|
1
|
Srisantitham S, Walker AL, Markel U, Tezcan FA. De Novo Design of Proteins for Autocatalytic Isopeptide Bond Formation. J Am Chem Soc 2025; 147:12338-12346. [PMID: 40138671 DOI: 10.1021/jacs.5c03319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Isopeptide bonds (IPBs)─formed between the amine group of a Lys residue and the carboxamide/carboxy group of Asn/Gln or Asp/Glu─play essential roles in many biological processes, ranging from cellular signaling and regulation to blood clotting and bacterial pathogenesis. The formation of IPBs is not a spontaneous process and requires enzymatic machinery that provides a specialized active site environment to enable this challenging catalytic reaction. Here we report the de novo design and characterization of two proteins (dnIPB-1 and dnIPB-2) capable of autocatalytic IPB formation. While these designed proteins preserve the key active-site residues of their structural template (the bacterial pilin protein RrgA), they possess less than 31% sequence identity to RrgA. Extensive structural and Ala-scanning analyses indicate that IPB formation requires a solvent-protected core motif composed of several critical residues, yet there is also a large tolerance to different protein topologies and overall protein sizes in terms of accommodating an IPB-forming motif. Notably, the structural insights gained from the study of dnIPB-1 and dnIPB-2 also guided the redesign of an initially failed construct (dnIPB-3) and enabled it to form an IPB, highlighting the value of de novo design in examining sequence-structure-function relationships not explored in natural evolution. Our study highlights the versatility of IPBs as designable elements which can be used to construct functional proteins or protein-based materials with enhanced chemical, thermal, and mechanical stabilities.
Collapse
Affiliation(s)
- Suppachai Srisantitham
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
| | - Alyssa L Walker
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
| | - Ulrich Markel
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
| | - F Akif Tezcan
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States
| |
Collapse
|
|
2
|
Lim YJ, Lee YH. Solo or in Concert: SUMOylation in Pathogenic Fungi. THE PLANT PATHOLOGY JOURNAL 2025; 41:140-152. [PMID: 40211619 PMCID: PMC11986368 DOI: 10.5423/ppj.rw.11.2024.0180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 04/14/2025]
Abstract
SUMOylation plays a pivotal role in DNA replication and repair, transcriptional stability, and stress response. Although SUMOylation is a conserved posttranslational modification (PTM) in eukaryotes, the number, type, and function of SUMOylation-associated components vary among mammals, plants, and fungi. SUMOylation shares overlapping features with ubiquitination, another well-known PTM. However, comparative studies on the interplay between these two PTMs are largely limited to yeast among fungal species. Recently, the role of SUMOylation in pathogenicity and its potential for crosstalk with ubiquitination have gained attention in fungal pathogens. In this review, we summarize recent findings on the distinct components of SUMOylation across organisms and describe its critical functions in fungal pathogens. Furthermore, we propose new research directions for SUMOylation in fungal pathogens, both independently and in coordination with other PTMs. This review aims to illuminate the potential for advancing PTM crosstalk research in fungal systems.
Collapse
Affiliation(s)
- You-Jin Lim
- Research Institute of Agriculture and Life Sciences and Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
| | - Yong-Hwan Lee
- Research Institute of Agriculture and Life Sciences and Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
- Interdisciplinary Program in Agricultural Genomics, Center for Fungal Genetic Resources, Plant Immunity Research Center, and Center for Plant Microbiome Research, Seoul National University, Seoul 08826, Korea
| |
Collapse
|
|
3
|
Connolly JG, Plant LD. SUMO Regulation of Ion Channels in Health and Disease. Physiology (Bethesda) 2025; 40:0. [PMID: 39499247 DOI: 10.1152/physiol.00034.2024] [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] [Scholar Register] [Received: 07/15/2024] [Revised: 10/10/2024] [Accepted: 10/30/2024] [Indexed: 11/07/2024] Open
Abstract
The small ubiquitin-like modifier (SUMO) protein pathway governs a panoply of vital biological processes including cell death, proliferation, differentiation, metabolism, and signal transduction by diversifying the functions, half-lives, and partnerships of target proteins in situ. More recently, SUMOylation has emerged as a key regulator of ion homeostasis and excitability across multiple tissues due to the regulation of a plethora of ion channels expressed in a range of tissue subtypes. Altogether, the balance of SUMOylation states among relevant ion channels can result in graded biophysical effects that tune excitability and contribute to a range of disease states including cardiac arrhythmia, epilepsy, pain transmission, and inflammation. Here, we consolidate these concepts by focusing on the role of ion channel SUMOylation in the central nervous system, peripheral nervous system, and cardiovascular system. In addition, we review what is known about the enigmatic factors that regulate the SUMO pathway and consider the emerging role of small molecule SUMO modulators as potential therapeutics in a range of diseases.
Collapse
Affiliation(s)
- Jenna G Connolly
- Department of Pharmaceutical Sciences and the Center for Drug Discovery, The School of Pharmacy and Pharmaceutical SciencesBouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, United States
| | - Leigh D Plant
- Department of Pharmaceutical Sciences and the Center for Drug Discovery, The School of Pharmacy and Pharmaceutical SciencesBouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, United States
| |
Collapse
|
|
4
|
Zhu G, Tong N, Zhu Y, Wang L, Wang Q. The crosstalk between SUMOylation and immune system in host-pathogen interactions. Crit Rev Microbiol 2025; 51:164-186. [PMID: 38619159 DOI: 10.1080/1040841x.2024.2339259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/27/2024] [Accepted: 04/01/2024] [Indexed: 04/16/2024]
Abstract
Pathogens can not only cause infectious diseases, immune system diseases, and chronic diseases, but also serve as potential triggers or initiators for certain tumors. They directly or indirectly damage human health and are one of the leading causes of global deaths. Small ubiquitin-like modifier (SUMO) modification, a type of protein post-translational modification (PTM) that occurs when SUMO groups bond covalently to particular lysine residues on substrate proteins, plays a crucial role in both innate and adaptive immunologic responses, as well as pathogen-host immune system crosstalk. SUMOylation participates in the host's defense against pathogens by regulating immune responses, while numerically vast and taxonomically diverse pathogens have evolved to exploit the cellular SUMO modification system to break through innate defenses. Here, we describe the characteristics and multiple functions of SUMOylation as a pivotal PTM mechanism, the tactics employed by various pathogens to counteract the immune system through targeting host SUMOylation, and the character of the SUMOylation system in the fight between pathogens and the host immune system. We have also included a summary of the potential anti-pathogen SUMO enzyme inhibitors. This review serves as a reference for basic research and clinical practice in the diagnosis, prognosis, and treatment of pathogenic microorganism-caused disorders.
Collapse
Affiliation(s)
- Gangli Zhu
- Guangdong Province Solid Waste Recycling and Heavy Metal Pollution Control Engineering Technology Research Center, Guangdong Polytechnic of Environment Protection Engineering, Foshan, Guangdong, China
| | - Ni Tong
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China
| | - Yipeng Zhu
- Guagnzhou NO.6 Middle school, Guangzhou, Guangdong, China
| | - Lize Wang
- General Department, Institute of Software Chinese Academy of Sciences, Beijing, China
| | - Qirui Wang
- Department of Molecular Biology, State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
5
|
Guha S, Jagadeesan Y, Pandey MM, Mittal A, Chitkara D. Targeting the epigenome with advanced delivery strategies for epigenetic modulators. Bioeng Transl Med 2025; 10:e10710. [PMID: 39801754 PMCID: PMC11711227 DOI: 10.1002/btm2.10710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 01/16/2025] Open
Abstract
Epigenetics mechanisms play a significant role in human diseases by altering DNA methylation status, chromatin structure, and/or modifying histone proteins. By modulating the epigenetic status, the expression of genes can be regulated without any change in the DNA sequence itself. Epigenetic drugs exhibit promising therapeutic efficacy against several epigenetically originated diseases including several cancers, neurodegenerative diseases, metabolic disorders, cardiovascular disorders, and so forth. Currently, a considerable amount of research is focused on discovering new drug molecules to combat the existing research gap in epigenetic drug therapy. A novel and efficient delivery system can be established as a promising approach to overcome the drawbacks associated with the current epigenetic modulators. Therefore, formulating the existing epigenetic drugs with distinct encapsulation strategies in nanocarriers, including solid lipid nanoparticles, nanogels, bio-engineered nanocarriers, liposomes, surface modified nanoparticles, and polymer-drug conjugates have been examined for therapeutic efficacy. Nonetheless, several epigenetic modulators are untouched for their therapeutic potential through different delivery strategies. This review provides a comprehensive up to date discussion on the research findings of various epigenetics mechanism, epigenetic modulators, and delivery strategies utilized to improve their therapeutic outcome. Furthermore, this review also highlights the recently emerged CRISPR tool for epigenome editing.
Collapse
Affiliation(s)
- Sonia Guha
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Yogeswaran Jagadeesan
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Murali Monohar Pandey
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Anupama Mittal
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| | - Deepak Chitkara
- Department of PharmacyBirla Institute of Technology and Science Pilani (BITS Pilani)JhunjhunuRajasthanIndia
| |
Collapse
|
|
6
|
Ikeda Y, Yuki R, Saito Y, Nakayama Y. DeSUMOylating isopeptidase 1 participates in the faithful chromosome segregation and vincristine sensitivity. FASEB J 2024; 38:e70261. [PMID: 39698932 DOI: 10.1096/fj.202401560rr] [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] [Scholar Register] [Received: 07/08/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024]
Abstract
SUMOylation, the modification of proteins with a small ubiquitin-like modifier (SUMO), is known to regulate various cellular events, including cell division. This process is dynamic, with its status depending on the balance between SUMOylation and deSUMOylation. While the regulation of cell division by sentrin-specific protease (SENP) family proteins through deSUMOylation has been investigated, the role of another deSUMOylase, deSUMOylating isopeptidase 1 (DESI1), remains unknown. In this study, we explored DESI1's role in cell division. Knockdown of DESI1 accelerated cell division progression, leading to a significant increase in abnormal chromosome segregation. These phenotypes were rescued by re-expression of wild-type DESI1, but not catalytically inactive DESI1. DESI1 knockdown reduced the mitotic arrest caused by nocodazole, suggesting DESI1's involvement in the spindle assembly checkpoint (SAC). Localization of Aurora B, a key SAC regulator, at the metaphase chromosomes was reduced due to decreased Aurora B expression upon DESI1 knockdown. Consistently, DESI1 knockdown reduced transcription of FoxM1 target genes, such as Aurora B, cyclin B1, and CENP-F. The TCGA database showed that both decreased and increased DESI1 expression levels are associated with poor prognosis in patients with certain cancer types. Importantly, we found that DESI1 knockdown reduced sensitivity to vincristine by inducing mitotic slippage. These results suggest that DESI1 is required for faithful chromosome segregation via regulating FoxM1 transcriptional activity and thereby SAC activity in an isopeptidase activity-dependent manner. Our findings identified DESI1 as a novel regulator of cell division and a factor affecting cancer chemotherapy.
