaverine staining. In contrast, 40 µg/L catalpol reversed these triptolide-induced changes in the liver function index, autophagy level, and apoptotic protein expression, including Cleaved-caspase3 and Cleaved-caspase9 by inhibiting excessive autophagy. Simultaneously, catalpol reversed endoplasmic reticulum stress, including the expression of PERK, which regulates autophagy. Moreover, we used the PERK inhibitor GSK2656157 to prove that the PERK-ATF4-CHOP pathway of the unfolded protein response is an important pathway that could induce autophagy. Catalpol inhibited excessive autophagy by suppressing the PERK pathway. Altogether, catalpol protects against triptolide-induced hepatotoxicity by inhibiting excessive autophagy via the PERK-ATF4-CHOP pathway. The results of this study are beneficial to clarify the detoxification mechanism of catalpol against triptolide-induced hepatotoxicity and to promote the application of triptolide.
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Affiliation(s)
- Linluo Zhang
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Changqing Li
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Ling Fu
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China,Department of Second Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Zhichao Yu
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Gengrui Xu
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Jie Zhou
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Meiyu Shen
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Zhe Feng
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Huaxu Zhu
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Tong Xie
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Lingling Zhou
- Department of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
| | - Xueping Zhou
- Department of First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu, China
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16
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Abstract
Viruses are intracellular parasites that subvert the functions of their host cells to accomplish their infection cycle. The endoplasmic reticulum (ER)-residing chaperone proteins are central for the achievement of different steps of the viral cycle, from entry and replication to assembly and exit. The most abundant ER chaperones are GRP78 (78-kDa glucose-regulated protein), GRP94 (94-kDa glucose-regulated protein), the carbohydrate or lectin-like chaperones calnexin (CNX) and calreticulin (CRT), the protein disulfide isomerases (PDIs), and the DNAJ chaperones. This review will focus on the pleiotropic roles of ER chaperones during viral infection. We will cover their essential role in the folding and quality control of viral proteins, notably viral glycoproteins which play a major role in host cell infection. We will also describe how viruses co-opt ER chaperones at various steps of their infectious cycle but also in order to evade immune responses and avoid apoptosis. Finally, we will discuss the different molecules targeting these chaperones and the perspectives in the development of broad-spectrum antiviral drugs.
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17
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Basler M, Christ M, Goebel H, Groettrup M. Immunoproteasome Upregulation Is Not Required to Control Protein Homeostasis during Viral Infection. THE JOURNAL OF IMMUNOLOGY 2021; 206:1697-1708. [PMID: 33731337 DOI: 10.4049/jimmunol.2000822] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/14/2020] [Accepted: 02/01/2021] [Indexed: 12/28/2022]
Abstract
The prime function of proteasomes is the control of protein homeostasis in cells (i.e., the removal of proteins that are not properly folded, damaged by stress conditions like reactive oxygen species formation, or degraded on the basis of regular protein turnover). During viral infection, the standard proteasome is replaced by the so-called immunoproteasome (IP) in an IFN-γ-dependent manner. It has been proposed that the IP is required to protect cell viability under conditions of IFN-induced oxidative stress. In this study, we investigated the requirement for IP to cope with the enhanced need for protein degradation during lymphocytic choriomeningitis virus (LCMV) infection in mice lacking the IP subunit LMP7. We found that IP are upregulated in the liver but not in the spleen during LCMV infection, although the total proteasome content was not altered. The expression of standard proteasome subunits is not induced in LMP7-deficient mice, indicating that enhanced proteasomal activity is not required during viral infection. Furthermore, ubiquitin accumulation, apoptosis induction, and viral titers were similar in LCMV-infected mice lacking LMP7 compared with wild-type mice. Taken together, these data indicate that the IP is not required to regulate protein homeostasis during LCMV infection.
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Affiliation(s)
- Michael Basler
- Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany; and .,Biotechnology Institute Thurgau at the University of Konstanz, 8280 Kreuzlingen, Switzerland
| | - Marleen Christ
- Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany; and
| | - Heike Goebel
- Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany; and
| | - Marcus Groettrup
- Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany; and.,Biotechnology Institute Thurgau at the University of Konstanz, 8280 Kreuzlingen, Switzerland
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18
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Chattopadhyay P, Srinivasa Vasudevan J, Pandey R. Noncoding RNAs: modulators and modulatable players during infection-induced stress response. Brief Funct Genomics 2021; 20:28-41. [PMID: 33491070 PMCID: PMC7929421 DOI: 10.1093/bfgp/elaa026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/17/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 12/16/2022] Open
Abstract
The human genome has an almost equal distribution of unique and transposable genetic elements. Although at the transcriptome level, a relatively higher contribution from transposable elements derived RNA has been reported. This is further highlighted with evidence from pervasive transcription. Of the total RNA, noncoding RNAs (ncRNAs) are significant contributors to the transcriptome pool with sizeable fraction from repetitive elements of the human genome, inclusive of Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs). ncRNAs are increasingly being implicated in diverse functional roles especially during conditions of stress. These stress responses are driven through diverse mediators, inclusive of long and short ncRNAs. ncRNAs such as MALAT1, GAS5, miR-204 and miR-199a-5p have been functionally involved during oxidative stress, endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Also, within SINEs, Alu RNAs derived from primate-specific Alu repeats with ~11% human genome contribution, playing a significant role. Pathogenic diseases, including the recent COVID-19, leads to differential regulation of ncRNAs. Although, limited evidence suggests the need for an inquest into the role of ncRNAs in determining the host response towards pathogen challenge.
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Affiliation(s)
| | | | - Rajesh Pandey
- Corresponding author: Rajesh Pandey, INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) laboratory. CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), North Campus, Near Jubilee Hall, Mall Road, Delhi-110007, India. Tel.: +91 9811029551; E-mail:
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19
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Kryvenko V, Vadász I. Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19. Am J Physiol Lung Cell Mol Physiol 2021; 320:L1186-L1193. [PMID: 33689516 PMCID: PMC8238442 DOI: 10.1152/ajplung.00056.2021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/08/2023] Open
Abstract
A significant number of patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) that is associated with a poor outcome. The molecular mechanisms driving failure of the alveolar barrier upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain incompletely understood. The Na,K-ATPase is an adhesion molecule and a plasma membrane transporter that is critically required for proper alveolar epithelial function by both promoting barrier integrity and resolution of excess alveolar fluid, thus enabling appropriate gas exchange. However, numerous SARS-CoV-2-mediated and COVID-19-related signals directly or indirectly impair the function of the Na,K-ATPase, thereby potentially contributing to disease progression. In this Perspective, we highlight some of the putative mechanisms of SARS-CoV-2-driven dysfunction of the Na,K-ATPase, focusing on expression, maturation, and trafficking of the transporter. A therapeutic mean to selectively inhibit the maladaptive signals that impair the Na,K-ATPase upon SARS-CoV-2 infection might be effective in reestablishing the alveolar epithelial barrier and promoting alveolar fluid clearance and thus advantageous in patients with COVID-19-associated ARDS.
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Affiliation(s)
- Vitalii Kryvenko
- Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.,The Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - István Vadász
- Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.,The Cardio-Pulmonary Institute (CPI), Giessen, Germany
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20
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Zhu E, Wu H, Chen W, Qin Y, Liu J, Fan S, Ma S, Wu K, Mao Q, Luo C, Qin Y, Yi L, Ding H, Zhao M, Chen J. Classical swine fever virus employs the PERK- and IRE1-dependent autophagy for viral replication in cultured cells. Virulence 2020; 12:130-149. [PMID: 33380286 PMCID: PMC7781608 DOI: 10.1080/21505594.2020.1845040] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023] Open
Abstract
Endoplasmic reticulum stress (ERS)-mediated autophagy is indispensable for modulation of replication and pathogenesis of numerous mammalian viruses. We have previously shown that classical swine fever virus (CSFV) infection induces ERS-mediated autophagy for maintaining viral replication both in vivo and in vitro, however, the underlying mechanism remains unclarified. Here we found that CSFV infection activates the PERK pathway-dependent complete autophagy to promote viral replication in cultured PK-15 and 3D4/2 cells. Likewise, our results also suggested the essential roles of the IRE1/GRP78-mediated complete autophagy in CSFV replication in vitro. Furthermore, we suggested that CSFV infection induces activation of the PERK and IRE1 pathway for potential immunoregulation via promoting transcription of proinflammatory cytokine (IFN-γ and TNF-α) genes in the CSFV-infected cells. Finally, pharmacological treatment of PERK- or IRE1-pathway regulators, and the corresponding SiRNAs interventions did not affect the viabilities of the cells, excluding the potential interference elicited by altered cell viabilities. Taken together, our results suggest that CSFV infection induces complete autophagy through activation of the PERK and IRE1 pathway to facilitate viral replication in cultured cells, and modulation of proinflammatory cytokines may be a potential mechanism involved in this event. Our findings will open new horizons for molecular mechanisms of sustainable replication and pathogenesis of CSFV, and lay a theoretical foundation for the development of ERS-autophagy-targeting therapeutic strategies for clinical control of CSF.
