|
1
|
Tharuka MDN, Courelli AS, Chen Y. Immune regulation by the SUMO family. Nat Rev Immunol 2025:10.1038/s41577-025-01155-4. [PMID: 40108400 DOI: 10.1038/s41577-025-01155-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 03/22/2025]
Abstract
Post-translational protein modifications by the small ubiquitin-like modifier (SUMO) family have been shown to regulate immune cells in the context of infection, autoimmunity and, more recently, cancer. Recent clinical trials investigating sumoylation inhibition as a therapeutic approach for cancer have established that sumoylation has important immune modulatory effects. Sumoylation suppresses transcription factors in innate immune cells and in cytotoxic T cells through the direct modification of these factors, which leads to the recruitment of transcriptional repressor complexes containing histone deacetylases. By contrast, in regulatory T cells and T helper 17 cells, sumoylation of transcription factors can enhance transcriptional activity by recruiting transcriptional coactivators. Sumoylation is also involved in the repression of IFNB1 and endogenous retroviruses and is therefore important for regulating interferon expression. A central theme from literature is that the sumoylation of a group of proteins, instead of a single target, collectively contributes to the regulation of various immune processes. In this Review, we consider how these studies provide scientific basis for future exploration of SUMO-mediated immune modulation for the treatment of cancers and autoimmune disorders.
Collapse
Affiliation(s)
- Mohottige D Neranjan Tharuka
- Division of Surgical Sciences, Department of Surgery, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Asimina S Courelli
- Division of Surgical Sciences, Department of Surgery, School of Medicine, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Yuan Chen
- Division of Surgical Sciences, Department of Surgery, School of Medicine, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
| |
Collapse
|
|
2
|
Liu JCY, Ackermann L, Hoffmann S, Gál Z, Hendriks IA, Jain C, Morlot L, Tatham MH, McLelland GL, Hay RT, Nielsen ML, Brummelkamp T, Haahr P, Mailand N. Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation. Nat Struct Mol Biol 2024; 31:1355-1367. [PMID: 38649616 PMCID: PMC11402782 DOI: 10.1038/s41594-024-01294-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 03/26/2024] [Indexed: 04/25/2024]
Abstract
Protein SUMOylation provides a principal driving force for cellular stress responses, including DNA-protein crosslink (DPC) repair and arsenic-induced PML body degradation. In this study, using genome-scale screens, we identified the human E3 ligase TOPORS as a key effector of SUMO-dependent DPC resolution. We demonstrate that TOPORS promotes DPC repair by functioning as a SUMO-targeted ubiquitin ligase (STUbL), combining ubiquitin ligase activity through its RING domain with poly-SUMO binding via SUMO-interacting motifs, analogous to the STUbL RNF4. Mechanistically, TOPORS is a SUMO1-selective STUbL that complements RNF4 in generating complex ubiquitin landscapes on SUMOylated targets, including DPCs and PML, stimulating efficient p97/VCP unfoldase recruitment and proteasomal degradation. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, involving defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Our findings establish TOPORS as a STUbL whose parallel action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO-ubiquitin crosstalk.
Collapse
Affiliation(s)
- Julio C Y Liu
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Leena Ackermann
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Saskia Hoffmann
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Zita Gál
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Ivo A Hendriks
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Charu Jain
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Louise Morlot
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Michael H Tatham
- Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK
| | - Gian-Luca McLelland
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ronald T Hay
- Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, UK
| | - Michael Lund Nielsen
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Thijn Brummelkamp
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Peter Haahr
- Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Cellular and Molecular Medicine, Center for Gene Expression, University of Copenhagen, Copenhagen, Denmark.
| | - Niels Mailand
- Protein Signaling Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
- Department of Cellular and Molecular Medicine, Center for Chromosome Stability, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
3
|
Truong P, Shen S, Joshi S, Islam MI, Zhong L, Raftery MJ, Afrasiabi A, Alinejad-Rokny H, Nguyen M, Zou X, Bhuyan GS, Sarowar CH, Ghodousi ES, Stonehouse O, Mohamed S, Toscan CE, Connerty P, Kakadia PM, Bohlander SK, Michie KA, Larsson J, Lock RB, Walkley CR, Thoms JAI, Jolly CJ, Pimanda JE. TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells. Nat Commun 2024; 15:7360. [PMID: 39198401 PMCID: PMC11358519 DOI: 10.1038/s41467-024-51646-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.
Collapse
MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Animals
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Cell Line, Tumor
- Mice
- Myelodysplastic Syndromes/drug therapy
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/pathology
- Myelodysplastic Syndromes/metabolism
- CRISPR-Cas Systems
- Sumoylation/drug effects
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/genetics
- DNA Damage/drug effects
- DNA Methylation/drug effects
- Xenograft Model Antitumor Assays
- DNA (Cytosine-5-)-Methyltransferase 1/metabolism
- DNA (Cytosine-5-)-Methyltransferase 1/genetics
- DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors
- Female
Collapse
Affiliation(s)
- Peter Truong
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | - Sylvie Shen
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Swapna Joshi
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | | | - Ling Zhong
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
| | - Mark J Raftery
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
| | - Ali Afrasiabi
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
| | - Hamid Alinejad-Rokny
- UNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
- Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Sydney, NSW, Australia
| | - Mary Nguyen
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | - Xiaoheng Zou
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | | | | | - Elaheh S Ghodousi
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
| | | | - Sara Mohamed
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Cara E Toscan
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Patrick Connerty
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Purvi M Kakadia
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Stefan K Bohlander
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Katharine A Michie
- Structural Biology Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
| | - Jonas Larsson
- Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund University, Lund, Sweden
| | - Richard B Lock
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
- UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia
| | - Carl R Walkley
- St Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia
- Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Julie A I Thoms
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
| | | | - John E Pimanda
- School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
- School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
- Haematology Department, Prince of Wales Hospital, Sydney, NSW, Australia.