Collapse
Affiliation(s)
- Yuki Ikeda
- Laboratory of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Ryuzaburo Yuki
- Laboratory of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Youhei Saito
- Laboratory of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Yuji Nakayama
- Laboratory of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan
| |
Collapse
|
|
7
|
Shao Z, Liu S, Sun W, Zhuang X, Yin S, Cheng J, Xia X, Liao Y, Liu J, Huang H. SENP3 mediates deSUMOylation of SIX1 to promote prostate cancer proliferation and migration. Cell Mol Biol Lett 2024; 29:146. [PMID: 39623295 PMCID: PMC11613746 DOI: 10.1186/s11658-024-00665-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/08/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Sentrin/SUMO-specific protease 3 (SENP3) is essential to regulate protein stability and function in normal and cancer cells. Nevertheless, its role and action mechanisms in prostate cancer (PCa) remain elusive. Thus, clarification of SENP3's involvement and the SUMOylation process in PCa is pivotal for discovering potential targets and understanding SUMOylation dynamics. METHODS Cell viability, EdU staining, live cell imaging, and cell cycle assays were used to determine proliferation of PCa cells. Transwell and wound-healing assays were used to detect migration of PCa cells. The interaction between SENP3 and SIX1 was determined by co-immunoprecipitation, western blotting, and immunofluorescence assays. Xenograft models established on NOD-SCID mice were used to evaluate in vivo effects post SENP3 knockdown. Immunohistochemistry was performed to investigate the expression of SENP3 in PCa tissues. RESULTS This study found that SENP3 is highly expressed in PCa cell lines and tissues from PCa patients. Overexpressed SENP3 is associated with metastatic malignancy in PCa. Various in vivo and in vitro experiments confirmed that SENP3 promotes the proliferation and migration of PCa. In addition, SENP3 interacts with the SD domain of SIX1 and mediates its deSUMOylation and protein stability. Lys154 (K154) is required for the SUMOylation of SIX1. More importantly, SENP3 promotes the malignancy of PCa through the regulation of SIX1. CONCLUSIONS We unravel the significant role of SENP3 in regulating protein stability of SIX1 and progression of PCa, which may deepen our understanding of the SUMOylation modification and provide a promising target for management of metastatic PCa.
Collapse
Affiliation(s)
- Zhenlong Shao
- Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Shutong Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Wenshuang Sun
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Xuefen Zhuang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Shusha Yin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Ji Cheng
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Xiaohong Xia
- Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China
| | - Yuning Liao
- Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
| | - Jinbao Liu
- Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
| | - Hongbiao Huang
- Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
| |
Collapse
|
|
8
|
Claessens LA, Vertegaal ACO. SUMO proteases: from cellular functions to disease. Trends Cell Biol 2024; 34:901-912. [PMID: 38326147 DOI: 10.1016/j.tcb.2024.01.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/04/2024] [Accepted: 01/09/2024] [Indexed: 02/09/2024]
Abstract
Posttranslational modification by small ubiquitin-like modifiers (SUMOs) is critical in regulating diverse cellular processes including gene expression, cell cycle progression, genome integrity, cellular metabolism, and inflammation and immunity. The covalent attachment of SUMOs to target proteins is highly dynamic and reversible through the concerted action of SUMO conjugating and deconjugating enzymes. In mammalian cells, sentrin-specific proteases (SENPs) are the most abundant family of deconjugating enzymes. This review highlights recent advances in our knowledge of the substrates and cellular and physiological processes controlled by SENPs. Notably, SENPs are emerging as significant players in cancer, as well as in other diseases, making them attractive targets for therapeutic intervention. Consequently, a growing amount of effort in the field is being directed towards the development of SENP inhibitors.
Collapse
Affiliation(s)
- Laura A Claessens
- Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Alfred C O Vertegaal
- Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands.
| |
Collapse
|
|
9
|
Jiaerken B, Liu W, Zheng J, Qu W, Wu Q, Ai Z. The SUMO Family: Mechanisms and Implications in Thyroid Cancer Pathogenesis and Therapy. Biomedicines 2024; 12:2408. [PMID: 39457720 PMCID: PMC11505470 DOI: 10.3390/biomedicines12102408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/12/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Background: Small ubiquitin-like modifiers (SUMOs) are pivotal in post-translational modifications, influencing various cellular processes, such as protein localization, stability, and genome integrity. (2) Methods: This review explores the SUMO family, including its isoforms and catalytic cycle, highlighting their significance in regulating key biological functions in thyroid cancer. We discuss the multifaceted roles of SUMOylation in DNA repair mechanisms, protein stability, and the modulation of receptor activities, particularly in the context of thyroid cancer. (3) Results: The aberrant SUMOylation machinery contributes to tumorigenesis through altered gene expression and immune evasion mechanisms. Furthermore, we examine the therapeutic potential of targeting SUMOylation pathways in thyroid cancer treatment, emphasizing the need for further research to develop effective SUMOylation inhibitors. (4) Conclusions: By understanding the intricate roles of SUMOylation in cancer biology, we can pave the way for innovative therapeutic strategies to improve outcomes for patients with advanced tumors.
Collapse
Affiliation(s)
- Bahejuan Jiaerken
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
- School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Wei Liu
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jiaojiao Zheng
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Weifeng Qu
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qiao Wu
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhilong Ai
- Department of Surgery (Thyroid & Breast), Zhongshan Hospital, Fudan University, Shanghai 200032, China
| |
Collapse
|
|
10
|
Wang J, Zhang R, Wu C, Wang L, Liu P, Li P. Exploring potential targets for natural product therapy of DN: the role of SUMOylation. Front Pharmacol 2024; 15:1432724. [PMID: 39431155 PMCID: PMC11486755 DOI: 10.3389/fphar.2024.1432724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 09/20/2024] [Indexed: 10/22/2024] Open
Abstract
Diabetic nephropathy (DN) is a common and serious micro-vascular complication of diabetes and a leading cause of end-stage renal disease globally. This disease primarily affects middle-aged and elderly individuals, especially those with a diabetes history of over 10 years and poor long-term blood glucose control. Small ubiquitin-related modifiers (SUMOs) are a group of reversible post-translational modifications of proteins that are widely expressed in eukaryotes. SUMO proteins intervene in the progression of DN by modulating various signaling cascades, such as Nrf2-mediated oxidative stress, NF-κB, TGF-β, and MAPK pathways. Recent advancements indicate that natural products regulating SUMOylation hold promise as targets for intervening in DN. In a previous article published in 2022, we reviewed the mechanisms by which SUMOylation intervenes in renal fibrosis and presented a summary of some natural products with therapeutic potential. Therefore, this paper will focus on DN. The aim of this review is to elucidate the mechanism of action of SUMOylation in DN and related natural products with therapeutic potential, thereby summarising the targets and candidate natural products for the treatment of DN through the modulation of SUMOylation, such as ginkgolic acid, ginkgolide B, resveratrol, astragaloside IV, etc., and highlighting that natural product-mediated modulation of SUMOylation is a potential therapeutic strategy for the treatment of DN as a potential therapeutic strategy.
Collapse
Affiliation(s)
- Jingjing Wang
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Rui Zhang
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Chenguang Wu
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Lifan Wang
- Renal Division, Heilongjiang Academy of Chinese Medicine Sciences, Harbin, China
| | - Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Ping Li
- China-Japan Friendship Hospital, Beijing, China
| |
Collapse
|
|
11
|
Cheng Y, Hou W, Fang H, Yan Y, Lu Y, Meng T, Ma C, Liu Q, Zhou Z, Li H, Li H, Xiao N. SENP2-NDR2-p21 axis modulates lung cancer cell growth. Eur J Pharmacol 2024; 978:176761. [PMID: 38908669 DOI: 10.1016/j.ejphar.2024.176761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/04/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Sentrin/small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) perform pivotal roles in SUMO maturation and recycling, which modulate the balance of SUMOylation/de-SUMOylation and spatiotemporal functions of SUMOylation targets. The malfunction of SENPs often results in cellular dysfunction and various diseases. However, studies rarely investigated the correlation between SENP2 and lung cancer. This study revealed that SENP2 is a required contributor to lung cancer-cell growth and targets nuclear Dbf2-related 2 (NDR2, also known as serine/threonine kinase 38L or STK38L) for de-SUMOylation, which improves NDR2 kinase activity. This condition leads to the instability of downstream target p21 in accelerating the G1/S cell cycle transition and suggests SENP2 as a promising therapeutic target for lung cancer in the future. Specifically, astragaloside IV, an active ingredient of Jinfukang Oral Liquid (JOL, a clinical combination antilung cancer drug approved by the National Food and Drug Administration (FDA) of China), can repress lung cancer-cell growth via the SENP2-NDR2-p21 axis, which provides new insights into the molecular mechanism of JOL for lung cancer treatment.
Collapse
Affiliation(s)
- Yixuan Cheng
- Institute of Traditional Chinese Medicine Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Longhua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wanxin Hou
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Houshun Fang
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yinjie Yan
- Department of Medical Affairs, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Lu
- Longhua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tian Meng
- Department of Breast Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chunshuang Ma
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qinghai Liu
- Department of Performance Management, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhiyi Zhou
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Oncology, Tianshan Hospital of Traditional Chinese Medicine in Changning District, Shanghai, China
| | - Hui Li
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fujian, China.
| | - Hegen Li
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Ning Xiao
- Institute of Traditional Chinese Medicine Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| |
Collapse
|
|
12
|
Bhachoo JS, Garvin AJ. SUMO and the DNA damage response. Biochem Soc Trans 2024; 52:773-792. [PMID: 38629643 PMCID: PMC11088926 DOI: 10.1042/bst20230862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/25/2024]
Abstract
The preservation of genome integrity requires specialised DNA damage repair (DDR) signalling pathways to respond to each type of DNA damage. A key feature of DDR is the integration of numerous post-translational modification signals with DNA repair factors. These modifications influence DDR factor recruitment to damaged DNA, activity, protein-protein interactions, and ultimately eviction to enable access for subsequent repair factors or termination of DDR signalling. SUMO1-3 (small ubiquitin-like modifier 1-3) conjugation has gained much recent attention. The SUMO-modified proteome is enriched with DNA repair factors. Here we provide a snapshot of our current understanding of how SUMO signalling impacts the major DNA repair pathways in mammalian cells. We highlight repeating themes of SUMO signalling used throughout DNA repair pathways including the assembly of protein complexes, competition with ubiquitin to promote DDR factor stability and ubiquitin-dependent degradation or extraction of SUMOylated DDR factors. As SUMO 'addiction' in cancer cells is protective to genomic integrity, targeting components of the SUMO machinery to potentiate DNA damaging therapy or exacerbate existing DNA repair defects is a promising area of study.
Collapse
Affiliation(s)
- Jai S. Bhachoo
- SUMO Biology Lab, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT, U.K
| | - Alexander J. Garvin
- SUMO Biology Lab, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire LS2 9JT, U.K
| |
Collapse
|
|
13
|
Campos Alonso M, Knobeloch KP. In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases. Front Mol Biosci 2024; 11:1349509. [PMID: 38455765 PMCID: PMC10919355 DOI: 10.3389/fmolb.2024.1349509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of the organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given their potential as novel therapeutic targets, it is essential to fully understand their mechanisms of action. Traditionally, observed effects resulting from deficiencies in deubiquitinases (DUBs) and UBL proteases have often been attributed to the misregulation of substrate modification by ubiquitin or UBLs. Therefore, much research has focused on understanding the catalytic activities of these proteins. However, this view has overlooked the possibility that DUBs and UBL proteases might also have significant non-catalytic functions, which are more prevalent than previously believed and urgently require further investigation. Moreover, multiple examples have shown that either selective loss of only the protease activity or complete absence of these proteins can have different functional and physiological consequences. Furthermore, DUBs and UBL proteases have been shown to often contain domains or binding motifs that not only modulate their catalytic activity but can also mediate entirely different functions. This review aims to shed light on the non-catalytic, moonlighting functions of DUBs and UBL proteases, which extend beyond the hydrolysis of ubiquitin and UBL chains and are just beginning to emerge.