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Affiliation(s)
- Erpeng Zhu
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China.,Department of Veterinary Medicine, College of Animal Science, Guizhou University , Guiyang, China
| | - Huawei Wu
- Department of Viral Biologics, China Institute of Veterinary Drug Control , Beijing, China
| | - Wenxian Chen
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Yuwei Qin
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Jiameng Liu
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Shuangqi Fan
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Shengming Ma
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Keke Wu
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Qian Mao
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Chaowei Luo
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Yixian Qin
- Department of Viral Biologics, China Institute of Veterinary Drug Control , Beijing, China
| | - Lin Yi
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Hongxing Ding
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Mingqiu Zhao
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
| | - Jinding Chen
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University , Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture , Guangzhou, China
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21
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Sun P, Jin J, Wang L, Wang J, Zhou H, Zhang Q, Xu X. Porcine epidemic diarrhea virus infections induce autophagy in Vero cells via ROS-dependent endoplasmic reticulum stress through PERK and IRE1 pathways. Vet Microbiol 2020; 253:108959. [PMID: 33360915 DOI: 10.1016/j.vetmic.2020.108959] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2020] [Accepted: 12/13/2020] [Indexed: 12/12/2022]
Abstract
Porcine epidemic diarrhea virus (PEDV), the causative agent of PED, belongs to the genus Alphacoronavirus in the family Coronaviridae. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy play crucial roles in regulating a variety of cellular processes during viral infection. However, the precise role of autophagy in PEDV-infected Vero cells remains largely elusive. To elucidate how PEDV infection induces autophagy, this study ascertained whether ER stress was present in PEDV-infected Vero cells. The results showed PEDV infection significantly increased the expression of GRP78 and LC3Ⅱ. Treatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA) could significantly inhibit PEDV-induced autophagy. Antioxidants, such as N-acetylcysteine (NAC), could significantly inhibit PEDV-induced ER stress and autophagy, indicating that ROS act as an upstream regulator of ER stress-mediated autophagy. Further research found that activation of ER stress triggered the unfolded protein response (UPR) through PERK, IRE1, and ATF6 pathways during PEDV infection. However, treatment with the PERK inhibitor GSK2606414, IRE1 inhibitor STF-083010 but not ATF6 inhibitor AEBSF reversed PEDV-induced autophagy. Taken together, the results of this study showed that accumulated ROS played an essential role in regulating ER stress-mediated autophagy during PEDV infection. We also found that PERK and IER1 pathways of UPR signalling were involved in PEDV-induced autophagy. Furthermore, PEDV induced autophagy to promote viral replication via PERK and IER1 pathways in Vero cells. These results provide the mechanism of PEDV-induced ROS-dependent ER stress-mediated autophagy in Vero cells through activating PERK and IRE1 pathways.
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Affiliation(s)
- Pei Sun
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, Anhui, 230036, China
| | - Jian Jin
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, Anhui, 230036, China
| | - Lixiang Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jingjing Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Hongchao Zhou
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Qi Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China.
| | - Xingang Xu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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22
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Zou H, Sun J, Wu B, Yuan Y, Gu J, Bian J, Liu X, Liu Z. Effects of Cadmium and/or Lead on Autophagy and Liver Injury in Rats. Biol Trace Elem Res 2020; 198:206-215. [PMID: 32006201 DOI: 10.1007/s12011-020-02045-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/22/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022]
Abstract
Exposure to cadmium (Cd) and lead (Pb) can induce liver damage. However, the effects of the combined exposure to Cd and Pb on liver function have not been fully clarified. In the present study, we investigated the liver function in rats co-exposed to Cd and Pb. A total of 24 female SD rats were divided into 4 groups as follows: control group (DDW), Cd group (50 mg/l Cd), Pb group (300 mg/l Pb), Pb + Cd group (300 mg/l + 50 mg/l Cd). Following 12 weeks of continuous exposure, the results showed a large accumulation of Cd and Pb in the liver. The Liver weight and Liver coefficient were decreased, as well as liver structure and function was destroyed. In addition, Pb + Cd group exhibited additional pathological alterations. Moreover, the indices of oxidative stress and related trace elements were detected following treatment. The results showed that the single treatment of Pb or Cd and the combined Cd and Pb treatment could upregulate the contents of antioxidant enzymes and related trace elements. We further examined the expression levels of autophagy-related proteins and mRNAs, and we found that the single treatment of Pb or Cd and the combined Cd and Pb treatment could upregulate the expression of levels of autophagy-related proteins and mRNAs (Atg5, Atg7, Beclin-1, p62, and LC3). Transmission electron microscopy revealed the presence of autophagosomes in the exposed groups. All the results indicated that Cd and Pb may affect the level of oxidative stress and autophagy in hepatocytes, whereas the combination of Cd and Pb showed a tendency of escalation compared with the single treatment group.
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Affiliation(s)
- Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Jian Sun
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Bo Wu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Xuezhong Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, 225009, People's Republic of China.
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23
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Akhbari P, Richardson SJ, Morgan NG. Type 1 Diabetes: Interferons and the Aftermath of Pancreatic Beta-Cell Enteroviral Infection. Microorganisms 2020; 8:microorganisms8091419. [PMID: 32942706 PMCID: PMC7565444 DOI: 10.3390/microorganisms8091419] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/21/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
Enteroviruses (EVs) have long been implicated in the pathogenesis of type 1 diabetes (T1D), and accumulating evidence has associated virus-induced autoimmunity with the loss of pancreatic beta cells in T1D. Inflammatory cytokines including interferons (IFN) form a primary line of defence against viral infections, and their chronic elevation is a hallmark feature of many autoimmune diseases. IFNs play a key role in activating and regulating innate and adaptive immune responses, and to do so they modulate the expression of networks of genes and transcription factors known generically as IFN stimulated genes (ISGs). ISGs in turn modulate critical cellular processes ranging from cellular metabolism and growth regulation to endoplasmic reticulum (ER) stress and apoptosis. More recent studies have revealed that IFNs also modulate gene expression at an epigenetic as well as post-transcriptional and post-translational levels. As such, IFNs form a key link connecting the various genetic, environmental and immunological factors involved in the initiation and progression of T1D. Therefore, gaining an improved understanding of the mechanisms by which IFNs modulate beta cell function and survival is crucial in explaining the pathogenesis of virally-induced T1D. This should provide the means to prevent, decelerate or even reverse beta cell impairment.
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24
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Wan Q, Song D, Li H, He ML. Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development. Signal Transduct Target Ther 2020; 5:125. [PMID: 32661235 PMCID: PMC7356129 DOI: 10.1038/s41392-020-00233-4] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/10/2020] [Revised: 05/26/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023] Open
Abstract
Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson’s diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.
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Affiliation(s)
- Qianya Wan
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Dan Song
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Huangcan Li
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China
| | - Ming-Liang He
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China. .,CityU Shenzhen Research Institute, Shenzhen, China.