| |
Collapse
|
|
4
|
Carnie CJ, Götz MJ, Palma-Chaundler CS, Weickert P, Wanders A, Serrano-Benitez A, Li HY, Gupta V, Awwad SW, Blum CJ, Sczaniecka-Clift M, Cordes J, Zagnoli-Vieira G, D'Alessandro G, Richards SL, Gueorguieva N, Lam S, Beli P, Stingele J, Jackson SP. Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS. EMBO J 2024; 43:2397-2423. [PMID: 38760575 PMCID: PMC11183266 DOI: 10.1038/s44318-024-00108-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 03/15/2024] [Accepted: 04/16/2024] [Indexed: 05/19/2024] Open
Abstract
The nucleoside analogue decitabine (or 5-aza-dC) is used to treat several haematological cancers. Upon its triphosphorylation and incorporation into DNA, 5-aza-dC induces covalent DNA methyltransferase 1 DNA-protein crosslinks (DNMT1-DPCs), leading to DNA hypomethylation. However, 5-aza-dC's clinical outcomes vary, and relapse is common. Using genome-scale CRISPR/Cas9 screens, we map factors determining 5-aza-dC sensitivity. Unexpectedly, we find that loss of the dCMP deaminase DCTD causes 5-aza-dC resistance, suggesting that 5-aza-dUMP generation is cytotoxic. Combining results from a subsequent genetic screen in DCTD-deficient cells with the identification of the DNMT1-DPC-proximal proteome, we uncover the ubiquitin and SUMO1 E3 ligase, TOPORS, as a new DPC repair factor. TOPORS is recruited to SUMOylated DNMT1-DPCs and promotes their degradation. Our study suggests that 5-aza-dC-induced DPCs cause cytotoxicity when DPC repair is compromised, while cytotoxicity in wild-type cells arises from perturbed nucleotide metabolism, potentially laying the foundations for future identification of predictive biomarkers for decitabine treatment.
Collapse
Affiliation(s)
- Christopher J Carnie
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
| | - Maximilian J Götz
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Pedro Weickert
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Amy Wanders
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Almudena Serrano-Benitez
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Hao-Yi Li
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Vipul Gupta
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Samah W Awwad
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | | | | | - Jacqueline Cordes
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Guido Zagnoli-Vieira
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Giuseppina D'Alessandro
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Sean L Richards
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Nadia Gueorguieva
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Simon Lam
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Petra Beli
- Institute of Molecular Biology (IMB), Mainz, Germany
- Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität, Mainz, Germany
| | - Julian Stingele
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
| | - Stephen P Jackson
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
- The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
5
|
Yang Y, Li Y, Sears RC, Sun XX, Dai MS. SUMOylation regulation of ribosome biogenesis: Emerging roles for USP36. FRONTIERS IN RNA RESEARCH 2024; 2:1389104. [PMID: 38764604 PMCID: PMC11101209 DOI: 10.3389/frnar.2024.1389104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
Ribosome biogenesis is essential for cell growth, proliferation, and animal development. Its deregulation leads to various human disorders such as ribosomopathies and cancer. Thus, tight regulation of ribosome biogenesis is crucial for normal cell homeostasis. Emerging evidence suggests that posttranslational modifications such as ubiquitination and SUMOylation play a crucial role in regulating ribosome biogenesis. Our recent studies reveal that USP36, a nucleolar deubiquitinating enzyme (DUB), acts also as a SUMO ligase to regulate nucleolar protein group SUMOylation, thereby being essential for ribosome biogenesis. Here, we provide an overview of the current understanding of the SUMOylation regulation of ribosome biogenesis and discuss the role of USP36 in nucleolar SUMOylation.
Collapse
Affiliation(s)
- Yunhan Yang
- Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Yanping Li
- Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Rosalie C. Sears
- Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Xiao-Xin Sun
- Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| | - Mu-Shui Dai
- Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
| |
Collapse
|
|
6
|
Filippopoulou C, Thomé CC, Perdikari S, Ntini E, Simos G, Bohnsack KE, Chachami G. Hypoxia-driven deSUMOylation of EXOSC10 promotes adaptive changes in the transcriptome profile. Cell Mol Life Sci 2024; 81:58. [PMID: 38279024 PMCID: PMC10817850 DOI: 10.1007/s00018-023-05035-9] [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: 07/10/2023] [Revised: 10/12/2023] [Accepted: 11/06/2023] [Indexed: 01/28/2024]
Abstract
Reduced oxygen availability (hypoxia) triggers adaptive cellular responses via hypoxia-inducible factor (HIF)-dependent transcriptional activation. Adaptation to hypoxia also involves transcription-independent processes like post-translational modifications; however, these mechanisms are poorly characterized. Investigating the involvement of protein SUMOylation in response to hypoxia, we discovered that hypoxia strongly decreases the SUMOylation of Exosome subunit 10 (EXOSC10), the catalytic subunit of the RNA exosome, in an HIF-independent manner. EXOSC10 is a multifunctional exoribonuclease enriched in the nucleolus that mediates the processing and degradation of various RNA species. We demonstrate that the ubiquitin-specific protease 36 (USP36) SUMOylates EXOSC10 and we reveal SUMO1/sentrin-specific peptidase 3 (SENP3) as the enzyme-mediating deSUMOylation of EXOSC10. Under hypoxia, EXOSC10 dissociates from USP36 and translocates from the nucleolus to the nucleoplasm concomitant with its deSUMOylation. Loss of EXOSC10 SUMOylation does not detectably affect rRNA maturation but affects the mRNA transcriptome by modulating the expression levels of hypoxia-related genes. Our data suggest that dynamic modulation of EXOSC10 SUMOylation and localization under hypoxia regulates the RNA degradation machinery to facilitate cellular adaptation to low oxygen conditions.
Collapse
Affiliation(s)
- Chrysa Filippopoulou
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Chairini C Thomé
- Department of Molecular Biology, University Medical Center Göttingen, 37073, Göttingen, Germany
| | - Sofia Perdikari
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Greece
| | - Evgenia Ntini
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas (FORTH), 70013, Heraklion, Greece
| | - George Simos
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece
- Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Canada
| | - Katherine E Bohnsack
- Department of Molecular Biology, University Medical Center Göttingen, 37073, Göttingen, Germany
| | - Georgia Chachami
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41500, Larissa, Greece.
| |
Collapse
|
|
7
|
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
|
|
8
|
Vidal S, Bouzaher YH, El Motiam A, Seoane R, Rivas C. Overview of the regulation of the class IA PI3K/AKT pathway by SUMO. Semin Cell Dev Biol 2022; 132:51-61. [PMID: 34753687 DOI: 10.1016/j.semcdb.2021.10.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/14/2022]
Abstract
The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is a major regulator of metabolism, migration, survival, proliferation, and antiviral immunity. Both an overactivation and an inhibition of the PI3K/AKT pathway are related to different pathologies. Activation of this signaling pathway is tightly controlled through a multistep process and its deregulation can be associated with aberrant post-translational modifications including SUMOylation. Here, we review the complex modulation of the PI3K/AKT pathway by SUMOylation and we discuss its putative incvolvement in human disease.