Collapse
Affiliation(s)
- Marta Campos Alonso
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Klaus-Peter Knobeloch
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- CIBSS—Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
14
|
Wang W, Matunis MJ. Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases. Cells 2023; 13:8. [PMID: 38201212 PMCID: PMC10778024 DOI: 10.3390/cells13010008] [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] [Scholar Register] [Received: 11/16/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Small ubiquitin-related modifiers (SUMOs) function as post-translational protein modifications and regulate nearly every aspect of cellular function. While a single ubiquitin protein is expressed across eukaryotic organisms, multiple SUMO paralogues with distinct biomolecular properties have been identified in plants and vertebrates. Five SUMO paralogues have been characterized in humans, with SUMO1, SUMO2 and SUMO3 being the best studied. SUMO2 and SUMO3 share 97% protein sequence homology (and are thus referred to as SUMO2/3) but only 47% homology with SUMO1. To date, thousands of putative sumoylation substrates have been identified thanks to advanced proteomic techniques, but the identification of SUMO1- and SUMO2/3-specific modifications and their unique functions in physiology and pathology are not well understood. The SUMO2/3 paralogues play an important role in proteostasis, converging with ubiquitylation to mediate protein degradation. This function is achieved primarily through SUMO-targeted ubiquitin ligases (STUbLs), which preferentially bind and ubiquitylate poly-SUMO2/3 modified proteins. Effects of the SUMO1 paralogue on protein solubility and aggregation independent of STUbLs and proteasomal degradation have also been reported. Consistent with these functions, sumoylation is implicated in multiple human diseases associated with disturbed proteostasis, and a broad range of pathogenic proteins have been identified as SUMO1 and SUMO2/3 substrates. A better understanding of paralogue-specific functions of SUMO1 and SUMO2/3 in cellular protein quality control may therefore provide novel insights into disease pathogenesis and therapeutic innovation. This review summarizes current understandings of the roles of sumoylation in protein quality control and associated diseases, with a focus on the specific effects of SUMO1 and SUMO2/3 paralogues.
Collapse
Affiliation(s)
| | - Michael J. Matunis
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA;
| |
Collapse
|
|
15
|
Malkov MI, Flood D, Taylor CT. SUMOylation indirectly suppresses activity of the HIF-1α pathway in intestinal epithelial cells. J Biol Chem 2023; 299:105280. [PMID: 37742924 PMCID: PMC10616383 DOI: 10.1016/j.jbc.2023.105280] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/15/2023] [Accepted: 09/17/2023] [Indexed: 09/26/2023] Open
Abstract
The hypoxia-inducible factor (HIF) is a master regulator of the cellular transcriptional response to hypoxia. While the oxygen-sensitive regulation of HIF-1α subunit stability via the ubiquitin-proteasome pathway has been well described, less is known about how other oxygen-independent post-translational modifications impact the HIF pathway. SUMOylation, the attachment of SUMO (small ubiquitin-like modifier) proteins to a target protein, regulates the HIF pathway, although the impact of SUMO on HIF activity remains controversial. Here, we examined the effects of SUMOylation on the expression pattern of HIF-1α in response to pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) in intestinal epithelial cells. We evaluated the effects of SUMO-1, SUMO-2, and SUMO-3 overexpression and inhibition of SUMOylation using a novel selective inhibitor of the SUMO pathway, TAK-981, on the sensitivity of HIF-1α in Caco-2 intestinal epithelial cells. Our findings demonstrate that treatment with TAK-981 decreases global SUMO-1 and SUMO-2/3 modification and enhances HIF-1α protein levels, whereas SUMO-1 and SUMO-2/3 overexpression results in decreased HIF-1α protein levels in response to DMOG. Reporter assay analysis demonstrates reduced HIF-1α transcriptional activity in cells overexpressing SUMO-1 and SUMO-2/3, whereas pretreatment with TAK-981 increased HIF-1α transcriptional activity in response to DMOG. In addition, HIF-1α nuclear accumulation was decreased in cells overexpressing SUMO-1. Importantly, we showed that HIF-1α is not directly SUMOylated, but that SUMOylation affects HIF-1α stability and activity indirectly. Taken together, our results indicate that SUMOylation indirectly suppresses HIF-1α protein stability, transcriptional activity, and nuclear accumulation in intestinal epithelial cells.
Collapse
Affiliation(s)
- Mykyta I Malkov
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Belfield, Ireland
| | - Darragh Flood
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Belfield, Ireland
| | - Cormac T Taylor
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Belfield, Ireland.
| |
Collapse
|
|
16
|
Wu W, Huang C. SUMOylation and DeSUMOylation: Prospective therapeutic targets in cancer. Life Sci 2023; 332:122085. [PMID: 37722589 DOI: 10.1016/j.lfs.2023.122085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/05/2023] [Accepted: 09/12/2023] [Indexed: 09/20/2023]
Abstract
The SUMO family is a type of ubiquitin-like protein modification molecule. Its protein modification mechanism is similar to that of ubiquitination: both involve modifier-activating enzyme E1, conjugating enzyme E2 and substrate-specific ligase E3. However, polyubiquitination can lead to the degradation of substrate proteins, while poly-SUMOylation only leads to the degradation of substrate proteins through the proteasome pathway after being recognized by ubiquitin as a signal factor. There are currently five reported subtypes in the SUMO family, namely SUMO1-5. As a reversible dynamic modification, intracellular sentrin/SUMO-specific proteases (SENPs) mainly regulate the reverse reaction pathway of SUMOylation. The SUMOylation modification system affects the localization, activation and turnover of proteins in cells and participates in regulating most nuclear and extranuclear molecular reactions. Abnormal expression of proteins related to the SUMOylation pathway is commonly observed in tumors, indicating that this pathway is closely related to tumor occurrence, metastasis and invasion. This review mainly discusses the composition of members in the protein family related to SUMOylation pathways, mutual connections between SUMOylation and other post-translational modifications on proteins as well as therapeutic drugs developed based on these pathways.
Collapse
Affiliation(s)
- Wenyan Wu
- Kunming University of Science and Technology, Medical School, Kunming 650500, China
| | - Chao Huang
- Kunming University of Science and Technology, Medical School, Kunming 650500, China.
| |
Collapse
|
|
17
|
Ma X, Zhao C, Xu Y, Zhang H. Roles of host SUMOylation in bacterial pathogenesis. Infect Immun 2023; 91:e0028323. [PMID: 37725062 PMCID: PMC10580907 DOI: 10.1128/iai.00283-23] [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] [Scholar Register] [Indexed: 09/21/2023] Open
Abstract
Bacteria frequently interfere with the post-translational modifications of host cells to facilitate their survival and growth after invasion. SUMOylation, a reversible post-translational modification process, plays an important role in biological life activities. In addition to being critical to host cell metabolism and survival, SUMOylation also regulates gene expression and cell signal transmission. Moreover, SUMOylation in eukaryotic cells can be used by a variety of bacterial pathogens to advance bacterial invasion. In this minireview, we focused on the role and mechanism of host SUMOylation in the pathogenesis of six important clinical bacterial pathogens (Listeria monocytogenes, Shigella flexneri, Salmonella Typhimurium, Klebsiella pneumoniae, Staphylococcus aureus, and Escherichia coli). Taken together, this review provided new insights for understanding the unique pathogen-host interaction based on host SUMOylation and provided a novel perspective on the development of new strategies to combat bacterial infections in the future.
Collapse
Affiliation(s)
- Xin Ma
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Chenhao Zhao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yuyao Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Department of Clinical Laboratory, Zhangjiagang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, China
| | - Haifang Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| |
Collapse
|
|
18
|
Cheng X, Yang W, Lin W, Mei F. Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates? Pharmacol Rev 2023; 75:979-1006. [PMID: 37137717 PMCID: PMC10441629 DOI: 10.1124/pharmrev.122.000784] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/20/2023] [Accepted: 04/27/2023] [Indexed: 05/05/2023] Open
Abstract
Protein SUMOylation is a major post-translational modification essential for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all small ubiquitin-like modifiers (SUMOs) are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an enigma. Here we review recent progress toward understanding the mechanisms of SUMO regulation, particularly the potential roles of liquid-liquid phase separation/biomolecular condensates in regulating cellular SUMOylation during cellular stresses. In addition, we discuss the role of protein SUMOylation in pathogenesis and the development of novel therapeutics targeting SUMOylation. SIGNIFICANCE STATEMENT: Protein SUMOylation is one of the most prevalent post-translational modifications and plays a vital role in maintaining cellular homeostasis in response to stresses. Protein SUMOylation has been implicated in human pathogenesis, such as cancer, cardiovascular diseases, neurodegeneration, and infection. After more than a quarter century of extensive research, intriguing enigmas remain regarding the mechanism of cellular SUMOylation regulation and the therapeutic potential of targeting SUMOylation.
Collapse
Affiliation(s)
- Xiaodong Cheng
- Department of Integrative Biology & Pharmacology and Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Wenli Yang
- Department of Integrative Biology & Pharmacology and Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Wei Lin
- Department of Integrative Biology & Pharmacology and Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Fang Mei
- Department of Integrative Biology & Pharmacology and Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| |
Collapse
|
|
19
|
Liczmanska M, Tatham MH, Mojsa B, Eugui-Anta A, Rojas-Fernandez A, Ibrahim AFM, Hay RT. SUMO protease SENP6 protects the nucleus from hyperSUMOylation-induced laminopathy-like alterations. Cell Rep 2023; 42:112960. [PMID: 37556322 DOI: 10.1016/j.celrep.2023.112960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 05/22/2023] [Accepted: 07/24/2023] [Indexed: 08/11/2023] Open
Abstract
The small ubiquitin-like modifier (SUMO) protease SENP6 disassembles SUMO chains from cellular substrate proteins. We use a proteomic method to identify putative SENP6 substrates based on increased apparent molecular weight after SENP6 depletion. Proteins of the lamin family of intermediate filaments show substantially increased SUMO modification after SENP6 depletion. This is accompanied by nuclear structural changes remarkably like those associated with laminopathies. Two SUMO attachment sites on lamin A/C are close to sites of mutations in Emery-Driefuss and limb girdle muscular dystrophy. To establish a direct link between lamin SUMOylation and the observed phenotype, we developed proximity-induced SUMO modification (PISM), which fuses a lamin A/C targeting DARPin to a SUMO E3 ligase domain. This directly targets lamin A/C for SUMO conjugation and demonstrates that enhanced lamin SUMO modification recapitulates the altered nuclear structure manifest after SENP6 depletion. This shows SENP6 activity protects the nucleus against hyperSUMOylation-induced laminopathy-like alterations.
Collapse
Affiliation(s)
- Magda Liczmanska
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Michael H Tatham
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Barbara Mojsa
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Ania Eugui-Anta
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Alejandro Rojas-Fernandez
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Adel F M Ibrahim
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
| | - Ronald T Hay
- Division of Molecular, Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
| |
Collapse
|
|
20
|
Hu J, Li P, Han H, Ji P, Zhao X, Li Z. Integrated analysis of metabolomic and transcriptomic profiling reveals the effect of Buyang Huanwu decoction on Parkinson's disease in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154755. [PMID: 36948142 DOI: 10.1016/j.phymed.2023.154755] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 02/28/2023] [Accepted: 03/08/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Parkinson's disease (PD) is a common, complex, and chronic neurodegenerative disorder involved in multi-system. At present, medicine for PD has many limitations. Buyang Huanwu decoction (BHD), a famous traditional Chinese medicinal (TCM) formulae, is used in the treatment of PD clinically in China. However, the therapeutic mechanism is still unknown. PURPOSE We aimed to explore the pharmacological mechanism of BHD alleviating PD through an integrated liver metabolome and brain transcriptome analysis. METHODS The mice with PD were induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral tests and immunohistochemistry were used to evaluate the neuroprotective effects of BHD. The non-targeted metabolomics analysis was conducted to profile differentially accumulated metabolites (DAMs) in the liver using a UHPLC-Q-Exactive MS/MS method. The differentially expressed genes (DEGs) in the brain were investigated by transcriptomic analysis on an Illumina sequencing platform. The correlations of DAMs and DEGs were investigated using an integrated metabolomic and transcriptomic approach. RESULTS The results of behavioral tests and immunohistochemistry proved the alleviated effects of BHD on PD symptoms. A total of 14 and 36 DAMs were detected in the groups treated with low- (L group) and high-dose (H group) BHD respectively under the positive ion mode. Compared with the PD model group (M group), three enriched pathways including metabolic pathways, ABC transporters, and biosynthesis of amino acids were common in the L and H group. Transcriptomic analysis proved that BHD could regulate the expression of numerous genes, some of which were targeted by Ben-Ldopa such as Creb5, Gm45623, Ccer2, Cd180, Fosl2, Crip3, and Noxred1. Based on the integrated metabolomic and transcriptomic analysis, 7 metabolite-gene pairs were found in four comparisons, including C vs M, M vs P, M vs L, and M vs H, and 6 enriched pathways containing purine metabolism, glycine/serine/threonine metabolism, phenylalanine metabolism, carbon fixation in photosynthetic organisms, thiamine metabolism, and ABC transporters were overlapped. CONCLUSIONS Though the underlying pharmacological mechanism of BHD is still lacking, we provided evidence that BHD could improve dopaminergic neurons in MPTP-induced PD mice by regulating liver metabolism and brain transcriptome. The correlation between the liver and the brain was preliminarily revealed in this study.