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25
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Banerjee A, Czinn SJ, Reiter RJ, Blanchard TG. Crosstalk between endoplasmic reticulum stress and anti-viral activities: A novel therapeutic target for COVID-19. Life Sci 2020; 255:117842. [PMID: 32454157 PMCID: PMC7245231 DOI: 10.1016/j.lfs.2020.117842] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/10/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
The outbreak of COVID-19 caused by 2019–nCov/SARS-CoV-2 has become a pandemic with an urgent need for understanding the mechanisms and identifying a treatment. Viral infections including SARS-CoV are associated with increased levels of reactive oxygen species, disturbances of Ca++ caused by unfolded protein response (UPR) mediated by endoplasmic reticulum (ER) stress and is due to the exploitation of virus's own protein i.e., viroporins into the host cells. Several clinical trials are on-going including testing Remdesivir (anti-viral), Chloroquine and Hydroxychloroquine derivatives (anti-malarial drugs) etc. Unfortunately, each drug has specific limitations. Herein, we review the viral protein involvement to activate ER stress transducers (IRE-1, PERK, ATF-6) and their downstream signals; and evaluate combination therapies for COVID-19 mediated ER stress alterations. Melatonin is an immunoregulator, anti-pyretic, antioxidant, anti-inflammatory and ER stress modulator during viral infections. It enhances protective mechanisms for respiratory tract disorders. Andrographolide, isolated from Andrographis paniculata, has versatile biological activities including immunomodulation and determining SARS-CoV-2 binding site. Considering the properties of both compounds in terms of anti-inflammatory, antioxidant, anti-pyrogenic, anti-viral and ER stress modulation and computational approaches revealing andrographolide docks with the SARS-CoV2 binding site, we predict that this combination therapy may have potential utility against COVID-19.
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Affiliation(s)
- Aditi Banerjee
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Steven J Czinn
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Thomas G Blanchard
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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26
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Farag NS, Breitinger U, Breitinger HG, El Azizi MA. Viroporins and inflammasomes: A key to understand virus-induced inflammation. Int J Biochem Cell Biol 2020; 122:105738. [PMID: 32156572 PMCID: PMC7102644 DOI: 10.1016/j.biocel.2020.105738] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/02/2019] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023]
Abstract
The article provides a summary on cellular receptors involved in virus immunity. It summarizes key findings on viroporins, a novel class of viral proteins and their role in the virus life cycle and host cell interactions. It presents an overview of the current understanding of inflammasomes complex activation, with special focus on NLRP3. It discusses the correlation between viroporins and inflammasomes activation and aggravated inflammatory cytokines production. Viroporins are virus encoded proteins that alter membrane permeability and can trigger subsequent cellular signals. Oligomerization of viroporin subunits results in formation of a hydrophilic pore which facilitates ion transport across host cell membranes. These viral channel proteins may be involved in different stages of the virus infection cycle. Inflammasomes are large multimolecular complexes best recognized for their ability to control activation of caspase-1, which in turn regulates the maturation of interleukin-1 β (IL-1β) and interleukin 18 (IL-18). IL-1β was originally identified as a pro-inflammatory cytokine able to induce both local and systemic inflammation and a febrile reaction in response to infection or injury. Excessive production of IL-1β is associated with autoimmune and inflammatory diseases. Microbial derivatives, bacterial pore-forming toxins, extracellular ATP and other pathogen-associated molecular patterns trigger activation of NLRP3 inflammasomes. Recent studies have reported that viroporin activity is capable of inducing inflammasome activity and production of IL-1β, where NLRP3 is shown to be regulated by fluxes of K+, H+ and Ca2+ in addition to reactive oxygen species, autophagy and endoplasmic reticulum stress. The aim of this review is to present an overview of the key findings on viroporin activity with special emphasis on their role in virus immunity and as possible activators of inflammasomes.
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Affiliation(s)
- N S Farag
- Department of Microbiology and Immunology, German University inCairo, New Cairo, Egypt.
| | - U Breitinger
- Department of Biochemistry, German University in Cairo, New Cairo, Egypt
| | - H G Breitinger
- Department of Biochemistry, German University in Cairo, New Cairo, Egypt
| | - M A El Azizi
- Department of Microbiology and Immunology, German University inCairo, New Cairo, Egypt
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27
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Li C, Liu J, Zhang X, Yu Y, Huang X, Wei J, Qin Q. Red grouper nervous necrosis virus (RGNNV) induces autophagy to promote viral replication. FISH & SHELLFISH IMMUNOLOGY 2020; 98:908-916. [PMID: 31770643 DOI: 10.1016/j.fsi.2019.11.053] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/21/2019] [Revised: 11/20/2019] [Accepted: 11/22/2019] [Indexed: 06/10/2023]
Abstract
Autophagy is an evolutionarily conserved cellular degradation process that is essential for homeostasis. As a cell steward, autophagy is thought to be a process that may have evolved to combat intracellular pathogens. However, some virus can subvert or utilize autophagy-related membrane structures to increase viral replication. The red-spotted grouper nervous necrosis virus (RGNNV) is a fish pathogen which leads to disastrous viral nervous necrosis in larvae and juvenile groupers and other marine fishes. To better comprehend the pathogenesis and replication mechanism of RGNNV, we investigated the relationship between RGNNV and autophagy. Here, we demonstrated that RGNNV induced autophagy in grouper spleen (GS) cells, as the significant increase in ultrastructural autophagosome-like vesicles, fluorescent punctate pattern of microtubule-associated protein 1 light chain 3 (LC3), and the conversion of LC3-I to LC3-II. Additionally, ultraviolet-inactivated RGNNV and the capsid protein also triggered autophagy. Enhancement of autophagy contributed to RGNNV replication, whereas blocked autophagy decreased RGNNV replication. Moreover, impeded fusion of autophagosomes and lysosomes also reduced RGNNV replication, indicating that RGNNV utilized the different steps of autophagy pathway to facilitate viral replication. The further study showed that RGNNV induced autophagy through activating the phosphorylation of eIF2α and inhibiting the phosphorylation of mTOR. These results will assist the search for novel drugs targets and vaccine design against RGNNV from the perspective of downregulating autophagy.
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Affiliation(s)
- Chen Li
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Jiaxin Liu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Xin Zhang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Yepin Yu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Xiaohong Huang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Jingguang Wei
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China.
| | - Qiwei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, PR China.
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28
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Chen Z, Li C, Qian YH, Fu Y, Feng ZM. Enhancement of autophagy flux by isopsoralen ameliorates interleukin-1β-stimulated apoptosis in rat chondrocytes. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2020; 22:179-192. [PMID: 30621446 DOI: 10.1080/10286020.2018.1537265] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/23/2018] [Accepted: 10/10/2018] [Indexed: 06/09/2023]
Abstract
Chondrocyte apoptosis contributes to the pathogenesis of cartilage degeneration in osteoarthritis (OA). We found that isopsoralen pretreatment significantly reversed the increase in DNA fragmentation and apoptosis rate, and significantly decreased the caspase-3 activity and PARP cleavage in IL-1β-treated chondrocytes. Isopsoralen pretreatment markedly inhibited disruption of matrix proteins. Moreover, the expressions of LC3-II and LAMP-1 were markedly increased but the expression of p62/SQSTM1 was remarkably decreased by isopsoralen pretreatment. Importantly, the protective effects of isopsoralen against IL-1β were blocked by pretreatment with autophagy inhibitor 3-MA and bafilomycin A1. These results suggest that isopsoralen ameliorates chondrocyte apoptosis by promoting autophagy flux.[Formula: see text].