Collapse
Affiliation(s)
- Santiago Vidal
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain
| | - Yanis Hichem Bouzaher
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain
| | - Ahmed El Motiam
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health Systems, Department of Ophthalmology and Vision Science, and Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1X5, Canada
| | - Rocío Seoane
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain
| | - Carmen Rivas
- Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), 15706 Santiago de Compostela, Spain; Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain.
| |
Collapse
|
|
9
|
Lin W, Zhang X, Zhang C, Li L, Zhang J, Xie P, Zhan Y, An W. Deletion of Smurf1 attenuates liver steatosis via stabilization of p53. J Transl Med 2022; 102:1075-1087. [PMID: 36775348 DOI: 10.1038/s41374-022-00802-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/19/2022] [Accepted: 04/28/2022] [Indexed: 11/09/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, characterized by excessive hepatic lipid accumulation. Recently, we demonstrated that Smad ubiquitination regulatory factor 1 (Smurf1) deficiency significantly alleviates mouse hepatic steatosis. However, the mechanism of Smurf1-regulating hepatic lipid accumulation requires further exploration and clarification. Hence, this study explores the potential mechanism of Smurf1 in hepatic steatosis. In this study, hepatic Smurf1 proteins in NAFLD patients and healthy individuals were determined using immunohistochemical staining. Control and NAFLD mouse models were established by feeding Smurf1-knockout (KO) and wild-type mice with either a high-fat diet (HFD) or a chow diet (CD) for eight weeks. Oleic acid (OA)-induced steatotic hepatocytes were used as the NAFLD mode cells. Lipid content in liver tissues was analyzed. Smurf1-MDM2 interaction, MDM2 and p53 ubiquitination, and p53 target genes expression in liver tissues and hepatocytes were analyzed. We found that hepatic Smurf1 is highly expressed in NAFLD patients and HFD-induced NAFLD mice. Its deletion attenuates hepatocyte steatosis. Mechanistically, Smurf1 interacts with and stabilizes mouse double minute 2 (MDM2), promoting p53 degradation. In Smurf1-deficient hepatocytes, an increase in p53 suppresses SREBP-1c expression and elevates the expression of both malonyl-CoA decarboxylase (MCD) and lipin1 (Lpin1), two essential proteins in lipid catabolism. Contrarily, the activities of these three proteins and hepatocyte steatosis are reversed by p53 knockdown in Smurf1-deficient hepatocytes. This study shows that Smurf1 is involved in the pathogenesis of NAFLD by balancing de novo lipid synthesis and lipolysis.
Collapse
Affiliation(s)
- Wenjun Lin
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Xin Zhang
- State Key Laboratory of Proteomics, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Chuan Zhang
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Li Li
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- The Third Unit, Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ping Xie
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.
| | - Yutao Zhan
- Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
| | - Wei An
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.
| |
Collapse
|
|
10
|
Shi X, Du Y, Li S, Wu H. The Role of SUMO E3 Ligases in Signaling Pathway of Cancer Cells. Int J Mol Sci 2022; 23:3639. [PMID: 35408996 PMCID: PMC8998487 DOI: 10.3390/ijms23073639] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Small ubiquitin-like modifier (SUMO)ylation is a reversible post-translational modification that plays a crucial role in numerous aspects of cell physiology, including cell cycle regulation, DNA damage repair, and protein trafficking and turnover, which are of importance for cell homeostasis. Mechanistically, SUMOylation is a sequential multi-enzymatic process where SUMO E3 ligases recruit substrates and accelerate the transfer of SUMO onto targets, modulating their interactions, localization, activity, or stability. Accumulating evidence highlights the critical role of dysregulated SUMO E3 ligases in processes associated with the occurrence and development of cancers. In the present review, we summarize the SUMO E3 ligases, in particular, the novel ones recently identified, and discuss their regulatory roles in cancer pathogenesis.
Collapse
Affiliation(s)
| | | | | | - Huijian Wu
- School of Bioengineering & Province Key Laboratory of Protein Modification and Disease, Dalian University of Technology, Dalian 116024, China; (X.S.); (Y.D.); (S.L.)
| |
Collapse
|
|
11
|
Insights in Post-Translational Modifications: Ubiquitin and SUMO. Int J Mol Sci 2022; 23:ijms23063281. [PMID: 35328702 PMCID: PMC8952880 DOI: 10.3390/ijms23063281] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/23/2022] Open
Abstract
Both ubiquitination and SUMOylation are dynamic post-translational modifications that regulate thousands of target proteins to control virtually every cellular process. Unfortunately, the detailed mechanisms of how all these cellular processes are regulated by both modifications remain unclear. Target proteins can be modified by one or several moieties, giving rise to polymers of different morphology. The conjugation cascades of both modifications comprise a few activating and conjugating enzymes but close to thousands of ligating enzymes (E3s) in the case of ubiquitination. As a result, these E3s give substrate specificity and can form polymers on a target protein. Polymers can be quickly modified forming branches or cleaving chains leading the target protein to its cellular fate. The recent development of mass spectrometry(MS) -based approaches has increased the understanding of ubiquitination and SUMOylation by finding essential modified targets in particular signaling pathways. Here, we perform a concise overview comprising from the basic mechanisms of both ubiquitination and SUMOylation to recent MS-based approaches aimed to find specific targets for particular E3 enzymes.
Collapse
|
|
12
|
Hariharasudhan G, Jeong SY, Kim MJ, Jung SM, Seo G, Moon JR, Lee S, Chang IY, Kee Y, You H, Lee JH. OUP accepted manuscript. Nucleic Acids Res 2022; 50:1501-1516. [PMID: 35061896 PMCID: PMC8860612 DOI: 10.1093/nar/gkac009] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 12/23/2021] [Accepted: 01/13/2022] [Indexed: 11/24/2022] Open
Abstract
Homologous recombination (HR) is critical for error-free repair of DNA double-strand breaks. Chromatin loading of RAD51, a key protein that mediates the recombination, is a crucial step in the execution of the HR repair. Here, we present evidence that SUMOylation of RAD51 is crucial for the RAD51 recruitment to chromatin and HR repair. We found that topoisomerase 1-binding arginine/serine-rich protein (TOPORS) induces the SUMOylation of RAD51 at lysine residues 57 and 70 in response to DNA damaging agents. The SUMOylation was facilitated by an ATM-induced phosphorylation of TOPORS at threonine 515 upon DNA damage. Knockdown of TOPORS or expression of SUMOylation-deficient RAD51 mutants caused reduction in supporting normal RAD51 functions during the HR repair, suggesting the physiological importance of the modification. We found that the SUMOylation-deficient RAD51 reduces the association with its crucial binding partner BRCA2, explaining its deficiency in supporting the HR repair. These findings altogether demonstrate a crucial role for TOPORS-mediated RAD51 SUMOylation in promoting HR repair and genomic maintenance.