Collapse
Affiliation(s)
- Jianran Hu
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China; Department of Biological Science and Technology, Jinzhong University, Jinzhong 030619, China
| | - Ping Li
- Department of Biological Science and Technology, Jinzhong University, Jinzhong 030619, China
| | - Hongyan Han
- Department of Biological Science and Technology, Jinzhong University, Jinzhong 030619, China
| | - Pengyu Ji
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China; Department of Biological Science and Technology, Jinzhong University, Jinzhong 030619, China
| | - Xin Zhao
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030001, China
| | - Zhuoyu Li
- Institute of Biotechnology, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China.
| |
Collapse
|
|
21
|
Ozhelvaci F, Steczkiewicz K. Identification and Classification of Papain-like Cysteine Proteinases. J Biol Chem 2023:104801. [PMID: 37164157 DOI: 10.1016/j.jbc.2023.104801] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/11/2023] [Accepted: 05/05/2023] [Indexed: 05/12/2023] Open
Abstract
Papain-like cysteine peptidases form a big and highly diverse superfamily of proteins involved in many important biological functions, such as protein turnover, deubiquitination, tissue remodeling, blood clotting, virulence, defense, and cell wall remodeling. High sequence and structure diversity observed within these proteins hinders their comprehensive classification as well as the identification of new representatives. Moreover, in general protein databases, many families already classified as papain-like lack details regarding their mechanism of action or biological function. Here, we use transitive remote homology searches and 3D modeling to newly classify 21 families to the papain-like cysteine peptidase superfamily. We attempt to predict their biological function, and provide structural chacterization of 89 protein clusters defined based on sequence similarity altogether spanning 106 papain-like families. Moreover, we systematically discuss observed diversity in sequences, structures, and catalytic sites. Eventually, we expand the list of human papain-related proteins by seven representatives, including dopamine receptor-interacting protein (DRIP1) as potential deubiquitinase, and centriole duplication regulating CEP76 as retaining catalytically active peptidase-like domain. The presented results not only provide structure-based rationales to already existing peptidase databases but also may inspire further experimental research focused on peptidase-related biological processes.
Collapse
Affiliation(s)
- Fatih Ozhelvaci
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Kamil Steczkiewicz
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| |
Collapse
|
|
22
|
Aguilar-Venegas M, Quintana-Rodríguez E, Aguilar-Hernández V, López-García CM, Conejo-Dávila E, Brito-Argáez L, Loyola-Vargas VM, Vega-Arreguín J, Orona-Tamayo D. Protein Profiling of Psittacanthus calyculatus during Mesquite Infection. PLANTS (BASEL, SWITZERLAND) 2023; 12:464. [PMID: 36771550 PMCID: PMC9920738 DOI: 10.3390/plants12030464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 06/18/2023]
Abstract
Psittacanthus calyculatus is a hemiparasite mistletoe that represents an ecological problem due to the impacts caused to various tree species of ecological and commercial interest. Although the life cycle for the Psittacanthus genus is well established in the literature, the development stages and molecular mechanism implicated in P. calyculatus host infection are poorly understood. In this study, we used a manageable infestation of P. laevigata with P. calyculatus to clearly trace the infection, which allowed us to describe five phenological infective stages of mistletoe on host tree branches: mature seed (T1), holdfast formation (T2), haustorium activation (T3), haustorium penetration (T4), and haustorium connection (T5) with the host tree. Proteomic analyses revealed proteins with a different accumulation and cellular processes in infective stages. Activities of the cell wall-degrading enzymes cellulase and β-1,4-glucosidase were primarily active in haustorium development (T3), while xylanase, endo-glucanase, and peptidase were highly active in the haustorium penetration (T4) and xylem connection (T5). Patterns of auxins and cytokinin showed spatial concentrations in infective stages and moreover were involved in haustorium development. These results are the first evidence of proteins, cell wall-degrading enzymes, and phytohormones that are involved in early infection for the Psittacanthus genus, and thus represent a general infection mechanism for other mistletoe species. These results could help to understand the molecular dialogue in the establishment of P. calyculatus parasitism.
Collapse
Affiliation(s)
- Montserrat Aguilar-Venegas
- Ciencias Agrogenómicas, Escuela Nacional de Estudios Superiores, Unidad León, UNAM, León CP 37684, Guanajuato, Mexico
| | | | - Víctor Aguilar-Hernández
- Unidad de Bioquímica y Biología Molecular de Plantas, CICY, A.C., Mérida CP 97205, Yucatán, Mexico
| | | | - Efraín Conejo-Dávila
- Unidad Profesional Interdisciplinaria de Ingeniería Campus Guanajuato, Instituto Politécnico Nacional, Silao de la Victoria CP 36275, Guanajuato, Mexico
| | - Ligia Brito-Argáez
- Unidad de Bioquímica y Biología Molecular de Plantas, CICY, A.C., Mérida CP 97205, Yucatán, Mexico
| | - Víctor M. Loyola-Vargas
- Unidad de Bioquímica y Biología Molecular de Plantas, CICY, A.C., Mérida CP 97205, Yucatán, Mexico
| | - Julio Vega-Arreguín
- Ciencias Agrogenómicas, Escuela Nacional de Estudios Superiores, Unidad León, UNAM, León CP 37684, Guanajuato, Mexico
| | | |
Collapse
|
|
23
|
Li Y, De Bolòs A, Amador V, Reverter D. Structural Basis for the SUMO2 Isoform Specificity of SENP7. J Mol Biol 2022; 434:167875. [PMID: 36334780 DOI: 10.1016/j.jmb.2022.167875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 10/25/2022] [Accepted: 10/29/2022] [Indexed: 11/07/2022]
Abstract
SUMO proteases or deSUMOylases regulate the lifetime of SUMO-conjugated targets in the cell by cleaving off the isopetidic bond between the substrate and the SUMO modifier, thus reversing the conjugation activity of the SUMO E3 ligases. In humans the deSUMOylating activity is mainly conducted by the SENP/ULP protease family, which is constituted of six members sharing a homologous catalytic globular domain. SENP6 and SENP7 are the most divergent members of the family and they show a unique SUMO2/3 isoform preference and a particular activity for dismantling polySUMO2 chains. Here, we present the crystal structure of the catalytic domain of human SENP7 bound to SUMO2, revealing structural key elements for the SUMO2 isoform specificity of SENP7. In particular, we describe the specific contacts between SUMO2 and a unique insertion in SENP7 (named Loop1) that is responsible for the SUMO2 isoform specificity. All the other interface contacts between SENP7 and SUMO2, including the SUMO2 C-terminal tail interaction, are conserved among members of the SENP/ULP family. Our data give insight into an evolutionary adaptation to restrict the deSUMOylating activity in SENP6 and SENP7 for the SUMO2/3 isoforms.
Collapse
Affiliation(s)
- Ying Li
- Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Anna De Bolòs
- Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS), Barcelona 08036, Spain
| | - Virginia Amador
- Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS), Barcelona 08036, Spain
| | - David Reverter
- Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
| |
Collapse
|
|
24
|
Garvin AJ, Lanz AJ, Morris JR. SUMO monoclonal antibodies vary in sensitivity, specificity, and ability to detect types of SUMO conjugate. Sci Rep 2022; 12:21343. [PMID: 36494414 PMCID: PMC9734647 DOI: 10.1038/s41598-022-25665-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022] Open
Abstract
Monoclonal antibodies (MAb) to members of the Small Ubiquitin-like modifier (SUMO) family are essential tools in the study of cellular SUMOylation. However, many anti-SUMO MAbs are poorly validated, and antibody matching to detection format is without an evidence base. Here we test the specificity and sensitivity of twenty-four anti-SUMO MAbs towards monomeric and polymeric SUMO1-4 in dot-blots, immunoblots, immunofluorescence and immunoprecipitation. We find substantial variability between SUMO MAbs for different conjugation states, for detecting increased SUMOylation in response to thirteen different stress agents, and as enrichment reagents for SUMOylated RanGAP1 or KAP1. All four anti-SUMO4 monoclonal antibodies tested cross-reacted wit SUMO2/3, and several SUMO2/3 monoclonal antibodies cross-reacted with SUMO4. These data characterize the specificity of twenty-four anti-SUMO antibodies across commonly used assays, creating an enabling resource for the SUMO research community.
Collapse
Affiliation(s)
- Alexander J Garvin
- Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences, College of Medical and Dental Schools, University of Birmingham, Birmingham, B15 2TT, UK.
| | - Alexander J Lanz
- Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences, College of Medical and Dental Schools, University of Birmingham, Birmingham, B15 2TT, UK
| | - Joanna R Morris
- Birmingham Centre for Genome Biology and Institute of Cancer and Genomic Sciences, College of Medical and Dental Schools, University of Birmingham, Birmingham, B15 2TT, UK.
| |
Collapse
|
|
25
|
García-Gutiérrez P, García-Domínguez M. SUMO control of nervous system development. Semin Cell Dev Biol 2022; 132:203-212. [PMID: 34848148 DOI: 10.1016/j.semcdb.2021.11.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022]
Abstract
In the last decades, the post-translational modification system by covalent attachment of the SUMO polypeptide to proteins has emerged as an essential mechanism controlling virtually all the physiological processes in the eukaryotic cell. This includes vertebrate development. In the nervous system, SUMO plays crucial roles in synapse establishment and it has also been linked to a variety of neurodegenerative diseases. However, to date, the involvement of the modification of specific targets in key aspects of nervous system development, like patterning and differentiation, has remained largely elusive. A number of recent works confirm the participation of target-specific SUMO modification in critical aspects of nervous system development. Here, we review pioneering and new findings demonstrating the essential role SUMO plays in neurogenesis and other facets of neurodevelopment, which will help to precisely understand the variety of mechanisms SUMO utilizes to control most fundamental processes in the cell.
Collapse
Affiliation(s)
- Pablo García-Gutiérrez
- Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain
| | - Mario García-Domínguez
- Andalusian Centre for Molecular Biology and Regenerative Medicine-CABIMER, CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain.
| |
Collapse
|
|
26
|
Wu Q, Jiang Y, You C. The SUMO components in rheumatoid arthritis. Rheumatology (Oxford) 2022; 61:4619-4630. [PMID: 35595244 DOI: 10.1093/rheumatology/keac297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/30/2022] [Accepted: 04/19/2022] [Indexed: 01/10/2023] Open
Abstract
Small ubiquitin-like modifier (SUMO) proteins can reversibly attach covalently or non-covalently to lysine residues of various substrates. The processes are named SUMOylation and de-SUMOylation, which maintain a dynamic balance in the physiological state, and are regulated by SUMO components. However, the dysregulation of components disturbs the balance and alters the functions of target proteins, which causes the occurrence of diseases. To date, certain SUMO components, including SUMO-1, SUMO-2/3, SAE1/Uba2, Ubc9, PIASs (protein inhibitors of activated signal transducer and activator of transcription) and SENPs (SUMO-specific proteases), have been found to participate in the pathogenesis of RA and their potential value as therapeutic targets also have been highlighted. In addition, single nucleotide polymorphisms (SNPs) in the SUMO components have been reported to be associated with disease susceptibility. Until now, only the SNP site of SUMO-4 has been reported in RA. Here we provided a systematic overview of the general characteristics of SUMO components and highlighted a summary of their impact on RA.