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Affiliation(s)
- Zhi Chen
- Department of Critical Care Medicine, People's Hospital of Jiangxi Province, Nanchang 330006, China
| | - Chen Li
- Department of Orthopedics, People's Hospital of Jiangxi Province, Nanchang 330006, China
| | - Yi-Hong Qian
- Department of Anesthesiology, People's Hospital of Jiangxi Province, Nanchang 330006, China
| | - Yang Fu
- Department of Orthopedics, People's Hospital of Jiangxi Province, Nanchang 330006, China
| | - Zi-Ming Feng
- Department of Orthopedics, People's Hospital of Jiangxi Province, Nanchang 330006, China
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29
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Zhu E, Chen W, Qin Y, Ma S, Fan S, Wu K, Li W, Fan J, Yi L, Ding H, Chen J, Zhao M. Classical Swine Fever Virus Infection Induces Endoplasmic Reticulum Stress-Mediated Autophagy to Sustain Viral Replication in vivo and in vitro. Front Microbiol 2019; 10:2545. [PMID: 31798542 PMCID: PMC6861840 DOI: 10.3389/fmicb.2019.02545] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/22/2019] [Accepted: 10/22/2019] [Indexed: 01/10/2023] Open
Abstract
Endoplasmic reticulum (ER) stress-mediated autophagy plays significant roles in replication and pathogenesis of many animal viruses. However, the relationship between ER stress, autophagy, and viral replication during in vivo and in vitro infection of classical swine fever virus (CSFV) remains unclear. In this study, we established a pig model for CSFV infection and found that viral loads of CSFV differed in 10 kinds of infected organs, and that the degree of tissue lesions was to some extent positively correlated with CSFV replication in vivo. Next, we found that CSFV infection not only induced ER stress and subsequently activated three unfolded protein responses (UPR) pathways including protein kinase R-like ER kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor-6 (ATF-6) pathways, but also triggered complete autophagy in main immune organs and partial nonimmune organs exhibiting severer pathological injuries and higher viral loads. However, only the IRE1 pathway and no autophagy were activated in some other nonimmune organs with slighter pathologies and lower viral loads. These results indicate a potential link between CSFV-induced ER stress and autophagy, both of which are associated with the CSFV replication in vivo. We further performed in vitro experiments and found that CSFV infection activates the PERK and IRE1 pathways and autophagy in cultured porcine kidney cell lines (PK-15) and macrophage cell lines (3D4/2), and pharmacological regulation of ER stress remarkably changed autophagic activities induced by CSFV, suggesting that CSFV-induced autophagy can be mediated by ER stress possibly via the PERK and IRE1 pathway. Furthermore, treatment with ER stress regulators significantly altered copy numbers of NS5B genes, expression of Npro proteins, and viral titers in CSFV-infected cells or in cells treated with autophagy regulators prior to CSFV infection, suggesting the requirement of ER stress-mediated autophagy for CSFV replication in vitro. Collectively, our data demonstrate that CSFV induces ER stress-mediated autophagy to sustain its replication in vivo and in vitro, which may be one of the potential strategies exploited by CSFV for immune evasion. This finding will provide new insights into mechanisms of replication and pathogenesis of CSFV, and development of new strategies for controlling CSF.
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Affiliation(s)
- Erpeng Zhu
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Wenxian Chen
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Yuwei Qin
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Shengming Ma
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Shuangqi Fan
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Keke Wu
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Wenhui Li
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Jindai Fan
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Lin Yi
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Hongxing Ding
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Jinding Chen
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
| | - Mingqiu Zhao
- Department of Microbiology and Immunology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
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30
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Sun D, Wen X, Wang M, Mao S, Cheng A, Yang X, Jia R, Chen S, Yang Q, Wu Y, Zhu D, Liu M, Zhao X, Zhang S, Wang Y, Xu Z, Chen Z, Zhu L, Luo Q, Liu Y, Yu Y, Zhang L, Chen X. Apoptosis and Autophagy in Picornavirus Infection. Front Microbiol 2019; 10:2032. [PMID: 31551969 PMCID: PMC6733961 DOI: 10.3389/fmicb.2019.02032] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/11/2019] [Accepted: 08/19/2019] [Indexed: 12/13/2022] Open
Abstract
Cell death is a fundamental process in maintaining cellular homeostasis, which can be either accidental or programed. Programed cell death depends on the specific signaling pathways, resulting in either lytic or non-lytic morphology. It exists in two primary forms: apoptosis and autophagic cell death. Apoptosis is a non-lytic and selective cell death program, which is executed by caspases in response to non-self or external stimuli. In contrast, autophagy is crucial for maintaining cellular homeostasis via the degradation and recycling of cellular components. These two mechanisms also function in the defense against pathogen attack. However, picornaviruses have evolved to utilize diverse strategies and target critical components to regulate the apoptotic and autophagic processes for optimal replication and the release from the host cell. Although an increasing number of investigations have shown that the apoptosis and autophagy are altered in picornavirus infection, the mechanism by which viruses take advantage of these two processes remains unknown. In this review, we discuss the mechanisms of picornavirus executes cellular apoptosis and autophagy at the molecular level and the relationship between these interactions and viral pathogenesis.
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Affiliation(s)
- Di Sun
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xingjian Wen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Sai Mao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoyao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xinxin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yin Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhiwen Xu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Zhengli Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qihui Luo
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoyue Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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31
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Wei C, Yang X, Liu N, Geng J, Tai Y, Sun Z, Mei G, Zhou P, Peng Y, Wang C, Zhang X, Zhang P, Geng Y, Wang Y, Zhang X, Liu X, Zhang Y, Wu F, He X, Zhong H. Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice. Hepatology 2019; 70:851-870. [PMID: 30723919 DOI: 10.1002/hep.30549] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2018] [Accepted: 01/31/2019] [Indexed: 12/12/2022]
Abstract
The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor-promoting inflammation by up-regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi-associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor-associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose-regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion: Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.
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Affiliation(s)
- Congwen Wei
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Xiaoli Yang
- Department of Clinical Laboratory, the Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, P.R. China
| | - Ning Liu
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China.,Department of Clinical Laboratory, the Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, P.R. China
| | - Jin Geng
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China.,Institute of Physical Science and Information Technology, Anhui University, Hefei, P.R. China
| | - Yanhong Tai
- Department of Pathology, the Fifth Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, P.R. China
| | - Zhenyu Sun
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Gangwu Mei
- Wecyte Biotehnology Company, Beijing, P.R. China
| | - Pengyu Zhou
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, P.R. China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, P.R. China.,Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Yumeng Peng
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, P.R. China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, P.R. China.,Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Chenbin Wang
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Xiaoli Zhang
- Department of Clinical Laboratory, the Third Medical Centre, Chinese PLA (People's Liberation Army) General Hospital, Beijing, P.R. China
| | - Pingping Zhang
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Yunqi Geng
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Yujie Wang
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Xiaotong Zhang
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Xin Liu
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China.,Department of Colorectal Surgery, Cancer Hospital of China Medical University, Shenyang, P.R. China
| | - Yanhong Zhang
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Feixiang Wu
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, P.R. China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, P.R. China.,Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China
| | - Xiang He
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
| | - Hui Zhong
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, P.R. China
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32
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Tomar PPS, Oren R, Krugliak M, Arkin IT. Potential Viroporin Candidates From Pathogenic Viruses Using Bacteria-Based Bioassays. Viruses 2019; 11:v11070632. [PMID: 31324045 PMCID: PMC6669592 DOI: 10.3390/v11070632] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/30/2019] [Revised: 06/23/2019] [Accepted: 07/05/2019] [Indexed: 12/13/2022] Open
Abstract
Viroporins are a family of small hydrophobic proteins found in many enveloped viruses that are capable of ion transport. Building upon the ability to inhibit influenza by blocking its archetypical M2 H+ channel, as a family, viroporins may represent a viable target to curb viral infectivity. To this end, using three bacterial assays we analyzed six small hydrophobic proteins from biomedically important viruses as potential viroporin candidates. Our results indicate that Eastern equine encephalitis virus 6k, West Nile virus MgM, Dengue virus 2k, Dengue virus P1, Variola virus gp170, and Variola virus gp151 proteins all exhibit channel activity in the bacterial assays, and as such may be considered viroporin candidates. It is clear that more studies, such as patch clamping, will be needed to characterize the ionic conductivities of these proteins. However, our approach presents a rapid procedure to analyze open reading frames in other viruses, yielding new viroporin candidates for future detailed investigation. Finally, if conductivity is proven vital to their cognate viruses, the bio-assays presented herein afford a simple approach to screen for new channel blockers.
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Affiliation(s)
- Prabhat Pratap Singh Tomar
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, Jerusalem 91904, Israel
| | - Rivka Oren
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, Jerusalem 91904, Israel
| | - Miriam Krugliak
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, Jerusalem 91904, Israel
| | - Isaiah T Arkin
- Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus Givat-Ram, Jerusalem 91904, Israel.
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33
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Abstract
Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years, we have witnessed the emergence of two zoonotic, highly pathogenic HCoVs: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Replication of HCoV is regulated by a diversity of host factors and induces drastic alterations in cellular structure and physiology. Activation of critical signaling pathways during HCoV infection modulates the induction of antiviral immune response and contributes to the pathogenesis of HCoV. Recent studies have begun to reveal some fundamental aspects of the intricate HCoV-host interaction in mechanistic detail. In this review, we summarize the current knowledge of host factors co-opted and signaling pathways activated during HCoV infection, with an emphasis on HCoV-infection-induced stress response, autophagy, apoptosis, and innate immunity. The cross talk among these pathways, as well as the modulatory strategies utilized by HCoV, is also discussed.