Collapse
Affiliation(s)
- Gurusamy Hariharasudhan
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Seo-Yeon Jeong
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Pharmacology, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Min-Ji Kim
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Sung Mi Jung
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Gwanwoo Seo
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Pharmacology, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Ju-Ran Moon
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Sumi Lee
- Laboratory of Genomic Instability and Cancer Therapeutics, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
- Department of Cellular and Molecular Medicine, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - In-Youb Chang
- Department of Anatomy, Chosun University School of Medicine, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
| | - Younghoon Kee
- Correspondence may also be addressed to Younghoon Kee. Tel: +82 53 785 1610;
| | - Ho Jin You
- Correspondence may also be addressed to Ho Jin You. Tel: +82 62 230 6337;
| | - Jung-Hee Lee
- To whom correspondence should be addressed. Tel: +82 62 230 6399;
| |
Collapse
|
|
13
|
SUMO-Based Regulation of Nuclear Positioning to Spatially Regulate Homologous Recombination Activities at Replication Stress Sites. Genes (Basel) 2021; 12:genes12122010. [PMID: 34946958 PMCID: PMC8701742 DOI: 10.3390/genes12122010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/20/2022] Open
Abstract
DNA lesions have properties that allow them to escape their nuclear compartment to achieve DNA repair in another one. Recent studies uncovered that the replication fork, when its progression is impaired, exhibits increased mobility when changing nuclear positioning and anchors to nuclear pore complexes, where specific types of homologous recombination pathways take place. In yeast models, increasing evidence points out that nuclear positioning is regulated by small ubiquitin-like modifier (SUMO) metabolism, which is pivotal to maintaining genome integrity at sites of replication stress. Here, we review how SUMO-based pathways are instrumental to spatially segregate the subsequent steps of homologous recombination during replication fork restart. In particular, we discussed how routing towards nuclear pore complex anchorage allows distinct homologous recombination pathways to take place at halted replication forks.
Collapse
|
|
14
|
RNF166 plays a dual role for Lys63-linked ubiquitination and sumoylation of its target proteins. J Neural Transm (Vienna) 2021; 129:463-475. [PMID: 34837535 DOI: 10.1007/s00702-021-02442-9] [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: 08/23/2021] [Accepted: 11/08/2021] [Indexed: 10/19/2022]
Abstract
Ubiquitination and sumoylation are two important posttranslational modifications in cells. RING (Really Interesting New Gene)-type E3 ligases play essential roles in regulating a plethora of biological processes such as cell survival and death. In our previous study, we performed a microarray using inputs from MN9D dopaminergic neuronal cells treated with 6-hydroxydopamine and identified a novel RING-type E3 ligase, RNF166. We showed that RNF166 exerts proapoptotic effects via ubiquitin-dependent degradation of X-linked inhibitor of apoptosis and subsequent overactivation of caspase-dependent neuronal death following 6-hydroxydopamine treatment. In the present study, we further expanded the list of RNF166's binding substrates using mass spectral analyses of immunoprecipitates obtained from RNF166-overexpressing HEK293 cells. Poly (ADP-ribose) polymerase 1, ATPase WRNIP1, X-ray repair cross-complementing protein 5 (Ku80), and replication protein A 70 were identified as potential binding partners of RNF166. Additionally, we confirmed that RNF166 interacts with and forms lysine 63-linked polyubiquitin chains in Ku80. Consequently, these events promoted the increased stability of Ku80. Intriguingly, we found that RNF166 also contains distinct consensus sequences termed SUMO-interacting motifs and interacts with apoptosis signal-regulating kinase 1 (ASK1). We determined that RNF166 induces the sumoylation of ASK1. Overall, our data provide novel evidence that RNF166 has a dual function of Lys63-linked ubiquitination and sumoylation of its cellular targets.
Collapse
|
|
15
|
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
|
|
16
|
Pan M, Blattner C. Regulation of p53 by E3s. Cancers (Basel) 2021; 13:745. [PMID: 33670160 PMCID: PMC7916862 DOI: 10.3390/cancers13040745] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/15/2021] [Accepted: 02/05/2021] [Indexed: 12/18/2022] Open
Abstract
More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, inflammation and autophagy. In the nucleus, p53 functions as a bona-fide transcription factor which activates and represses transcription of a number of target genes. In the cytoplasm, p53 can interact with proteins of the apoptotic machinery and by this also induces cell death. Despite being so important for the fate of the cell, expression levels of p53 are kept low in unstressed cells and the protein is largely inactive. The reason for the low expression level is that p53 is efficiently degraded by the ubiquitin-proteasome system and the vast inactivity of the tumor suppressor protein under normal growth conditions is due to the absence of activating and the presence of inactivating posttranslational modifications. E3s are important enzymes for these processes as they decorate p53 with ubiquitin and small ubiquitin-like proteins and by this control p53 degradation, stability and its subcellular localization. In this review, we provide an overview about E3s that target p53 and discuss the connection between p53, E3s and tumorigenesis.
Collapse
Affiliation(s)
| | - Christine Blattner
- Institute of Biological and Chemical Systems—Biological Information Processing, Karlsruhe Institute of Technology, PO-box 3640, 76021 Karlsruhe, Germany;
| |
Collapse
|
|
17
|
The Role of Sumoylation in the Response to Hypoxia: An Overview. Cells 2020; 9:cells9112359. [PMID: 33114748 PMCID: PMC7693722 DOI: 10.3390/cells9112359] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
Sumoylation is the covalent attachment of the small ubiquitin-related modifier (SUMO) to a vast variety of proteins in order to modulate their function. Sumoylation has emerged as an important modification with a regulatory role in the cellular response to different types of stress including osmotic, hypoxic and oxidative stress. Hypoxia can occur under physiological or pathological conditions, such as ischemia and cancer, as a result of an oxygen imbalance caused by low supply and/or increased consumption. The hypoxia inducible factors (HIFs), and the proteins that regulate their fate, are critical molecular mediators of the response to hypoxia and modulate procedures such as glucose and lipid metabolism, angiogenesis, erythropoiesis and, in the case of cancer, tumor progression and metastasis. Here, we provide an overview of the sumoylation-dependent mechanisms that are activated under hypoxia and the way they influence key players of the hypoxic response pathway. As hypoxia is a hallmark of many diseases, understanding the interrelated connections between the SUMO and the hypoxic signaling pathways can open the way for future molecular therapeutic interventions.
Collapse
|
|
18
|
Abstract
Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.