Collapse
Affiliation(s)
- Qian Wu
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Yao Jiang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Chongge You
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, China
| |
Collapse
|
|
27
|
SUMOylation targeting mitophagy in cardiovascular diseases. J Mol Med (Berl) 2022; 100:1511-1538. [PMID: 36163375 DOI: 10.1007/s00109-022-02258-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022]
Abstract
Small ubiquitin-like modifier (SUMO) plays a key regulatory role in cardiovascular diseases, such as cardiac hypertrophy, hypertension, atherosclerosis, and cardiac ischemia-reperfusion injury. As a multifunctional posttranslational modification molecule in eukaryotic cells, SUMOylation is essentially associated with the regulation of mitochondrial dynamics, especially mitophagy, which is involved in the progression and development of cardiovascular diseases. SUMOylation targeting mitochondrial-associated proteins is admittedly considered to regulate mitophagy activation and mitochondrial functions and dynamics, including mitochondrial fusion and fission. SUMOylation triggers mitochondrial fusion to promote mitochondrial dysfunction by modifying Fis1, OPA1, MFN1/2, and DRP1. The interaction between SUMO and DRP1 induces SUMOylation and inhibits lysosomal degradation of DRP1, which is further involved in the regulation of mitochondrial fission. Both SUMOylation and deSUMOylation contribute to the initiation and activation of mitophagy by regulating the conjugation of MFN1/2 SERCA2a, HIF1α, and PINK1. SUMOylation mediated by the SUMO molecule has attracted much attention due to its dual roles in the development of cardiovascular diseases. In this review, we systemically summarize the current understanding underlying the expression, regulation, and structure of SUMO molecules; explore the biochemical functions of SUMOylation in the initiation and activation of mitophagy; discuss the biological roles and mechanisms of SUMOylation in cardiovascular diseases; and further provide a wider explanation of SUMOylation and deSUMOylation research to provide a possible therapeutic strategy for cardiovascular diseases. Considering the precise functions and exact mechanisms of SUMOylation in mitochondrial dysfunction and mitophagy will provide evidence for future experimental research and may serve as an effective approach in the development of novel therapeutic strategies for cardiovascular diseases. Regulation and effect of SUMOylation in cardiovascular diseases via mitophagy. SUMOylation is involved in multiple cardiovascular diseases, including cardiac hypertrophy, hypertension, atherosclerosis, and cardiac ischemia-reperfusion injury. Since it is expressed in multiple cells associated with cardiovascular disease, SUMOylation can be regulated by numerous ligases, including the SENP family proteins PIAS1, PIASy/4, UBC9, and MAPL. SUMOylation regulates the activation and degradation of PINK1, SERCA2a, PPARγ, ERK5, and DRP1 to mediate mitochondrial dynamics, especially mitophagy activation. Mitophagy activation regulated by SUMOylation further promotes or inhibits ventricular diastolic dysfunction, perfusion injury, ventricular remodelling and ventricular noncompaction, which contribute to the development of cardiovascular diseases.
Collapse
|
|
28
|
Kumar G, Sudhagar A, Shivam S, Nilsen F, Bartholomew JL, El-Matbouli M. Identification of in vivo induced antigens of the malacosporean parasite Tetracapsuloides bryosalmonae (Cnidaria) using in vivo induced antigen technology. Front Cell Infect Microbiol 2022; 12:1032347. [PMID: 36389158 PMCID: PMC9644027 DOI: 10.3389/fcimb.2022.1032347] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/30/2022] [Indexed: 11/28/2024] Open
Abstract
Tetracapsuloides bryosalmonae is a malacosporean endoparasite that causes proliferative kidney disease (PKD) in wild and farmed salmonids in Europe and North America. The life cycle of T. bryosalmonae completes between invertebrate bryozoan and vertebrate fish hosts. Inside the fish, virulence factors of T. bryosalmonae are induced during infection or interactions with host cells. T. bryosalmonae genes expressed in vivo are likely to be important in fish pathogenesis. Herein, we identify in vivo induced antigens of T. bryosalmonae during infection in brown trout (Salmo trutta) using in vivo induced antigen technology (IVIAT). Brown trout were exposed to the spores of T. bryosalmonae and were sampled at different time points. The pooled sera were first pre-adsorbed with antigens to remove false positive results. Subsequently, adsorbed sera were used to screen a T. bryosalmonae cDNA phage expression library. Immunoscreening analysis revealed 136 immunogenic T. bryosalmonae proteins induced in brown trout during parasite development. They are involved in signal transduction, transport, metabolism, ion-protein binding, protein folding, and also include hypothetical proteins, of so far unknown functions. The identified in vivo induced antigens will be useful in the understanding of T. bryosalmonae pathogenesis during infection in susceptible hosts. Some of the antigens found may have significant implications for the discovery of candidate molecules for the development of potential therapies and preventive measures against T. bryosalmonae in salmonids.
Collapse
Affiliation(s)
- Gokhlesh Kumar
- Clinical Division of Fish Medicine, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Arun Sudhagar
- Clinical Division of Fish Medicine, University of Veterinary Medicine Vienna, Vienna, Austria
- Peninsular and Marine Fish Genetic Resources Centre, Indian Council of Agricultural Research (ICAR) – National Bureau of Fish Genetic Resources, Kochi, India
| | - Saloni Shivam
- Clinical Division of Fish Medicine, University of Veterinary Medicine Vienna, Vienna, Austria
- Karwar Regional Station of Indian Council of Agricultural Research (ICAR)-Central Marine Fisheries Research Institute, Karwar, India
| | - Frank Nilsen
- Sea Lice Research Centre, Department of Biological Sciences, University of Bergen, Bergen, Norway
| | - Jerri L. Bartholomew
- Department of Microbiology, Oregon State University, Corvallis, OR, United States
| | - Mansour El-Matbouli
- Clinical Division of Fish Medicine, University of Veterinary Medicine Vienna, Vienna, Austria
- School of Biotechnology, Badr University in Cairo, Badr City, Cairo, Egypt
| |
Collapse
|
|
29
|
Liu H, Craig SEL, Molchanov V, Floramo JS, Zhao Y, Yang T. SUMOylation in Skeletal Development, Homeostasis, and Disease. Cells 2022; 11:cells11172710. [PMID: 36078118 PMCID: PMC9454984 DOI: 10.3390/cells11172710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/19/2022] [Accepted: 08/27/2022] [Indexed: 11/18/2022] Open
Abstract
The modification of proteins by small ubiquitin-related modifier (SUMO) molecules, SUMOylation, is a key post-translational modification involved in a variety of biological processes, such as chromosome organization, DNA replication and repair, transcription, nuclear transport, and cell signaling transduction. In recent years, emerging evidence has shown that SUMOylation regulates the development and homeostasis of the skeletal system, with its dysregulation causing skeletal diseases, suggesting that SUMOylation pathways may serve as a promising therapeutic target. In this review, we summarize the current understanding of the molecular mechanisms by which SUMOylation pathways regulate skeletal cells in physiological and disease contexts.
Collapse
Affiliation(s)
| | | | | | | | | | - Tao Yang
- Laboratory of Skeletal Biology, Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
- Correspondence: ; Tel.: +1-616-234-5820
| |
Collapse
|
|
30
|
Lara-Ureña N, Jafari V, García-Domínguez M. Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases. Int J Mol Sci 2022; 23:8012. [PMID: 35887358 PMCID: PMC9316396 DOI: 10.3390/ijms23148012] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/14/2022] [Accepted: 07/19/2022] [Indexed: 02/04/2023] Open
Abstract
SUMOylation is a post-translational modification that has emerged in recent decades as a mechanism involved in controlling diverse physiological processes and that is essential in vertebrates. The SUMO pathway is regulated by several enzymes, proteases and ligases being the main actors involved in the control of sumoylation of specific targets. Dysregulation of the expression, localization and function of these enzymes produces physiological changes that can lead to the appearance of different types of cancer, depending on the enzymes and target proteins involved. Among the most studied proteases and ligases, those of the SENP and PIAS families stand out, respectively. While the proteases involved in this pathway have specific SUMO activity, the ligases may have additional functions unrelated to sumoylation, which makes it more difficult to study their SUMO-associated role in cancer process. In this review we update the knowledge and advances in relation to the impact of dysregulation of SUMO proteases and ligases in cancer initiation and progression.
Collapse
Affiliation(s)
| | | | - Mario García-Domínguez
- Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Américo Vespucio 24, 41092 Seville, Spain; (N.L.-U.); (V.J.)
| |
Collapse
|
|
31
|
Fan L, Yang X, Zheng M, Yang X, Ning Y, Gao M, Zhang S. Regulation of SUMOylation Targets Associated With Wnt/β-Catenin Pathway. Front Oncol 2022; 12:943683. [PMID: 35847921 PMCID: PMC9280480 DOI: 10.3389/fonc.2022.943683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/07/2022] [Indexed: 11/23/2022] Open
Abstract
Wnt/β-catenin signaling is a delicate and complex signal transduction pathway mediated by multiple signaling molecules, which plays a significant role in regulating human physiology and pathology. Abnormally activated Wnt/β-catenin signaling pathway plays a crucial role in promoting malignant tumor occurrence, development, recurrence, and metastasis, particularly in cancer stem cells. Studies have shown that the Wnt/β-catenin signaling pathway controls cell fate and function through the transcriptional and post-translational regulation of omics networks. Therefore, precise regulation of Wnt/β-catenin signaling as a cancer-targeting strategy may contribute to the treatment of some malignancies. SUMOylation is a post-translational modification of proteins that has been found to play a major role in the Wnt/β-catenin signaling pathway. Here, we review the complex regulation of Wnt/β-catenin signaling by SUMOylation and discuss the potential targets of SUMOylation therapy.
Collapse
Affiliation(s)
- Linlin Fan
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xudong Yang
- Tianjin Rehabilitation Center, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Xiaohui Yang
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Yidi Ning
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Ming Gao
- Department of Thyroid Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| |
Collapse
|
|
32
|
Vertegaal ACO. Signalling mechanisms and cellular functions of SUMO. Nat Rev Mol Cell Biol 2022; 23:715-731. [PMID: 35750927 DOI: 10.1038/s41580-022-00500-y] [Citation(s) in RCA: 157] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2022] [Indexed: 12/22/2022]
Abstract
Sumoylation is an essential post-translational modification that is catalysed by a small number of modifying enzymes but regulates thousands of target proteins in a dynamic manner. Small ubiquitin-like modifiers (SUMOs) can be attached to target proteins as one or more monomers or in the form of polymers of different types. Non-covalent readers recognize SUMO-modified proteins via SUMO interaction motifs. SUMO simultaneously modifies groups of functionally related proteins to regulate predominantly nuclear processes, including gene expression, the DNA damage response, RNA processing, cell cycle progression and proteostasis. Recent progress has increased our understanding of the cellular and pathophysiological roles of SUMO modifications, extending their functions to the regulation of immunity, pluripotency and nuclear body assembly in response to oxidative stress, which partly occurs through the recently characterized mechanism of liquid-liquid phase separation. Such progress in understanding the roles and regulation of sumoylation opens new avenues for the targeting of SUMO to treat disease, and indeed the first drug blocking sumoylation is currently under investigation in clinical trials as a possible anticancer agent.
Collapse
Affiliation(s)
- Alfred C O Vertegaal
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
| |
Collapse
|
|
33
|
Luebben AV, Bender D, Becker S, Crowther LM, Erven I, Hofmann K, Söding J, Klemp H, Bellotti C, Stäuble A, Qiu T, Kathayat RS, Dickinson BC, Gärtner J, Sheldrick GM, Krätzner R, Steinfeld R. Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration. SCIENCE ADVANCES 2022; 8:eabj8633. [PMID: 35427157 PMCID: PMC9012467 DOI: 10.1126/sciadv.abj8633] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 03/01/2022] [Indexed: 05/26/2023]
Abstract
Genetic CLN5 variants are associated with childhood neurodegeneration and Alzheimer's disease; however, the molecular function of ceroid lipofuscinosis neuronal protein 5 (Cln5) is unknown. We solved the Cln5 crystal structure and identified a region homologous to the catalytic domain of members of the N1pC/P60 superfamily of papain-like enzymes. However, we observed no protease activity for Cln5; and instead, we discovered that Cln5 and structurally related PPPDE1 and PPPDE2 have efficient cysteine palmitoyl thioesterase (S-depalmitoylation) activity using fluorescent substrates. Mutational analysis revealed that the predicted catalytic residues histidine-166 and cysteine-280 are critical for Cln5 thioesterase activity, uncovering a new cysteine-based catalytic mechanism for S-depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting S-depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of S-depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins.