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Affiliation(s)
- To Sing Fung
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control and Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou 510642, Guangdong, People's Republic of China;
| | - Ding Xiang Liu
- Guangdong Province Key Laboratory of Microbial Signals and Disease Control and Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou 510642, Guangdong, People's Republic of China;
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34
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Colli ML, Paula FM, Marselli L, Marchetti P, Roivainen M, Eizirik DL, Op de Beeck A. Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells. J Innate Immun 2019; 11:375-390. [PMID: 30799417 DOI: 10.1159/000496034] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/26/2018] [Accepted: 12/03/2018] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic β cell destruction. The disease is triggered by a combination of genetic and environmental factors, but the mechanisms leading to the triggering of early innate and late adaptive immunity and consequent progressive pancreatic β cell death remain unclear. The insulin-producing β cells are active secretory cells and are thus particularly sensitive to endoplasmic reticulum (ER) stress. ER stress plays an important role in the pathologic pathway leading to autoimmunity, islet inflammation, and β cell death. We show here that group B coxsackievirus (CVB) infection, a putative causative factor for T1D, induces a partial ER stress in rat and human β cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1α branch leads to increased spliced XBP1 expression and c-Jun N-terminal kinase (JNK) activation. Interestingly, JNK1 activation is essential for CVB amplification in both human and rat β cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1α activation. Our findings show that CVB tailors the unfolded protein response in β cells to support their replication, preferentially triggering the pro-viral IRE1α/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway.
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Affiliation(s)
- Maikel L Colli
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Flavia M Paula
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Merja Roivainen
- Viral Infections Unit, Department of Infectious Disease, National Institute for Health and Welfare, Helsinki, Finland
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Anne Op de Beeck
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium,
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35
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Asha K, Sharma-Walia N. Virus and tumor microenvironment induced ER stress and unfolded protein response: from complexity to therapeutics. Oncotarget 2018; 9:31920-31936. [PMID: 30159133 PMCID: PMC6112759 DOI: 10.18632/oncotarget.25886] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/31/2018] [Accepted: 07/21/2018] [Indexed: 12/28/2022] Open
Abstract
Endoplasmic reticulum (ER) stress can be activated by various pathological and physiological conditions including the unfolded protein response (UPR) to restore homeostasis. The UPR signaling pathways initiated by double-stranded RNA-activated protein kinase (PKR) like ER kinase (PERK), inositol requiring enzyme 1 α (IRE1α), and activating transcription factor 6 (ATF6) are vital for tumor growth, aggressiveness, microenvironment remodeling, and resistance to cancer therapeutics. This review focuses on the role of ER stress and activity of UPR signaling pathways involved in tumor formation and uncontrolled cell proliferation during various cancers and viral malignancies.
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Affiliation(s)
- Kumari Asha
- Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, U.S.A
| | - Neelam Sharma-Walia
- Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, U.S.A
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36
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Yin H, Zhao L, Wang Y, Li S, Huo H, Chen H. Duck enteritis virus activates CaMKKβ-AMPK to trigger autophagy in duck embryo fibroblast cells via increased cytosolic calcium. Virol J 2018; 15:120. [PMID: 30081955 PMCID: PMC6090797 DOI: 10.1186/s12985-018-1029-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/23/2018] [Accepted: 07/18/2018] [Indexed: 01/03/2023] Open
Abstract
Background The results of our previous study showed that impaired cellular energy metabolism contributes to duck enteritis virus-induced autophagy via the 5`-adenosine monophosphate-activated protein kinase (AMPK)/tuberous sclerosis complex 2/mammalian target of rapamycin pathway in duck embryo fibroblast (DEF) cells. However, it remains unknown whether any other underlying mechanisms of AMPK activation are involved in autophagy induction. Methods The activity of CaMKKβ and AMPK in DEF cells infected with DEV were evaluated.The Effect of inhibitory activity of CaMKKβ on DEV-induced autophagy was investigated. In addtion to, the cytosolic calcium level in DEF cells infected with DEV were evaluated.The Effect of inhibitory cytosolic calcium level on DEV-induced autophagy was investigated. Results In this study, duck enteritis virus (DEV) infection activated CaMKKβ and its substrate molecule AMPK at 36, 48, and 60 h post-infection (hpi). STO-609, a CaMKKβ inhibitor, or CaMKKβ siRNA significantly inhibited the activation of DEV to AMPK, LC3I to LC3II transformation, and GFP-LC3 puncta distribution. In addition, inhibition of CaMKKβ activity also significantly reduced progeny DEV titer and gB protein expression. Besides, cytosolic calcium (Ca2+) was higher in DEV-infected cells than mock controls at 36, 48, and 60 hpi, respectively. Treatment of DEV-infected cells with 1,2-Bis (2-aminophenoxy) ethane-N, N, N′, N-tetraacetic acid (BAPTA-AM) significantly reduced intracellular Ca2+ ion concentrations, as well as CaMKKβ and AMPK activities, and subsequent autophagy, in addition to viral protein synthesis and viral titer. Conclusions These results showed that elevated [Ca2+]cyto-mediated activation of CaMKKβ managed the activation of AMPK, which then positively regulated autophagy, thereby providing further insight into DEV–host interactions.
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Affiliation(s)
- Haichang Yin
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Sciences, 678 Haping Road, Harbin, 150069, People's Republic of China.,College of Life Science and Agriculture Forestry, Qiqihar University, Qiqihar, 161006, China.,Heilongjiang Provincial Key Laboratory of Resistance Gene Engineering and Protection of Biodiversity in Cold Areas, Qiqihar, Heilongjiang, 161006, China
| | - Lili Zhao
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Sciences, 678 Haping Road, Harbin, 150069, People's Republic of China
| | - Yiping Wang
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Sciences, 678 Haping Road, Harbin, 150069, People's Republic of China
| | - Siqi Li
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Sciences, 678 Haping Road, Harbin, 150069, People's Republic of China
| | - Hong Huo
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Sciences, 678 Haping Road, Harbin, 150069, People's Republic of China
| | - Hongyan Chen
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Sciences, 678 Haping Road, Harbin, 150069, People's Republic of China.
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37
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Neerukonda SN, Katneni UK, Bott M, Golovan SP, Parcells MS. Induction of the unfolded protein response (UPR) during Marek's disease virus (MDV) infection. Virology 2018; 522:1-12. [PMID: 29979959 DOI: 10.1016/j.virol.2018.06.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/25/2018] [Revised: 06/14/2018] [Accepted: 06/27/2018] [Indexed: 12/22/2022]
Abstract
Marek's disease (MD) is a pathology of chickens associated with paralysis, immune suppression, and the rapid formation of T-cell lymphomas. MD is caused by the herpesvirus, Marek's disease virus (MDV). We examined endoplasmic reticulum (ER) stress and the activation of unfolded protein response (UPR) pathways during MDV infection of cells in culture and lymphocytes in vivo. MDV strains activate the UPR as measured by increased mRNA expression of GRP78/BiP with concomitant XBP1 splicing and induction of its target gene, EDEM1. Cell culture replication of virulent, but not vaccine MDVs, activated the UPR at late in infection. Pathotype-associated UPR activation was induced to a greater level by a vv + MDV. Discrete UPR activation was observed during MDV in vivo infection, with the level of UPR modulation being affected by the MDV oncoprotein Meq. Finally, ATF6 was found to be activated in vv + MDV-induced primary lymphomas, suggesting a possible role in tumor progression.
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Affiliation(s)
- Sabari Nath Neerukonda
- Department of Animal and Food Sciences, University of Delaware, 052 Townsend Hall, 531 South College Ave, Newark, DE 19716, United States.
| | - Upendra K Katneni
- Department of Animal and Food Sciences, University of Delaware, 052 Townsend Hall, 531 South College Ave, Newark, DE 19716, United States.
| | - Matthew Bott
- Department of Animal and Food Sciences, University of Delaware, 052 Townsend Hall, 531 South College Ave, Newark, DE 19716, United States.
| | | | - Mark S Parcells
- Department of Animal and Food Sciences, University of Delaware, 052 Townsend Hall, 531 South College Ave, Newark, DE 19716, United States.