Collapse
Affiliation(s)
- Hui-Ming Chang
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Edward T H Yeh
- Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| |
Collapse
|
|
19
|
Liu J, Guan D, Dong M, Yang J, Wei H, Liang Q, Song L, Xu L, Bai J, Liu C, Mao J, Zhang Q, Zhou J, Wu X, Wang M, Cong YS. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nat Cell Biol 2020; 22:1056-1063. [PMID: 32807901 DOI: 10.1038/s41556-020-0559-z] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 07/14/2020] [Indexed: 11/09/2022]
Abstract
p53 is the most intensively studied tumour suppressor1. The regulation of p53 homeostasis is essential for its tumour-suppressive function2,3. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses2-4, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions5-7. Deficiency in this modification leads to embryonic lethality in mice and disease in humans8-12. Here, we report that p53 can be covalently modified by UFM1 and that this modification stabilizes p53 by antagonizing its ubiquitination and proteasome degradation. Mechanistically, UFL1, the UFM1 ligase6, competes with MDM2 to bind to p53 for its stabilization. Depletion of UFL1 or DDRGK1, the critical regulator of UFMylation6,13, decreases p53 stability and in turn promotes cell growth and tumour formation in vivo. Clinically, UFL1 and DDRGK1 expression are downregulated and positively correlated with levels of p53 in a high percentage of renal cell carcinomas. Our results identify UFMylation as a crucial post-translational modification for maintenance of p53 stability and tumour-suppressive function, and point to UFMylation as a promising therapeutic target in cancer.
Collapse
Affiliation(s)
- Jiang Liu
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Di Guan
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Maogong Dong
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Jingjing Yang
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Haibin Wei
- Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Qian Liang
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Lizhi Song
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Lu Xu
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Junjie Bai
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Cui Liu
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Jian Mao
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Qian Zhang
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Junzhi Zhou
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Xiaoying Wu
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Miao Wang
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
| | - Yu-Sheng Cong
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.
| |
Collapse
|
|
20
|
PIAS1 and TIF1γ collaborate to promote SnoN SUMOylation and suppression of epithelial-mesenchymal transition. Cell Death Differ 2020; 28:267-282. [PMID: 32770107 DOI: 10.1038/s41418-020-0599-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023] Open
Abstract
SUMO E3 ligases specify protein substrates for SUMOylation. The SUMO E3 ligases PIAS1 and TIF1γ target the transcriptional regulator SnoN for SUMOylation leading to suppression of epithelial-mesenchymal transition (EMT). Whether and how TIF1γ and PIAS1 might coordinate SnoN SUMOylation and regulation of EMT remained unknown. Here, we reveal that SnoN associates simultaneously with both TIF1γ and PIAS1, leading to a trimeric protein complex. Hence, PIAS1 and TIF1γ collaborate to promote the SUMOylation of SnoN. Importantly, loss of function studies of PIAS1 and TIF1γ suggest that these E3 ligases act in an interdependent manner to suppress EMT of breast cell-derived tissue organoids. Collectively, our findings unveil a novel mechanism by which SUMO E3 ligases coordinate substrate SUMOylation with biological implications.
Collapse
|
|
21
|
Masucci MG. Viral Ubiquitin and Ubiquitin-Like Deconjugases-Swiss Army Knives for Infection. Biomolecules 2020; 10:E1137. [PMID: 32752270 PMCID: PMC7464072 DOI: 10.3390/biom10081137] [Citation(s) in RCA: 5] [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: 07/13/2020] [Revised: 07/31/2020] [Accepted: 07/31/2020] [Indexed: 12/16/2022] Open
Abstract
Posttranslational modifications of cellular proteins by covalent conjugation of ubiquitin and ubiquitin-like polypeptides regulate numerous cellular processes that are captured by viruses to promote infection, replication, and spreading. The importance of these protein modifications for the viral life cycle is underscored by the discovery that many viruses encode deconjugases that reverse their functions. The structural and functional characterization of these viral enzymes and the identification of their viral and cellular substrates is providing valuable insights into the biology of viral infections and the host's antiviral defense. Given the growing body of evidence demonstrating their key contribution to pathogenesis, the viral deconjugases are now recognized as attractive targets for the design of novel antiviral therapeutics.
Collapse
Affiliation(s)
- Maria Grazia Masucci
- Department of Cell and Molecular Biology, Karolinska Institutet, S-17177 Stockholm, Sweden
| |
Collapse
|
|
22
|
Rabellino A, Khanna KK. The implication of the SUMOylation pathway in breast cancer pathogenesis and treatment. Crit Rev Biochem Mol Biol 2020; 55:54-70. [PMID: 32183544 DOI: 10.1080/10409238.2020.1738332] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most commonly diagnosed malignancy in woman worldwide, and is the second most common cause of death in developed countries. The transformation of a normal cell into a malignant derivate requires the acquisition of diverse genomic and proteomic changes, including enzymatic post-translational modifications (PTMs) on key proteins encompassing critical cell signaling events. PTMs occur on proteins after translation, and regulate several aspects of proteins activity, including their localization, activation and turnover. Deregulation of PTMs can potentially lead to tumorigenesis, and several de-regulated PTM pathways contribute to abnormal cell proliferation during breast tumorigenesis. SUMOylation is a PTM that plays a pivotal role in numerous aspects of cell physiology, including cell cycle regulation, protein trafficking and turnover, and DNA damage repair. Consistently with this, the deregulation of the SUMO pathway is observed in different human pathologies, including breast cancer. In this review we will describe the role of SUMOylation in breast tumorigenesis and its implication for breast cancer therapy.
Collapse
Affiliation(s)
- Andrea Rabellino
- QIMR Berghofer Medical Research Institute, Brisbane City, Australia
| | - Kum Kum Khanna
- QIMR Berghofer Medical Research Institute, Brisbane City, Australia
| |
Collapse
|
|
23
|
Xie M, Yu J, Ge S, Huang J, Fan X. SUMOylation homeostasis in tumorigenesis. Cancer Lett 2020; 469:301-309. [DOI: 10.1016/j.canlet.2019.11.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 10/19/2019] [Accepted: 11/01/2019] [Indexed: 10/25/2022]
|
|
24
|
Malbec L, Zhang T, Chen YS, Zhang Y, Sun BF, Shi BY, Zhao YL, Yang Y, Yang YG. Dynamic methylome of internal mRNA N 7-methylguanosine and its regulatory role in translation. Cell Res 2019; 29:927-941. [PMID: 31520064 DOI: 10.1038/s41422-019-0230-z] [Citation(s) in RCA: 204] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Accepted: 08/25/2019] [Indexed: 12/22/2022] Open
Abstract
Over 150 types of RNA modifications are identified in RNA molecules. Transcriptome profiling is one of the key steps in decoding the epitranscriptomic panorama of these chemical modifications and their potential functions. N7-methylguanosine (m7G) is one of the most abundant modifications present in tRNA, rRNA and mRNA 5'cap, and has critical roles in regulating RNA processing, metabolism and function. Besides its presence at the cap position in mRNAs, m7G is also identified in internal mRNA regions. However, its transcriptome-wide distribution and dynamic regulation within internal mRNA regions remain unknown. Here, we have established m7G individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (m7G miCLIP-seq) to specifically detect internal mRNA m7G modification. Using this approach, we revealed that m7G is enriched at the 5'UTR region and AG-rich contexts, a feature that is well-conserved across different human/mouse cell lines and mouse tissues. Strikingly, the internal m7G modification is dynamically regulated under both H2O2 and heat shock treatments, with remarkable accumulations in the CDS and 3'UTR regions, and functions in promoting mRNA translation efficiency. Consistently, a PCNA 3'UTR minigene reporter harboring the native m7G modification site displays both enriched m7G modification and increased mRNA translation upon H2O2 treatment compared to the m7G site-mutated minigene reporter (G to A). Taken together, our findings unravel the dynamic profiles of internal mRNA m7G methylome and highlight m7G as a novel epitranscriptomic marker with regulatory roles in translation.