Collapse
Affiliation(s)
- Anna V. Luebben
- Institute of Inorganic Chemistry, University of
Göttingen, Tammannstrasse 4, 37077 Göttingen, Germany
| | - Daniel Bender
- Department of Pediatric Neurology, University
Children’s Hospital Zürich, University of Zurich,
Steinwiesstrasse 75, 8032 Zürich, Switzerland
| | - Stefan Becker
- Department of NMR-based Structural Biology, Max
Planck Institute for Biophysical Chemistry, Fassberg 11, 37077
Göttingen, Germany
| | - Lisa M. Crowther
- Department of Pediatric Neurology, University
Children’s Hospital Zürich, University of Zurich,
Steinwiesstrasse 75, 8032 Zürich, Switzerland
| | - Ilka Erven
- Institute for Genetics, University of Cologne,
Zülpicher Str.47a, 50674 Cologne, Germany
| | - Kay Hofmann
- Institute for Genetics, University of Cologne,
Zülpicher Str.47a, 50674 Cologne, Germany
| | - Johannes Söding
- Quantitative Biology and Bioinformatics and
Department of Molecular Biology, Max-Planck Institute for Biophysical Chemistry,
Am Fassberg 11, 37077 Göttingen, Germany
| | - Henry Klemp
- Department of Pediatrics and Adolescent Medicine,
Division of Pediatric Neurology, University of Göttingen,
Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - Cristina Bellotti
- Department of Pediatric Neurology, University
Children’s Hospital Zürich, University of Zurich,
Steinwiesstrasse 75, 8032 Zürich, Switzerland
| | - Andreas Stäuble
- Department of Pediatric Neurology, University
Children’s Hospital Zürich, University of Zurich,
Steinwiesstrasse 75, 8032 Zürich, Switzerland
| | - Tian Qiu
- Department of Chemistry, University of Chicago,
Chicago, IL, USA
| | | | | | - Jutta Gärtner
- Department of Pediatrics and Adolescent Medicine,
Division of Pediatric Neurology, University of Göttingen,
Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - George M. Sheldrick
- Institute of Inorganic Chemistry, University of
Göttingen, Tammannstrasse 4, 37077 Göttingen, Germany
| | - Ralph Krätzner
- Department of Pediatrics and Adolescent Medicine,
Division of Pediatric Neurology, University of Göttingen,
Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - Robert Steinfeld
- Department of Pediatric Neurology, University
Children’s Hospital Zürich, University of Zurich,
Steinwiesstrasse 75, 8032 Zürich, Switzerland
- Department of Pediatrics and Adolescent Medicine,
Division of Pediatric Neurology, University of Göttingen,
Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| |
Collapse
|
|
34
|
Sun Y, Nitiss JL, Pommier Y. SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases. Front Mol Biosci 2022; 9:871161. [PMID: 35463961 PMCID: PMC9019546 DOI: 10.3389/fmolb.2022.871161] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/11/2022] [Indexed: 01/03/2023] Open
Abstract
Topoisomerases play crucial roles in DNA metabolism that include replication, transcription, recombination, and chromatin structure by manipulating DNA structures arising in double-stranded DNA. These proteins play key enzymatic roles in a variety of cellular processes and are also likely to play structural roles. Topoisomerases allow topological transformations by introducing transient breaks in DNA by a transesterification reaction between a tyrosine residue of the enzyme and DNA. The cleavage reaction leads to a unique enzyme intermediate that allows cutting DNA while minimizing the potential for damage-induced genetic changes. Nonetheless, topoisomerase-mediated cleavage has the potential for inducing genome instability if the enzyme-mediated DNA resealing is impaired. Regulation of topoisomerase functions is accomplished by post-translational modifications including phosphorylation, polyADP-ribosylation, ubiquitylation, and SUMOylation. These modifications modulate enzyme activity and likely play key roles in determining sites of enzyme action and enzyme stability. Topoisomerase-mediated DNA cleavage and rejoining are affected by a variety of conditions including the action of small molecules, topoisomerase mutations, and DNA structural forms which permit the conversion of the short-lived cleavage intermediate to persistent topoisomerase DNA-protein crosslink (TOP-DPC). Recognition and processing of TOP-DPCs utilizes many of the same post-translational modifications that regulate enzyme activity. This review focuses on SUMOylation of topoisomerases, which has been demonstrated to be a key modification of both type I and type II topoisomerases. Special emphasis is placed on recent studies that indicate how SUMOylation regulates topoisomerase function in unperturbed cells and the unique roles that SUMOylation plays in repairing damage arising from topoisomerase malfunction.
Collapse
Affiliation(s)
- Yilun Sun
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| | - John L. Nitiss
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Rockford, IL, United States
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States
| |
Collapse
|
|
35
|
Gomarasca M, Lombardi G, Maroni P. SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone. Front Cell Dev Biol 2022; 10:889002. [PMID: 35465332 PMCID: PMC9020829 DOI: 10.3389/fcell.2022.889002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 03/25/2022] [Indexed: 12/22/2022] Open
Abstract
Post-translational modifications comprise series of enzymatically-driven chemical modifications, virtually involving the entire cell proteome, that affect the fate of a target protein and, in turn, cell activity. Different classes of modifications can be established ranging from phosphorylation, glycosylation, ubiquitination, acetylation, methylation, lipidation and their inverse reactions. Among these, SUMOylation and NEDDylation are ubiquitin-like multi-enzymatic processes that determine the bound of SUMOs and NEDD8 labels, respectively, on defined amino acidic residues of a specific protein and regulate protein function. As fate-determinants of several effectors and mediators, SUMOylation and NEDDylation play relevant roles in many aspects of tumor cell biology. Bone represents a preferential site of metastasis for solid tumors (e.g., breast and prostate cancers) and the primary site of primitive tumors (e.g., osteosarcoma, chondrosarcoma). Deregulation of SUMOylation and NEDDylation affects different aspects of neoplastic transformation and evolution such as epithelial-mesenchymal transition, adaptation to hypoxia, expression and action of tumor suppressors and oncogenic mediators, and drug resistance. Thereby, they represent potential therapeutic targets. This narrative review aims at describing the involvement and regulation of SUMOylation and NEDDylation in tumor biology, with a specific focus on primary and secondary bone tumors, and to summarize and highlight their potentiality in diagnostics and therapeutic strategies.
Collapse
Affiliation(s)
- Marta Gomarasca
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Polska
- *Correspondence: Giovanni Lombardi,
| | - Paola Maroni
- Laboratory of Experimental Biochemistry and Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
| |
Collapse
|
|
36
|
Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1. Nat Commun 2022; 13:1819. [PMID: 35383180 PMCID: PMC8983731 DOI: 10.1038/s41467-022-29485-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/17/2022] [Indexed: 12/23/2022] Open
Abstract
Post-translational protein modifications by ubiquitin and ubiquitin-like modifiers regulate many major pathways in the cell. These modifications can be reversed by de-ubiquitinating enzymes such as ubiquitin-specific proteases (USPs). Proteolytic activity towards ubiquitin-modified substrates is common to all USP family members except for USPL1, which shows a unique preference for the ubiquitin-like modifier SUMO. Here, we present the crystal structure of USPL1 bound to SUMO2, defining the key structural elements for the unusual deSUMOylase activity of USPL1. We identify specific contacts between SUMO2 and the USPL1 subdomains, including a unique hydrogen bond network of the SUMO2 C-terminal tail. In addition, we find that USPL1 lacks major structural elements present in all canonical USPs members such as the so-called blocking loops, which facilitates SUMO binding. Our data give insight into how a structural protein scaffold designed to bind ubiquitin has evolved to bind SUMO, providing an example of divergent evolution in the USP family. USPL1 is a non-canonical member of the ubiquitin-specific protease (USP) family with activity toward SUMO instead of ubiquitin. Here, the authors present a crystal structure of USPL1 bound to SUMO2, revealing how this enzyme has evolved to bind SUMO as an example of divergent evolution in the USP family.
Collapse
|
|
37
|
Ozerov M, Noreikiene K, Kahar S, Huss M, Huusko A, Kõiv T, Sepp M, López M, Gårdmark A, Gross R, Vasemägi A. Whole-genome sequencing illuminates multifaceted targets of selection to humic substances in Eurasian perch. Mol Ecol 2022; 31:2367-2383. [PMID: 35202502 PMCID: PMC9314028 DOI: 10.1111/mec.16409] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/10/2022] [Accepted: 02/17/2022] [Indexed: 11/30/2022]
Abstract
Extreme environments are inhospitable to the majority of species, but some organisms are able to survive in such hostile conditions due to evolutionary adaptations. For example, modern bony fishes have colonized various aquatic environments, including perpetually dark, hypoxic, hypersaline and toxic habitats. Eurasian perch (Perca fluviatilis) is among the few fish species of northern latitudes that is able to live in very acidic humic lakes. Such lakes represent almost "nocturnal" environments; they contain high levels of dissolved organic matter, which in addition to creating a challenging visual environment, also affects a large number of other habitat parameters and biotic interactions. To reveal the genomic targets of humic-associated selection, we performed whole-genome sequencing of perch originating from 16 humic and 16 clear-water lakes in northern Europe. We identified over 800,000 single nucleotide polymorphisms, of which >10,000 were identified as potential candidates under selection (associated with >3000 genes) using multiple outlier approaches. Our findings suggest that adaptation to the humic environment may involve hundreds of regions scattered across the genome. Putative signals of adaptation were detected in genes and gene families with diverse functions, including organism development and ion transportation. The observed excess of variants under selection in regulatory regions highlights the importance of adaptive evolution via regulatory elements, rather than via protein sequence modification. Our study demonstrates the power of whole-genome analysis to illuminate the multifaceted nature of humic adaptation and provides the foundation for further investigation of causal mutations underlying phenotypic traits of ecological and evolutionary importance.