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38
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Wang R, Moniruzzaman M, Shuffle E, Lourie R, Hasnain SZ. Immune regulation of the unfolded protein response at the mucosal barrier in viral infection. Clin Transl Immunology 2018; 7:e1014. [PMID: 29632667 PMCID: PMC5881172 DOI: 10.1002/cti2.1014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/04/2017] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 01/12/2023] Open
Abstract
Protein folding in the endoplasmic reticulum (ER) is subject to stringent quality control. When protein secretion demand exceeds the protein folding capacity of the ER, the unfolded protein response (UPR) is triggered as a consequence of ER stress. Due to the secretory function of epithelial cells, UPR plays an important role in maintaining epithelial barrier function at mucosal sites. ER stress and activation of the UPR are natural mechanisms by which mucosal epithelial cells combat viral infections. In this review, we discuss the important role of UPR in regulating mucosal epithelium homeostasis. In addition, we review current insights into how the UPR is involved in viral infection at mucosal barriers and potential therapeutic strategies that restore epithelial cell integrity following acute viral infections via cytokine and cellular stress manipulation.
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Affiliation(s)
- Ran Wang
- Translational Research Institute Immunopathology Group at Mater Research Institute - The University of Queensland Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
| | - Md Moniruzzaman
- Translational Research Institute Immunopathology Group at Mater Research Institute - The University of Queensland Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
| | - Eric Shuffle
- Translational Research Institute Immunopathology Group at Mater Research Institute - The University of Queensland Brisbane QLD Australia
| | - Rohan Lourie
- Translational Research Institute Immunopathology Group at Mater Research Institute - The University of Queensland Brisbane QLD Australia.,Translational Research Institute Inflammatory Bowel Disease Group at Mater Research Institute - The University of Queensland Brisbane QLD Australia
| | - Sumaira Z Hasnain
- Translational Research Institute Immunopathology Group at Mater Research Institute - The University of Queensland Brisbane QLD Australia.,Faculty of Medicine The University of Queensland Brisbane QLD Australia
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39
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Sun P, Zhang S, Qin X, Chang X, Cui X, Li H, Zhang S, Gao H, Wang P, Zhang Z, Luo J, Li Z. Foot-and-mouth disease virus capsid protein VP2 activates the cellular EIF2S1-ATF4 pathway and induces autophagy via HSPB1. Autophagy 2018; 14:336-346. [PMID: 29166823 PMCID: PMC5902195 DOI: 10.1080/15548627.2017.1405187] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/18/2023] Open
Abstract
Foot-and-mouth disease virus (FMDV) can result in economical destruction of cloven-hoofed animals. FMDV infection has been reported to induce macroautophagy/autophagy; however, the precise molecular mechanisms of autophagy induction and effect of FMDV capsid protein on autophagy remain unknown. In the present study, we report that FMDV infection induced a complete autophagy process in the natural host cells of FMDV, and inhibition of autophagy significantly decreased FMDV production, suggesting that FMDV-induced autophagy facilitates viral replication. We found that the EIF2S1-ATF4 pathway was activated and the AKT-MTOR signaling pathway was inhibited by FMDV infection. We also observed that ultraviolet (UV)-inactivated FMDV can induce autophagy. Importantly, our work provides the first piece of evidence that expression of FMDV capsid protein VP2 can induce autophagy through the EIF2S1-ATF4-AKT-MTOR cascade, and we found that VP2 interacted with HSPB1 (heat shock protein family B [small] member 1) and activated the EIF2S1-ATF4 pathway, resulting in autophagy and enhanced FMDV replication. In addition, we show that VP2 induced autophagy in a variety of mammalian cell lines and decreased aggregates of a model mutant HTT (huntingtin) polyglutamine expansion protein (HTT103Q). Overall, our results demonstrate that FMDV capsid protein VP2 induces autophagy through interaction with HSPB1 and activation of the EIF2S1-ATF4 pathway.
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Affiliation(s)
- Peng Sun
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China.,b Department of Cell Biology, School of Life Sciences , Lanzhou University , Lanzhou , Gansu , China
| | - Shumin Zhang
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Xiaodong Qin
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Xingni Chang
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Xiaorui Cui
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Haitao Li
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Shuaijun Zhang
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Huanhuan Gao
- b Department of Cell Biology, School of Life Sciences , Lanzhou University , Lanzhou , Gansu , China
| | - Penghua Wang
- c Department of Microbiology and Immunology , New York Medical College, Valhalla , New York , USA
| | - Zhidong Zhang
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Jianxun Luo
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
| | - Zhiyong Li
- a State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture , Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences , Lanzhou , Gansu , China
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Yin H, Zhao L, Jiang X, Li S, Huo H, Chen H. DEV induce autophagy via the endoplasmic reticulum stress related unfolded protein response. PLoS One 2017; 12:e0189704. [PMID: 29272280 PMCID: PMC5741216 DOI: 10.1371/journal.pone.0189704] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/19/2017] [Accepted: 11/30/2017] [Indexed: 01/25/2023] Open
Abstract
Duck enteritis virus (DEV) can infect ducks, geese, and many other poultry species and leads to acute, septic and highly fatal infectious disease. Autophagy is an evolutionarily ancient pathway that plays an important role in many viral infections. We previously reported that DEV infection induces autophagy for its own benefit, but how this occurs remains unclear. In this study, endoplasmic reticulum (ER) stress was triggered by DEV infection, as demonstrated by the increased expression of the ER stress marker glucose-regulated protein 78 (GRP78) and the dilated morphology of the ER. Pathways associated with the unfolded protein response (UPR), including the PKR-like ER protein kinase (PERK) and inositol-requiring enzyme 1 (IRE1) pathways, but not the activating transcription factor 6 (ATF6) pathway, were activated in DEV-infected duck embryo fibroblast (DEF) cells. In addition, the knockdown of both PERK and IRE1 by small interfering RNAs (siRNAs) reduced the level of LC3-II and viral yields, which suggested that the PERK-eukaryotic initiation factor 2α (eIF2α) and IRE1-x-box protein1 (XBP1) pathways may contribute to DEV-induced autophagy. Collectively, these data offer new insight into the mechanisms of DEV -induced autophagy through activation of the ER stress-related UPR pathway.
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Affiliation(s)
- Haichang Yin
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Science, Harbin, P. R. China
| | - Lili Zhao
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Science, Harbin, P. R. China
| | - Xinjie Jiang
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Science, Harbin, P. R. China
| | - Siqi Li
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Science, Harbin, P. R. China
| | - Hong Huo
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Science, Harbin, P. R. China
| | - Hongyan Chen
- State Key Laboratory of Veterinary Biotechnology, Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, the Chinese Academy of Agriculture Science, Harbin, P. R. China
- * E-mail: hy
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Ramsey J, Mukhopadhyay S. Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins. Viruses 2017; 9:v9080228. [PMID: 28820485 PMCID: PMC5580485 DOI: 10.3390/v9080228] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/17/2017] [Revised: 08/03/2017] [Accepted: 08/16/2017] [Indexed: 01/04/2023] Open
Abstract
For 30 years it was thought the alphavirus 6K gene encoded a single 6 kDa protein. However, through a bioinformatics search 10 years ago, it was discovered that there is a frameshifting event and two proteins, 6K and transframe (TF), are translated from the 6K gene. Thus, many functions attributed to the 6K protein needed reevaluation to determine if they properly belong to 6K, TF, or both proteins. In this mini-review, we reevaluate the past research on 6K and put those results in context where there are two proteins, 6K and TF, instead of one. Additionally, we discuss the most cogent outstanding questions for 6K and TF research, including their collective importance in alphavirus budding and their potential importance in disease based on the latest virulence data.
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Affiliation(s)
- Jolene Ramsey
- Department of Biology at Indiana University, Bloomington, IN 47405, USA.