Collapse
Affiliation(s)
- Lionel Malbec
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ting Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yu-Sheng Chen
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ying Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China
| | - Bao-Fa Sun
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Bo-Yang Shi
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yong-Liang Zhao
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Ying Yang
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China.
| | - Yun-Gui Yang
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China.
| |
Collapse
|
|
25
|
Sha Z, Blyszcz T, González-Prieto R, Vertegaal ACO, Goldberg AL. Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem 2019; 294:15218-15234. [PMID: 31285264 PMCID: PMC6802522 DOI: 10.1074/jbc.ra119.009147] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/21/2019] [Indexed: 12/31/2022] Open
Abstract
Protein ubiquitination and SUMOylation are required for the maintenance of cellular protein homeostasis, and both increase in proteotoxic conditions (e.g. heat shock or proteasome inhibition). However, we found that when ubiquitination was blocked in several human cell lines by inhibiting the ubiquitin-activating enzyme with TAK243, there was an unexpected, large accumulation of proteins modified by SUMO2/3 chains or SUMO1, but not by several other ubiquitin-like proteins. This buildup of SUMOylated proteins was evident within 3–4 h. It required the small ubiquitin-like modifier (SUMO)-conjugating enzyme, UBC9, and the promyelocytic leukemia protein (PML) and thus was not due to nonspecific SUMO conjugation by ubiquitination enzymes. The SUMOylated proteins accumulated predominantly bound to chromatin and were localized to PML nuclear bodies. Because blocking protein synthesis with cycloheximide prevented the buildup of SUMOylated proteins, they appeared to be newly-synthesized proteins. The proteins SUMOylated after inhibition of ubiquitination were purified and analyzed by MS. In HeLa and U2OS cells, there was a cycloheximide-sensitive increase in a similar set of SUMOylated proteins (including transcription factors and proteins involved in DNA damage repair). Surprisingly, the inhibition of ubiquitination also caused a cycloheximide-sensitive decrease in a distinct set of SUMOylated proteins (including proteins for chromosome modification and mRNA splicing). More than 80% of the SUMOylated proteins whose levels rose or fell upon inhibiting ubiquitination inhibition underwent similar cycloheximide-sensitive increases or decreases upon proteasome inhibition. Thus, when nuclear substrates of the ubiquitin–proteasome pathway are not efficiently degraded, many become SUMO-modified and accumulate in PML bodies.
Collapse
Affiliation(s)
- Zhe Sha
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
| | - Tamara Blyszcz
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
| | - Román González-Prieto
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
| | - Alfred C O Vertegaal
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
| | - Alfred L Goldberg
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
| |
Collapse
|
|
26
|
Murga-Zamalloa C, Inamdar KV, Wilcox RA. The role of aurora A and polo-like kinases in high-risk lymphomas. Blood Adv 2019; 3:1778-1787. [PMID: 31186254 PMCID: PMC6560346 DOI: 10.1182/bloodadvances.2019000232] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 05/16/2019] [Indexed: 02/06/2023] Open
Abstract
High-risk lymphomas (HRLs) are associated with dismal outcomes and remain a therapeutic challenge. Recurrent genetic and molecular alterations, including c-myc expression and aurora A kinase (AAK) and polo-like kinase-1 (PLK1) activation, promote cell proliferation and contribute to the highly aggressive natural history associated with these lymphoproliferative disorders. In addition to its canonical targets regulating mitosis, the AAK/PLK1 axis directly regulates noncanonical targets, including c-myc. Recent studies demonstrate that HRLs, including T-cell lymphomas and many highly aggressive B-cell lymphomas, are dependent upon the AAK/PLK1 axis. Therefore, the AAK/PLK1 axis has emerged as an attractive therapeutic target in these lymphomas. In addition to reviewing these recent findings, we summarize the rationale for targeting AAK/PLK1 in high-risk and c-myc-driven lymphoproliferative disorders.
Collapse
Affiliation(s)
- Carlos Murga-Zamalloa
- Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI; and
| | | | - Ryan A Wilcox
- Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI; and
| |
Collapse
|
|
27
|
El Asmi F, Brantis-de-Carvalho CE, Blondel D, Chelbi-Alix MK. Rhabdoviruses, Antiviral Defense, and SUMO Pathway. Viruses 2018; 10:v10120686. [PMID: 30513968 PMCID: PMC6316701 DOI: 10.3390/v10120686] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/13/2018] [Accepted: 11/28/2018] [Indexed: 12/20/2022] Open
Abstract
Small Ubiquitin-like MOdifier (SUMO) conjugation to proteins has essential roles in several processes including localization, stability, and function of several players implicated in intrinsic and innate immunity. In human, five paralogs of SUMO are known of which three are ubiquitously expressed (SUMO1, 2, and 3). Infection by rhabdoviruses triggers cellular responses through the activation of pattern recognition receptors, which leads to the production and secretion of interferon. This review will focus on the effects of the stable expression of the different SUMO paralogs or Ubc9 depletion on rhabdoviruses-induced interferon production and interferon signaling pathways as well as on the expression and functions of restriction factors conferring the resistance to rhabdoviruses.