Collapse
Affiliation(s)
- Mikhail Ozerov
- Department of Aquatic ResourcesInstitute of Freshwater ResearchSwedish University of Agricultural SciencesDrottningholmSweden
- Department of BiologyUniversity of TurkuTurkuFinland
- Biodiversity UnitUniversity of TurkuTurkuFinland
| | - Kristina Noreikiene
- Chair of AquacultureInstitute of Veterinary Medicine and Animal SciencesEstonian University of Life SciencesTartuEstonia
| | - Siim Kahar
- Chair of AquacultureInstitute of Veterinary Medicine and Animal SciencesEstonian University of Life SciencesTartuEstonia
| | - Magnus Huss
- Department of Aquatic ResourcesSwedish University of Agricultural SciencesÖregrundSweden
| | - Ari Huusko
- Natural resources Institute Finland (Luke)PaltamoFinland
| | - Toomas Kõiv
- Chair of Hydrobiology and FisheryInstitute of Agricultural and Environmental SciencesEstonian University of Life SciencesTartuEstonia
| | - Margot Sepp
- Chair of Hydrobiology and FisheryInstitute of Agricultural and Environmental SciencesEstonian University of Life SciencesTartuEstonia
| | - María‐Eugenia López
- Department of Aquatic ResourcesInstitute of Freshwater ResearchSwedish University of Agricultural SciencesDrottningholmSweden
| | - Anna Gårdmark
- Department of Aquatic ResourcesSwedish University of Agricultural SciencesÖregrundSweden
| | - Riho Gross
- Chair of AquacultureInstitute of Veterinary Medicine and Animal SciencesEstonian University of Life SciencesTartuEstonia
| | - Anti Vasemägi
- Department of Aquatic ResourcesInstitute of Freshwater ResearchSwedish University of Agricultural SciencesDrottningholmSweden
- Chair of AquacultureInstitute of Veterinary Medicine and Animal SciencesEstonian University of Life SciencesTartuEstonia
| |
Collapse
|
|
38
|
Fan Y, Li X, Zhang L, Zong Z, Wang F, Huang J, Zeng L, Zhang C, Yan H, Zhang L, Zhou F. SUMOylation in Viral Replication and Antiviral Defense. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2104126. [PMID: 35060688 PMCID: PMC8895153 DOI: 10.1002/advs.202104126] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/07/2021] [Indexed: 05/22/2023]
Abstract
SUMOylation is a ubiquitination-like post-translational modification that plays an essential role in the regulation of protein function. Recent studies have shown that proteins from both RNA and DNA virus families can be modified by SUMO conjugation, which facilitates viral replication. Viruses can manipulate the entire process of SUMOylation through interplay with the SUMO pathway. By contrast, SUMOylation can eliminate viral infection by regulating host antiviral immune components. A deeper understanding of how SUMOylation regulates viral proteins and cellular antiviral components is necessary for the development of effective antiviral therapies. In the present review, the regulatory mechanism of SUMOylation in viral replication and infection and the antiviral immune response, and the consequences of this regulation for viral replication and engagement with antiviral innate immunity are summarized. The potential therapeutic applications of SUMOylation in diseases caused by viruses are also discussed.
Collapse
Affiliation(s)
- Yao Fan
- Department of PharmacologyZhejiang University City College School of MedicineHangzhouZhejiang310015China
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123China
| | - Xiang Li
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Lei Zhang
- Department of Orthopaedic SurgeryThe Third Affiliated Hospital of Wenzhou Medical UniversityRui'an325200China
| | - Zhi Zong
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Fangwei Wang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Jun Huang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Linghui Zeng
- Department of PharmacologyZhejiang University City College School of MedicineHangzhouZhejiang310015China
| | - Chong Zhang
- Department of PharmacologyZhejiang University City College School of MedicineHangzhouZhejiang310015China
| | - Haiyan Yan
- Department of PharmacologyZhejiang University City College School of MedicineHangzhouZhejiang310015China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123China
| |
Collapse
|
|
39
|
Soh SM, Kim YJ, Kim HH, Lee HR. Modulation of Ubiquitin Signaling in Innate Immune Response by Herpesviruses. Int J Mol Sci 2022; 23:ijms23010492. [PMID: 35008917 PMCID: PMC8745310 DOI: 10.3390/ijms23010492] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/16/2022] Open
Abstract
The ubiquitin proteasome system (UPS) is a protein degradation machinery that is crucial for cellular homeostasis in eukaryotes. Therefore, it is not surprising that the UPS coordinates almost all host cellular processes, including host-pathogen interactions. This protein degradation machinery acts predominantly by tagging substrate proteins designated for degradation with a ubiquitin molecule. These ubiquitin tags have been involved at various steps of the innate immune response. Hence, herpesviruses have evolved ways to antagonize the host defense mechanisms by targeting UPS components such as ubiquitin E3 ligases and deubiquitinases (DUBs) that establish a productive infection. This review delineates how herpesviruses usurp the critical roles of ubiquitin E3 ligases and DUBs in innate immune response to escape host-antiviral immune response, with particular focus on retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), cyclic-GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon (IFN) genes (STING) pathways, and inflammasome signaling.
Collapse
Affiliation(s)
- Sandrine-M. Soh
- Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong 30019, Korea; (S.-M.S.); (Y.-J.K.); (H.-H.K.)
| | - Yeong-Jun Kim
- Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong 30019, Korea; (S.-M.S.); (Y.-J.K.); (H.-H.K.)
| | - Hong-Hee Kim
- Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong 30019, Korea; (S.-M.S.); (Y.-J.K.); (H.-H.K.)
| | - Hye-Ra Lee
- Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong 30019, Korea; (S.-M.S.); (Y.-J.K.); (H.-H.K.)
- Department of Laboratory Medicine, College of Medicine, Korea University, Seoul 136-701, Korea
- Correspondence: ; Tel.: +82-44-860-1831
| |
Collapse
|
|
40
|
Dai X, Zhang T, Hua D. Ubiquitination and SUMOylation: protein homeostasis control over cancer. Epigenomics 2021; 14:43-58. [PMID: 34875856 DOI: 10.2217/epi-2021-0371] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Ubiquitination and SUMOylation are two essential components of the ubiquitination proteasome system playing fundamental roles in protein homeostasis maintenance and signal transduction, perturbation of which is associated with tumorigenesis. By comparing the mechanisms of ubiquitination and SUMOylation, assessing their crosstalk, reviewing their differential associations with cancer and identifying unaddressed yet important questions that may lead the field trend, this review sheds light on the similarities and differences of ubiquitination and SUMOylation toward the improved harnessing of both post-translational modification machineries, as well as forecasts novel onco-therapeutic opportunities through cell homeostasis control.
Collapse
Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122,China
| | - Tongxin Zhang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122,China
| | - Dong Hua
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122,China.,Wuxi People's Hospital, Wuxi, 214023, China.,Affiliated Hospital of Jiangnan University, Wuxi, 214122, China
| |
Collapse
|
|
41
|
Hotz PW, Müller S, Mendler L. SUMO-specific Isopeptidases Tuning Cardiac SUMOylation in Health and Disease. Front Mol Biosci 2021; 8:786136. [PMID: 34869605 PMCID: PMC8641784 DOI: 10.3389/fmolb.2021.786136] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022] Open
Abstract
SUMOylation is a transient posttranslational modification with small-ubiquitin like modifiers (SUMO1, SUMO2 and SUMO3) covalently attached to their target-proteins via a multi-step enzymatic cascade. SUMOylation modifies protein-protein interactions, enzymatic-activity or chromatin binding in a multitude of key cellular processes, acting as a highly dynamic molecular switch. To guarantee the rapid kinetics, SUMO target-proteins are kept in a tightly controlled equilibrium of SUMOylation and deSUMOylation. DeSUMOylation is maintained by the SUMO-specific proteases, predominantly of the SENP family. SENP1 and SENP2 represent family members tuning SUMOylation status of all three SUMO isoforms, while SENP3 and SENP5 are dedicated to detach mainly SUMO2/3 from its substrates. SENP6 and SENP7 cleave polySUMO2/3 chains thereby countering the SUMO-targeted-Ubiquitin-Ligase (StUbL) pathway. Several biochemical studies pinpoint towards the SENPs as critical enzymes to control balanced SUMOylation/deSUMOylation in cardiovascular health and disease. This study aims to review the current knowledge about the SUMO-specific proteases in the heart and provides an integrated view of cardiac functions of the deSUMOylating enzymes under physiological and pathological conditions.
Collapse
Affiliation(s)
- Paul W Hotz
- Institute of Biochemistry II, Gustav Embden Zentrum, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Stefan Müller
- Institute of Biochemistry II, Gustav Embden Zentrum, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| | - Luca Mendler
- Institute of Biochemistry II, Gustav Embden Zentrum, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
| |
Collapse
|
|
42
|
Yamazawa R, Kuwana R, Takeuchi K, Takamatsu H, Nakajima Y, Ito K. Identification of the active site and characterization of a novel sporulation-specific cysteine protease YabG from Bacillus subtilis. J Biochem 2021; 171:315-324. [PMID: 34865059 DOI: 10.1093/jb/mvab135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/28/2021] [Indexed: 11/15/2022] Open
Abstract
In order to characterize the probable protease gene yabG found in the genomes of spore-forming bacteria, Bacillus subtilis yabG was expressed as a 35 kDa His-tagged protein (BsYabG) in Escherichia coli cells. During purification using Ni-affinity chromatography, the 35 kDa protein was degraded via several intermediates to form a 24 kDa protein. Furthermore, it was degraded after an extended incubation period. The effect of protease inhibitors, including certain chemical modification reagents, on the conversion of the 35 kDa protein to the 24 kDa protein was investigated. Reagents reacting with sulfhydryl groups exerted significant effects, strongly suggesting that the yabG gene product is a cysteine protease with autolytic activity. Site-directed mutagenesis of the conserved Cys and His residues indicated that Cys218 and His172 are active site residues. No degradation was observed in the C218A/S and H172A mutants. In addition to the chemical modification reagents, benzamidine inhibited the degradation of the 24 kDa protein. Determination of the N-terminal amino acid sequences of the intermediates revealed trypsin-like specificity for YabG protease. Based on the relative positions of His172 and Cys218 and their surrounding sequences, we propose the classification of YabG as a new family of clan CD in the Merops peptidase database.
Collapse
Affiliation(s)
- Ryuji Yamazawa
- Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotouge-cho, Hirakata, Osaka 573-0101, Japan
| | - Ritsuko Kuwana
- Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotouge-cho, Hirakata, Osaka 573-0101, Japan
| | - Kenji Takeuchi
- Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotouge-cho, Hirakata, Osaka 573-0101, Japan
| | - Hiromu Takamatsu
- Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotouge-cho, Hirakata, Osaka 573-0101, Japan
| | - Yoshitaka Nakajima
- Department of Life Science, Faculty of Science and Engineering, Setsunan University, 17-8 Ikeda-nakamachi, Neyagawa, Osaka 572-8508, Japan
| | - Kiyoshi Ito
- Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotouge-cho, Hirakata, Osaka 573-0101, Japan
| |
Collapse
|
|
43
|
Bao J, Liang Z, Gong X, Yu J, Xiao Y, Liu W, Wang X, Wang JZ, Shu X. High Fat Diet Mediates Amyloid-β Cleaving Enzyme 1 Phosphorylation and SUMOylation, Enhancing Cognitive Impairment in APP/PS1 Mice. J Alzheimers Dis 2021; 85:863-876. [PMID: 34864680 DOI: 10.3233/jad-215299] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common form of dementia in older adults and extracellular accumulation of amyloid-β (Aβ) is one of the two characterized pathologies of AD. Obesity is significantly associated with AD developing factors. Several studies have reported that high fat diet (HFD) influenced Aβ accumulation and cognitive performance during AD pathology. However, the underlying neurobiological mechanisms have not yet been elucidated. OBJECTIVE The objective of this study was to explore the underlying neurobiological mechanisms of HFD influenced Aβ accumulation and cognitive performance during AD pathology. METHODS 2.5-month-old male APP/PS1 mice were randomly separated into two groups: 1) the normal diet (ND) group, fed a standard diet (10 kcal%fat); and 2) the HFD group, fed a high fat diet (40 kcal%fat, D12492; Research Diets). After 4 months of HFD or ND feeding, mice in the two groups were subjected for further ethological, morphological, and biochemical analyses. RESULTS A long-term HFD diet significantly increased perirenal fat and impaired dendritic integrity and aggravated neurodegeneration, and augmented learning and memory deficits in APP/PS1 mice. Furthermore, the HFD increased beta amyloid cleaving enzyme 1 (BACE1) dephosphorylation and SUMOylation, resulting in enhanced enzyme activity and stability, which exacerbated the deposition of amyloid plaques. CONCLUSION Our study demonstrates that long-term HFD consumption aggravates amyloid-β accumulation and cognitive impairments, and that modifiable lifestyle factors, such as obesity, can induce BACE1 post-modifications which may contribute to AD pathogenesis.