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Li J, Luo H, Dong X, Liu Q, Wu C, Zhang T, Hu X, Zhang Y, Song B, Li L. Therapeutic effect of urine-derived stem cells for protamine/lipopolysaccharide-induced interstitial cystitis in a rat model. Stem Cell Res Ther 2017; 8:107. [PMID: 28482861 PMCID: PMC5422864 DOI: 10.1186/s13287-017-0547-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/14/2016] [Revised: 01/04/2017] [Accepted: 03/31/2017] [Indexed: 01/21/2023] Open
Abstract
Background Interstitial cystitis (IC) is a chronic inflammation disorder mainly within the submucosal and muscular layers of the bladder. As the cause of IC remains unknown, no effective treatments are currently available. Administration of stem cell provides a potential for treatment of IC. Methods This study was conducted using urine-derived stem cells (USCs) for protamine/lipopolysaccharide (PS/LPS)-induced interstitial cystitis in a rodent model. In total, 60 female Sprague–Dawley rats were randomized into three experimental groups (n = 5/group): sham controls; IC model alone; and IC animals intravenously treated with USCs (1.2 × 106 suspended in 0.2 ml phosphate-buffered saline (PBS). Results Our data showed that the bladder micturition function was significantly improved in IC animals intravenously treated with USCs compared to those in the IC model alone group. The amount of antioxidants and antiapoptotic protein biomarkers heme oxygenase (HO)-1, NAD(P)H quinine oxidoreductase (NQO)-1, and Bcl-2 within the bladder tissues were significantly higher in IC animals intravenously treated with USCs and lower in the sham controls group as assessed by Western blot and immunofluorescent staining. In addition, the expression of autophagy-related protein LC3A was significantly higher in the IC model alone group than that in IC animals intravenously treated with USCs. Inflammatory biomarkers and apoptotic biomarkers (interleukin (IL)-6, tumor necrosis factor (TNF)α, nuclear factor (NF)-κB, caspase 3, and Bax) and the downstream inflammatory and oxidative stress biomarkers (endoplasmic reticulum stress and autophagy-related protein (GRP78, LC3, Beclin1)) in the bladder tissue revealed statistically different results between groups. Conclusions USCs restored the bladder function and histological construction via suppressing oxidative stress, inflammatory reaction, and apoptotic processes in a PS/LPS-induced IC rodent model, which provides potential for treatment of patients with IC.
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Affiliation(s)
- Jia Li
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Hui Luo
- Department of Physical examination, Second Affiliated Hospital, Third Military University, Chongqing, 40037, China
| | - Xingyou Dong
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Qian Liu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Chao Wu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Teng Zhang
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Xiaoyan Hu
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yuanyuan Zhang
- Wake Forest Institute of Regenerative Medicine, Wake Forest University, Winston Salem, North Carolina, USA
| | - Bo Song
- Department of Urology, First Affiliated Hospital, Third Military University, Chongqing, 40037, China.
| | - Longkun Li
- Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, 400037, China.
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Laukoter S, Rauschka H, Tröscher AR, Köck U, Saji E, Jellinger K, Lassmann H, Bauer J. Differences in T cell cytotoxicity and cell death mechanisms between progressive multifocal leukoencephalopathy, herpes simplex virus encephalitis and cytomegalovirus encephalitis. Acta Neuropathol 2017; 133:613-627. [PMID: 27817117 PMCID: PMC5348553 DOI: 10.1007/s00401-016-1642-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2016] [Revised: 10/25/2016] [Accepted: 10/30/2016] [Indexed: 12/29/2022]
Abstract
During the appearance of human immunodeficiency virus infection in the 1980 and the 1990s, progressive multifocal leukoencephalopathy (PML), a viral encephalitis induced by the JC virus, was the leading opportunistic brain infection. As a result of the use of modern immunomodulatory compounds such as Natalizumab and Rituximab, the number of patients with PML is once again increasing. Despite the presence of PML over decades, little is known regarding the mechanisms leading to death of infected cells and the role the immune system plays in this process. Here we compared the presence of inflammatory T cells and the targeting of infected cells by cytotoxic T cells in PML, herpes simplex virus encephalitis (HSVE) and cytomegalovirus encephalitis (CMVE). In addition, we analyzed cell death mechanisms in infected cells in these encephalitides. Our results show that large numbers of inflammatory cytotoxic T cells are present in PML lesions. Whereas in HSVE and CMVE, single or multiple appositions of CD8+ or granzyme-B+ T cells to infected cells are found, in PML such appositions are significantly less apparent. Analysis of apoptotic pathways by markers such as activated caspase-3, caspase-6, poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) showed upregulation of caspase-3 and loss of caspase-6 from mitochondria in CMVE and HSVE infected cells. Infected oligodendrocytes in PML did not upregulate activated caspase-3 but instead showed translocation of PARP-1 from nucleus to cytoplasm and AIF from mitochondria to nucleus. These findings suggest that in HSVE and CMVE, cells die by caspase-mediated apoptosis induced by cytotoxic T cells. In PML, on the other hand, infected cells are not eliminated by the immune system but seem to die by virus-induced PARP and AIF translocation in a type of cell death defined as parthanatos.
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Increased ERp57 Expression in HBV-Related Hepatocellular Carcinoma: Possible Correlation and Prognosis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1252647. [PMID: 28373975 PMCID: PMC5360968 DOI: 10.1155/2017/1252647] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 12/20/2016] [Accepted: 02/13/2017] [Indexed: 02/05/2023]
Abstract
Aim. ERp57 is involved in virus induced endoplasmic reticulum stress (ERS) and plays an important role in tumorigenesis. This study aimed to find whether HBV infection altered ERp57 expression and whether ERp57 regulation was involved in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) genesis. Materials and Methods. HBV-HCC tissues, chronic hepatitis B (CHB) liver tissues, and normal liver tissues were acquired. ERp57 expressions in these tissues were detected through immunohistochemistry (IHC). And ERp57 expression in liver cell line L02, HBV replicative liver cell line L02-pHBV4.1, and HCC cell lines were detected through western blot for verification. Then medical data on patients providing HCC tissues were collected and analyzed along with ERp57 expression. Results. Higher ERp57 expression was found in HCC and CHB tissues (p < 0.001). And HCC cell lines and L02-pHBV4.1 presented higher ERp57 expression as well. In patients, ERp57 expression showed significant differences between death and survival groups (p = 0.037). And cumulative survival in patients with higher ERp57 (score ⩾ 8.75) is significantly lower (p = 0.009). Conclusion. Our study found increased expression of ERp57 in HBV-HCC. Such altered expression could be related to HBV infection and high ERp57 expression may lead to poor prognosis of HBV-HCC patients.
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Porcine Circovirus Type 2 Activates CaMMKβ to Initiate Autophagy in PK-15 Cells by Increasing Cytosolic Calcium. Viruses 2016; 8:v8050135. [PMID: 27213427 PMCID: PMC4885090 DOI: 10.3390/v8050135] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/12/2016] [Revised: 05/11/2016] [Accepted: 05/12/2016] [Indexed: 12/25/2022] Open
Abstract
Porcine circovirus type 2 (PCV2) induces autophagy via the 5′ adenosine monophosphate-activated protein kinase (AMPK)/extracellular signal-regulated kinase (ERK)/tuberous sclerosis complex 2 (TSC2)/mammalian target of rapamycin (mTOR) pathway in pig kidney PK-15 cells. However, the underlying mechanisms of AMPK activation in autophagy induction remain unknown. With specific inhibitors and RNA interference (RNAi), we show that PCV2 infection upregulated calcium/calmodulin-dependent protein kinase kinase-beta (CaMKKβ) by increasing cytosolic Ca2+ via inositol 1,4,5-trisphosphate receptor (IP3R). Elevation of cytosolic calcium ion (Ca2+) did not seem to involve inositol 1,4,5-trisphosphate (IP3) release from phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphoinositide phospholipase C-gamma (PLC-γ). CaMKKβ then activated both AMPK and calcium/calmodulin-dependent protein kinase I (CaMKI). PCV2 employed CaMKI and Trp-Asp (WD) repeat domain phosphoinositide-interacting protein 1 (WIPI1) as another pathway additional to AMPK signaling in autophagy initiation. Our findings could help better understanding of the signaling pathways of autophagy induction as part of PCV2 pathogenesis. Further research is warranted to study if PCV2 interacts directly with IP3R or indirectly with the molecules that antagonize IP3R activity responsible for increased cytosolic Ca2+ both in PK-15 cells and PCV2-targeted primary cells from pigs.