Collapse
Affiliation(s)
- Faten El Asmi
- INSERM UMR-S 1124, Université Paris Descartes, 75006 Paris, France.
| | | | - Danielle Blondel
- Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRS UMR 9198, Université Paris-Sud, 91190 Gif-sur-Yvette, France.
| | | |
Collapse
|
|
28
|
Lemée JM, Clavreul A, Aubry M, Com E, de Tayrac M, Mosser J, Menei P. Integration of transcriptome and proteome profiles in glioblastoma: looking for the missing link. BMC Mol Biol 2018; 19:13. [PMID: 30463513 PMCID: PMC6249855 DOI: 10.1186/s12867-018-0115-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 11/09/2018] [Indexed: 12/21/2022] Open
Abstract
Background Glioblastoma (GB) is the most common and aggressive tumor of the brain. Genotype-based approaches and independent analyses of the transcriptome or the proteome have led to progress in understanding the underlying biology of GB. Joint transcriptome and proteome profiling may reveal new biological insights, and identify pathogenic mechanisms or therapeutic targets for GB therapy. We present a comparison of transcriptome and proteome data from five GB biopsies (TZ) vs their corresponding peritumoral brain zone (PBZ). Omic analyses were performed using RNA microarray chips and the isotope-coded protein label method (ICPL). Results As described in other cancers, we found a poor correlation between transcriptome and proteome data in GB. We observed only two commonly deregulated mRNAs/proteins (neurofilament light polypeptide and synapsin 1) and 12 altered biological processes; they are related to cell communication, synaptic transmission and nervous system processes. This poor correlation may be a consequence of the techniques used to produce the omic profiles, the intrinsic properties of mRNA and proteins and/or of cancer- or GB-specific phenomena. Of interest, the analysis of the transcription factor binding sites present upstream from the open reading frames of all altered proteins identified by ICPL method shows a common binding site for the topoisomerase I and p53-binding protein TOPORS. Its expression was observed in 7/11 TZ samples and not in PBZ. Some findings suggest that TOPORS may function as a tumor suppressor; its implication in gliomagenesis should be examined in future studies. Conclusions In this study, we showed a low correlation between transcriptome and proteome data for GB samples as described in other cancer tissues. We observed that NEFL, SYN1 and 12 biological processes were deregulated in both the transcriptome and proteome data. It will be important to analyze more specifically these processes and these two proteins to allow the identification of new theranostic markers or potential therapeutic targets for GB. Electronic supplementary material The online version of this article (10.1186/s12867-018-0115-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Jean-Michel Lemée
- Department of Neurosurgery, CHU Angers, University Hospital of Angers, 4, Rue Larrey, 49933, Angers Cedex 09, France. .,CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.
| | - Anne Clavreul
- Department of Neurosurgery, CHU Angers, University Hospital of Angers, 4, Rue Larrey, 49933, Angers Cedex 09, France.,CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| | - Marc Aubry
- UEB, UMS 3480 Biosit, Faculté de Médecine, Université Rennes 1, Rennes, France.,Plate-forme Génomique Santé Biosit, Université Rennes 1, Rennes, France
| | - Emmanuelle Com
- Inserm U1085 IRSET, Université de Rennes 1, Rennes, France.,Protim, Université de Rennes 1, Rennes, France
| | - Marie de Tayrac
- UEB, UMS 3480 Biosit, Faculté de Médecine, Université Rennes 1, Rennes, France.,Service de Génétique Moléculaire et Génomique, CHU Rennes, Rennes, France.,CNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR), Rennes, France
| | - Jean Mosser
- UEB, UMS 3480 Biosit, Faculté de Médecine, Université Rennes 1, Rennes, France.,Plate-forme Génomique Santé Biosit, Université Rennes 1, Rennes, France.,Service de Génétique Moléculaire et Génomique, CHU Rennes, Rennes, France.,CNRS, UMR 6290, Institut de Génétique et Développement de Rennes (IGdR), Rennes, France
| | - Philippe Menei
- Department of Neurosurgery, CHU Angers, University Hospital of Angers, 4, Rue Larrey, 49933, Angers Cedex 09, France.,CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| |
Collapse
|
|
29
|
Pan Y, Li P, Jia R, Wang M, Yin Z, Cheng A. Regulation of Apoptosis During Porcine Circovirus Type 2 Infection. Front Microbiol 2018; 9:2086. [PMID: 30233552 PMCID: PMC6131304 DOI: 10.3389/fmicb.2018.02086] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Accepted: 08/15/2018] [Indexed: 12/19/2022] Open
Abstract
Apoptosis, an indispensable innate immune mechanism, regulates cellular homeostasis by removing unnecessary or damaged cells. It contains three signaling pathways: the mitochondria-mediated pathway, the death receptor pathway and the endoplasmic reticulum pathway. The importance of apoptosis in host defenses is stressed by the observation that multiple viruses have evolved various strategies to inhibit apoptosis, thereby blunting the host immune responses and promoting viral propagation. Porcine Circovirus type 2 (PCV2) utilizes various strategies to induce or inhibit programmed cell death. In this article, we review the latest research progress of the apoptosis mechanisms during infection with PCV2, including several proteins of PCV2 regulate apoptosis via interacting with host proteins and multiple signaling pathways involved in PCV2-induced apoptosis, which provides scientific basis for the pathogenesis and prevention of PCV2.
Collapse
Affiliation(s)
- Yuhong Pan
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Pengfei Li
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Zhongqiong Yin
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, China
| |
Collapse
|
|
30
|
Yang-Hartwich Y, Tedja R, Roberts CM, Goodner-Bingham J, Cardenas C, Gurea M, Sumi NJ, Alvero AB, Glackin CA, Mor G. p53-Pirh2 Complex Promotes Twist1 Degradation and Inhibits EMT. Mol Cancer Res 2018; 17:153-164. [PMID: 30131448 DOI: 10.1158/1541-7786.mcr-18-0238] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 06/29/2018] [Accepted: 08/03/2018] [Indexed: 12/13/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is a critical process involved in cancer metastasis and chemoresistance. Twist1 is a key EMT-inducing transcription factor, which is upregulated in multiple types of cancers and has been shown to promote tumor cell invasiveness and support tumor progression. Conversely, p53 is a tumor suppressor gene that is frequently mutated in cancers. This study demonstrates the ability of wild-type (WT) p53 to promote the degradation of Twist1 protein. By forming a complex with Twist1 and the E3 ligase Pirh2, WT p53 promotes the ubiquitination and proteasomal degradation of Twist1, thus inhibiting EMT and maintaining the epithelial phenotype. The ability of p53 to induce Twist1 degradation is abrogated when p53 is mutated. Consequently, the loss of p53-induced Twist1 degradation leads to EMT and the acquisition of a more invasive cancer phenotype.Implication: These data provide new insight into the metastatic process at the molecular level and suggest a signaling pathway that can potentially be used to develop new prognostic markers and therapeutic targets to curtail cancer progression.