Collapse
Affiliation(s)
- Jian Bao
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Zheng Liang
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Xiaokang Gong
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Jing Yu
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Yifan Xiao
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Wei Liu
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Xiaochuan Wang
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiji Shu
- Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.,Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| |
Collapse
|
|
44
|
Swevers L, Kontogiannatos D, Kolliopoulou A, Ren F, Feng M, Sun J. Mechanisms of Cell Entry by dsRNA Viruses: Insights for Efficient Delivery of dsRNA and Tools for Improved RNAi-Based Pest Control. Front Physiol 2021; 12:749387. [PMID: 34858204 PMCID: PMC8632066 DOI: 10.3389/fphys.2021.749387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/11/2021] [Indexed: 12/18/2022] Open
Abstract
While RNAi is often heralded as a promising new strategy for insect pest control, a major obstacle that still remains is the efficient delivery of dsRNA molecules within the cells of the targeted insects. However, it seems overlooked that dsRNA viruses already have developed efficient strategies for transport of dsRNA molecules across tissue barriers and cellular membranes. Besides protecting their dsRNA genomes in a protective shell, dsRNA viruses also display outer capsid layers that incorporate sophisticated mechanisms to disrupt the plasma membrane layer and to translocate core particles (with linear dsRNA genome fragments) within the cytoplasm. Because of the perceived efficiency of the translocation mechanism, it is well worth analyzing in detail the molecular processes that are used to achieve this feat. In this review, the mechanism of cell entry by dsRNA viruses belonging to the Reoviridae family is discussed in detail. Because of the large amount of progress in mammalian versus insect models, the mechanism of infections of reoviruses in mammals (orthoreoviruses, rotaviruses, orbiviruses) will be treated as a point of reference against which infections of reoviruses in insects (orbiviruses in midges, plant viruses in hemipterans, insect-specific cypoviruses in lepidopterans) will be compared. The goal of this discussion is to uncover the basic principles by which dsRNA viruses cross tissue barriers and translocate their cargo to the cellular cytoplasm; such knowledge subsequently can be incorporated into the design of dsRNA virus-based viral-like particles for optimal delivery of RNAi triggers in targeted insect pests.
Collapse
Affiliation(s)
- Luc Swevers
- Insect Molecular Genetics and Biotechnology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens, Greece
| | - Dimitrios Kontogiannatos
- Insect Molecular Genetics and Biotechnology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens, Greece
| | - Anna Kolliopoulou
- Insect Molecular Genetics and Biotechnology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens, Greece
| | - Feifei Ren
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Min Feng
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jingchen Sun
- Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, China
| |
Collapse
|
|
45
|
Wang Y, Yu J. Dissecting multiple roles of SUMOylation in prostate cancer. Cancer Lett 2021; 521:88-97. [PMID: 34464672 DOI: 10.1016/j.canlet.2021.08.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/27/2022]
Abstract
Protein modification with small ubiquitin-like modifiers (SUMOs) plays dual roles in prostate cancer (PCa) tumorigenesis and development. Any intermediary of the SUMO conjugation cycle going awry may forfeit the balance between tumorigenic potential and anticancer effects. Deregulated SUMOylation on the androgen receptor and oncoproteins also takes part in this pathological process, as exemplified by STAT3/NF-κB and tumor suppressors such as PTEN and p53. Here, we outline recent developments and discoveries of SUMOylation in PCa and present an overview of its multiple roles in PCa tumorigenesis/promotion and suppression, while elucidating its potential as a therapeutic target for PCa.
Collapse
Affiliation(s)
- Yishu Wang
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Jianxiu Yu
- Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| |
Collapse
|
|
46
|
Seok HY, Bae H, Kim T, Mehdi SMM, Nguyen LV, Lee SY, Moon YH. Non-TZF Protein AtC3H59/ZFWD3 Is Involved in Seed Germination, Seedling Development, and Seed Development, Interacting with PPPDE Family Protein Desi1 in Arabidopsis. Int J Mol Sci 2021; 22:ijms22094738. [PMID: 33947021 PMCID: PMC8124945 DOI: 10.3390/ijms22094738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 04/23/2021] [Accepted: 04/28/2021] [Indexed: 11/16/2022] Open
Abstract
Despite increasing reports on the function of CCCH zinc finger proteins in plant development and stress response, the functions and molecular aspects of many non-tandem CCCH zinc finger (non-TZF) proteins remain uncharacterized. AtC3H59/ZFWD3 is an Arabidopsis non-TZF protein and belongs to the ZFWD subfamily harboring a CCCH zinc finger motif and a WD40 domain. In this study, we characterized the biological and molecular functions of AtC3H59, which is subcellularly localized in the nucleus. The seeds of AtC3H59-overexpressing transgenic plants (OXs) germinated faster than those of wild type (WT), whereas atc3h59 mutant seeds germinated slower than WT seeds. AtC3H59 OX seedlings were larger and heavier than WT seedlings, whereas atc3h59 mutant seedlings were smaller and lighter than WT seedlings. Moreover, AtC3H59 OX seedlings had longer primary root length than WT seedlings, whereas atc3h59 mutant seedlings had shorter primary root length than WT seedlings, owing to altered cell division activity in the root meristem. During seed development, AtC3H59 OXs formed larger and heavier seeds than WT. Using yeast two-hybrid screening, we isolated Desi1, a PPPDE family protein, as an interacting partner of AtC3H59. AtC3H59 and Desi1 interacted via their WD40 domain and C-terminal region, respectively, in the nucleus. Taken together, our results indicate that AtC3H59 has pleiotropic effects on seed germination, seedling development, and seed development, and interacts with Desi1 in the nucleus via its entire WD40 domain. To our knowledge, this is the first report to describe the biological functions of the ZFWD protein and Desi1 in Arabidopsis.
Collapse
Affiliation(s)
- Hye-Yeon Seok
- Institute of Systems Biology, Pusan National University, Busan 46241, Korea; (H.-Y.S.); (H.B.)
| | - Hyungjoon Bae
- Institute of Systems Biology, Pusan National University, Busan 46241, Korea; (H.-Y.S.); (H.B.)
| | - Taehyoung Kim
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (T.K.); (S.M.M.M.); (L.V.N.)
| | - Syed Muhammad Muntazir Mehdi
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (T.K.); (S.M.M.M.); (L.V.N.)
| | - Linh Vu Nguyen
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (T.K.); (S.M.M.M.); (L.V.N.)
| | - Sun-Young Lee
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;
| | - Yong-Hwan Moon
- Institute of Systems Biology, Pusan National University, Busan 46241, Korea; (H.-Y.S.); (H.B.)
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (T.K.); (S.M.M.M.); (L.V.N.)
- Department of Molecular Biology, Pusan National University, Busan 46241, Korea
- Correspondence: ; Tel.: +82-51-510-2592
| |
Collapse
|
|
47
|
Roy D, Sadanandom A. SUMO mediated regulation of transcription factors as a mechanism for transducing environmental cues into cellular signaling in plants. Cell Mol Life Sci 2021; 78:2641-2664. [PMID: 33452901 PMCID: PMC8004507 DOI: 10.1007/s00018-020-03723-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/25/2020] [Accepted: 11/25/2020] [Indexed: 12/31/2022]
Abstract
Across all species, transcription factors (TFs) are the most frequent targets of SUMOylation. The effect of SUMO conjugation on the functions of transcription factors has been extensively studied in animal systems, with over 200 transcription factors being documented to be modulated by SUMOylation. This has resulted in the establishment of a number of paradigms that seek to explain the mechanisms by which SUMO regulates transcription factor functions. For instance, SUMO has been shown to modulate TF DNA binding activity; regulate both localization as well as the abundance of TFs and also influence the association of TFs with chromatin. With transcription factors being implicated as master regulators of the cellular signalling pathways that maintain phenotypic plasticity in all organisms, in this review, we will discuss how SUMO mediated regulation of transcription factor activity facilitates molecular pathways to mount an appropriate and coherent biological response to environmental cues.
Collapse
Affiliation(s)
- Dipan Roy
- Department of Biosciences, Durham University, Stockton Road, Durham, DH1 3LE, UK
| | - Ari Sadanandom
- Department of Biosciences, Durham University, Stockton Road, Durham, DH1 3LE, UK.
| |
Collapse
|
|
48
|
The role of SUMOylation during development. Biochem Soc Trans 2021; 48:463-478. [PMID: 32311032 PMCID: PMC7200636 DOI: 10.1042/bst20190390] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/17/2022]
Abstract
During the development of multicellular organisms, transcriptional regulation plays an important role in the control of cell growth, differentiation and morphogenesis. SUMOylation is a reversible post-translational process involved in transcriptional regulation through the modification of transcription factors and through chromatin remodelling (either modifying chromatin remodelers or acting as a ‘molecular glue’ by promoting recruitment of chromatin regulators). SUMO modification results in changes in the activity, stability, interactions or localization of its substrates, which affects cellular processes such as cell cycle progression, DNA maintenance and repair or nucleocytoplasmic transport. This review focuses on the role of SUMO machinery and the modification of target proteins during embryonic development and organogenesis of animals, from invertebrates to mammals.
Collapse
|
|
49
|
Functions of nuclear receptors SUMOylation. Clin Chim Acta 2021; 516:27-33. [PMID: 33476589 DOI: 10.1016/j.cca.2021.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/18/2022]
Abstract
The nuclear receptor superfamily is a family of ligand-activated transcription factors that play a key role in cell metabolism and human diseases. They can be modified after translation, such as acetylation, ubiquitination, phosphorylation and SUMOylation. Crosstalk between SUMO and ubiquitin, phosphorylation and acetylation regulates a variety of metabolic and physiological activities. Nuclear receptors play an important role in lipid metabolism, inflammation, bile acid homeostasis and autophagy. SUMOylation nuclear receptors can regulate their function and affect cell metabolism. It also provides a potential therapeutic target for atherosclerosis, tumor and other metabolic and inflammation-related diseases. This review focuses on the function of SUMOylation nuclear receptors.
Collapse
|
|
50
|
Li Y, Gao L, Zhang C, Meng J. LncRNA SNHG3 Promotes Proliferation and Metastasis of Non-Small-Cell Lung Cancer Cells Through miR-515-5p/SUMO2 Axis. Technol Cancer Res Treat 2021; 20:15330338211019376. [PMID: 34032148 PMCID: PMC8155750 DOI: 10.1177/15330338211019376] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/23/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022] Open
Abstract
Lung cancer is a global disease and a major cause of cancer-related mortality worldwide. Accumulated studies have confirmed the essential role of long non-coding RNAs (lncRNAs) in the occurrence and development of cancers. Meanwhile, there have been reports concerning the role of Small Nucleolar RNA Host Gene 3 (SNHG3) in various cancers. However, there are so far few studies on the function and mechanism of SNHG3 in lung cancer. In the present study, SNHG3 was found to be highly expressed in lung cancer tissues and cells. Downregulation of SNHG3 could inhibit cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process. In addition, SNHG3 was found to have the ability to bind to miR-515-5p. Furthermore, Small Ubiquitin Like Modifier 2 (SUMO2) was identified to be the downstream target of miR-515-5p, which was negatively correlated with miR-515-5p expression. SNHG3 could positively regulate SUMO2 expression by sponging miR-515-5p. In addition, the rescue experiment showed that simultaneous transfection of miR-515-5p or SUMO2 siRNA could reverse the effect of SNHG3 expression on cell proliferation and metastasis. Collectively, our study demonstrates that SNHG3 can act on miR-515-5p in the form of competitive endogenous RNA (ceRNA) to regulate SUMO2 positively and thus affect the proliferation and metastasis of NSCLC cells. Findings in our study support that SNHG3/miR-515-5p/SUMO2 regulatory axis may become a potential therapeutic target for lung cancer.
Collapse
Affiliation(s)
- Yongqun Li
- Department of Respiratory Medicine, The Sixth Medical Center of PLA
General Hospital, Beijing, China
| | - Lipin Gao
- Department of Hematology, The Sixth Medical Center of PLA General
Hospital, Beijing, China
| | - Caiyun Zhang
- Department of Respiratory Medicine, The Sixth Medical Center of PLA
General Hospital, Beijing, China
| | - Jiguang Meng
- Department of Respiratory Medicine, The Sixth Medical Center of PLA
General Hospital, Beijing, China
| |
Collapse
|