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Cervantes-Ortiz SL, Zamorano Cuervo N, Grandvaux N. Respiratory Syncytial Virus and Cellular Stress Responses: Impact on Replication and Physiopathology. Viruses 2016; 8:v8050124. [PMID: 27187445 PMCID: PMC4885079 DOI: 10.3390/v8050124] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/09/2016] [Revised: 04/14/2016] [Accepted: 04/21/2016] [Indexed: 02/08/2023] Open
Abstract
Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is a major cause of severe acute lower respiratory tract infection in infants, elderly and immunocompromised adults. Despite decades of research, a complete integrated picture of RSV-host interaction is still missing. Several cellular responses to stress are involved in the host-response to many virus infections. The endoplasmic reticulum stress induced by altered endoplasmic reticulum (ER) function leads to activation of the unfolded-protein response (UPR) to restore homeostasis. Formation of cytoplasmic stress granules containing translationally stalled mRNAs is a means to control protein translation. Production of reactive oxygen species is balanced by an antioxidant response to prevent oxidative stress and the resulting damages. In recent years, ongoing research has started to unveil specific regulatory interactions of RSV with these host cellular stress responses. Here, we discuss the latest findings regarding the mechanisms evolved by RSV to induce, subvert or manipulate the ER stress, the stress granule and oxidative stress responses. We summarize the evidence linking these stress responses with the regulation of RSV replication and the associated pathogenesis.
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Affiliation(s)
- Sandra L Cervantes-Ortiz
- CRCHUM-Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.
- Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
- Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3C 3J7, Canada.
| | - Natalia Zamorano Cuervo
- CRCHUM-Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.
- Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
| | - Nathalie Grandvaux
- CRCHUM-Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.
- Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
- Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
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Guerrero CA, Acosta O. Inflammatory and oxidative stress in rotavirus infection. World J Virol 2016; 5:38-62. [PMID: 27175349 PMCID: PMC4861870 DOI: 10.5501/wjv.v5.i2.38] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/12/2015] [Revised: 10/23/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.
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Bu X, Zhao Y, Zhang Z, Wang M, Li M, Yan Y. Recombinant Newcastle disease virus (rL-RVG) triggers autophagy and apoptosis in gastric carcinoma cells by inducing ER stress. Am J Cancer Res 2016; 6:924-936. [PMID: 27293989 PMCID: PMC4889710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/28/2016] [Accepted: 03/10/2016] [Indexed: 06/06/2023] Open
Abstract
We have reported that the recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) could induce autophagy and apoptosis in gastric carcinoma cells. In the present study, we explored the upstream regulators, endoplasmic reticulum (ER) stress that induce autophagy and apoptosis and the relationships among them. For this purpose, SGC-7901 and HGC cells were infected with rL-RVG. NDV LaSota strain and phosphate-buffered saline (PBS) were treated as the control groups. Western blotting and immunofluorescence microscopy were used to detect the expression of the ER stress-related proteins glucose-regulated protein 78 (GRP78) and the transcription factor GADD153 (CHOP), among others. The expression of beclin-1 and the conversion of light chain (LC) 3-I were used to determine the occurrence of autophagy, and flow cytometry (FCM) and western blotting were used to examine apoptosis-related protein expression. Transmission electron microscopy was also performed to monitor the ultrastructure of the cells. Moreover, small interfering (si) RNA was used to knock down CHOP expression. rL-RVG treatment increased the expression of ER stress-related proteins, such as GRP78, CHOP, activating transcriptional factor 6 (ATF6), X-box-binding protein 1 (XBP-1), and phosphorylated eukaryotic initiation factor 2 (p-eIF2α), in a time- and concentration-dependent manner, and knockdown of CHOP reduced LC3-II conversion and beclin-1 expression. When ER stress was inhibited with 4-PBA, the expression of both autophagy-related proteins and apoptosis-related proteins markedly decreased. Interestingly, inhibition of autophagy with 3-methyladenine (3MA) decreased not only apoptosis-related protein expression but also ER stress-related protein expression. Moreover, we found that downregulation of the c-Jun N-terminal kinase (JNK) pathway by SP600125 reduced LC3-II conversion, beclin-1 expression and caspase-3 activation. Collectively, the results suggest that rL-RVG increased ER stress in three branch pathways (ATF6, inositol-requiring enzyme 1 (IRE1), and PKR-like ER protein kinase (PERK)) that are upstream regulators of autophagy and apoptosis. Moreover, the IRE1-JNK pathway played an important role in switching ER stress to autophagy. These findings will provide molecular bases for developing rL-RVG into a drug candidate for the treatment of gastric carcinoma.
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Affiliation(s)
- Xuefeng Bu
- Department of General Surgery, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
| | - Yinghai Zhao
- Department of General Surgery, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, Jiangsu, China
- Clinical Medicine College of Jiangsu UniversityZhenjiang, China
| | - Zhijian Zhang
- Clinical Medicine College of Jiangsu UniversityZhenjiang, China
| | - Mubin Wang
- Clinical Medicine College of Jiangsu UniversityZhenjiang, China
| | - Mi Li
- Clinical Medicine College of Jiangsu UniversityZhenjiang, China
| | - Yulan Yan
- Department of Internal Medicine, Affiliated People’s Hospital of Jiangsu UniversityZhenjiang, China
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Weitnauer M, Mijošek V, Dalpke AH. Control of local immunity by airway epithelial cells. Mucosal Immunol 2016; 9:287-98. [PMID: 26627458 DOI: 10.1038/mi.2015.126] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/06/2015] [Accepted: 10/25/2015] [Indexed: 02/04/2023]
Abstract
The lung is ventilated by thousand liters of air per day. Inevitably, the respiratory system comes into contact with airborne microbial compounds, most of them harmless contaminants. Airway epithelial cells are known to have innate sensor functions, thus being able to detect microbial danger. To avoid chronic inflammation, the pulmonary system has developed specific means to control local immune responses. Even though airway epithelial cells can act as proinflammatory promoters, we propose that under homeostatic conditions airway epithelial cells are important modulators of immune responses in the lung. In this review, we discuss epithelial cell regulatory functions that control reactivity of professional immune cells within the microenvironment of the airways and how these mechanisms are altered in pulmonary diseases. Regulation by epithelial cells can be divided into two mechanisms: (1) mediators regulate epithelial cells' innate sensitivity in cis and (2) factors are produced that limit reactivity of immune cells in trans.
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Affiliation(s)
- M Weitnauer
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany
| | - V Mijošek
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany
| | - A H Dalpke
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany.,Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
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50
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Lv S, Sun EC, Xu QY, Zhang JK, Wu DL. Endoplasmic reticulum stress-mediated autophagy contributes to bluetongue virus infection via the PERK-eIF2α pathway. Biochem Biophys Res Commun 2015; 466:406-12. [PMID: 26363458 DOI: 10.1016/j.bbrc.2015.09.039] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/17/2015] [Accepted: 09/08/2015] [Indexed: 12/16/2022]
Abstract
Bluetongue virus (BTV) is an important pathogen of wild and domestic ruminants. We have previously reported that BTV1 infection induced autophagy for its own benefit, but how this occurs remains unclear. Here, the classical autophagy features including autophagsomes formation, GFP-LC3 dots and LC3-II conversation were shown in BTV1-infected cells, we also found the endoplasmic reticulum (ER) stress was triggered by BTV1 infection, which was demonstrated by the increased transcription level of the ER stress marker GRP78 and the expanded morphology of ER. During ER stress, PERK and eIF2α phosphorylation increased along with BTV1 infection, consistent with the elevated LC3 level, indicating that the PERK pathway of the unfolded protein response (UPR) was activated. In addition, both the blockage of PERK by GSK2656157 or knockdown of eIF2α by siRNA reduced the level of LC3, which suggested that the PERK-eIF2α pathway contributed to autophagy induced by BTV1. Furthermore, inactivation of PERK or silencing of eIF2α both significantly reduced the expression of VP2 protein and the viral yields in the supernatants. In sum, these data suggest that ER stress mediates autophagy via the PERK-eIF2α pathway and contributes to BTV1 replication, thus offering new insight into the molecular mechanisms of the BTV-host interaction.
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Affiliation(s)
- Shuang Lv
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China
| | - En-Cheng Sun
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China
| | - Qing-Yuan Xu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China
| | - Ji-Kai Zhang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China
| | - Dong-Lai Wu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001, China.
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