Collapse
Affiliation(s)
- Yang Yang-Hartwich
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Roslyn Tedja
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Cai M Roberts
- Department of Stem Cell and Developmental Biology, City of Hope Beckman Research Institute, Duarte, California
| | - Jamie Goodner-Bingham
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Carlos Cardenas
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Marta Gurea
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Natalia J Sumi
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Ayesha B Alvero
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Carlotta A Glackin
- Department of Stem Cell and Developmental Biology, City of Hope Beckman Research Institute, Duarte, California
| | - Gil Mor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
| |
Collapse
|
|
31
|
Chaubal A, Pile LA. Same agent, different messages: insight into transcriptional regulation by SIN3 isoforms. Epigenetics Chromatin 2018; 11:17. [PMID: 29665841 PMCID: PMC5902990 DOI: 10.1186/s13072-018-0188-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022] Open
Abstract
SIN3 is a global transcriptional coregulator that governs expression of a large repertoire of gene targets. It is an important player in gene regulation, which can repress or activate diverse gene targets in a context-dependent manner. SIN3 is required for several vital biological processes such as cell proliferation, energy metabolism, organ development, and cellular senescence. The functional flexibility of SIN3 arises from its ability to interact with a large variety of partners through protein interaction domains that are conserved across species, ranging from yeast to mammals. Several isoforms of SIN3 are present in these different species that can perform common and specialized functions through interactions with distinct enzymes and DNA-binding partners. Although SIN3 has been well studied due to its wide-ranging functions and highly conserved interaction domains, precise roles of individual SIN3 isoforms have received less attention. In this review, we discuss the differences in structure and function of distinct SIN3 isoforms and provide possible avenues to understand the complete picture of regulation by SIN3.
Collapse
Affiliation(s)
- Ashlesha Chaubal
- Department of Biological Sciences, Wayne State University, Detroit, MI, 48202, USA
| | - Lori A Pile
- Department of Biological Sciences, Wayne State University, Detroit, MI, 48202, USA.
| |
Collapse
|
|
32
|
Gupta I, Singh K, Varshney NK, Khan S. Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis. Front Cell Dev Biol 2018; 6:11. [PMID: 29479529 PMCID: PMC5811474 DOI: 10.3389/fcell.2018.00011] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 01/26/2018] [Indexed: 01/10/2023] Open
Abstract
Regulatory functions of the ubiquitin-proteasome system (UPS) are exercised mainly by the ubiquitin ligases and deubiquitinating enzymes. Degradation of apoptotic proteins by UPS is central to the maintenance of cell health, and deregulation of this process is associated with several diseases including tumors, neurodegenerative disorders, diabetes, and inflammation. Therefore, it is the view that interrogating protein turnover in cells can offer a strategy for delineating disease-causing mechanistic perturbations and facilitate identification of drug targets. In this review, we are summarizing an overview to elucidate the updated knowledge on the molecular interplay between the apoptosis and UPS pathways. We have condensed around 100 enzymes of UPS machinery from the literature that ubiquitinates or deubiquitinates the apoptotic proteins and regulates the cell fate. We have also provided a detailed insight into how the UPS proteins are able to fine-tune the intrinsic, extrinsic, and p53-mediated apoptotic pathways to regulate cell survival or cell death. This review provides a comprehensive overview of the potential of UPS players as a drug target for cancer and other human disorders.
Collapse
Affiliation(s)
- Ishita Gupta
- Structural Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.,Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| | - Kanika Singh
- Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| | - Nishant K Varshney
- Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| | - Sameena Khan
- Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| |
Collapse
|
|
33
|
Graham AM, Lavretsky P, Muñoz-Fuentes V, Green AJ, Wilson RE, McCracken KG. Migration-Selection Balance Drives Genetic Differentiation in Genes Associated with High-Altitude Function in the Speckled Teal (Anas flavirostris) in the Andes. Genome Biol Evol 2018; 10:14-32. [PMID: 29211852 PMCID: PMC5757641 DOI: 10.1093/gbe/evx253] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2017] [Indexed: 12/30/2022] Open
Abstract
Local adaptation frequently occurs across populations as a result of migration-selection balance between divergent selective pressures and gene flow associated with life in heterogeneous landscapes. Studying the effects of selection and gene flow on the adaptation process can be achieved in systems that have recently colonized extreme environments. This study utilizes an endemic South American duck species, the speckled teal (Anas flavirostris), which has both high- and low-altitude populations. High-altitude speckled teal (A. f. oxyptera) are locally adapted to the Andean environment and mostly allopatric from low-altitude birds (A. f. flavirostris); however, there is occasional gene flow across altitudinal gradients. In this study, we used next-generation sequencing to explore genetic patterns associated with high-altitude adaptation in speckled teal populations, as well as the extent to which the balance between selection and migration have affected genetic architecture. We identified a set of loci with allele frequencies strongly correlated with altitude, including those involved in the insulin-like signaling pathway, bone morphogenesis, oxidative phosphorylation, responders to hypoxia-induced DNA damage, and feedback loops to the hypoxia-inducible factor pathway. These same outlier loci were found to have depressed gene flow estimates, as well as being highly concentrated on the Z-chromosome. Our results suggest a multifactorial response to life at high altitudes through an array of interconnected pathways that are likely under positive selection and whose genetic components seem to be providing an effective genomic barrier to interbreeding, potentially functioning as an avenue for population divergence and speciation.
Collapse
Affiliation(s)
| | | | - Violeta Muñoz-Fuentes
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
- Estación Biológica de Doñana, EBD-CSIC, Sevilla, Spain
| | - Andy J Green
- Estación Biológica de Doñana, EBD-CSIC, Sevilla, Spain
| | - Robert E Wilson
- Institute of Arctic Biology and University of Alaska Museum, University of Alaska, Fairbanks
| | - Kevin G McCracken
- Department of Biology, University of Miami
- Institute of Arctic Biology and University of Alaska Museum, University of Alaska, Fairbanks
- Rosenstiel School of Marine and Atmospheric Sciences, University of Miami
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine
| |
Collapse
|
|
34
|
Kim J, Tsuruta F, Okajima T, Yano S, Sato B, Chiba T. KLHL7 promotes TUT1 ubiquitination associated with nucleolar integrity: Implications for retinitis pigmentosa. Biochem Biophys Res Commun 2017; 494:220-226. [PMID: 29032201 DOI: 10.1016/j.bbrc.2017.10.049] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/10/2017] [Indexed: 01/06/2023]
Abstract
Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. Recent studies have revealed that mutations in klhl7 gene cause several disorders, such as retinitis pigmentosa (RP). Although KLHL7 is considered to be crucial for regulating the protein homeostasis, little is known about its biological functions. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity. TUT1 is normally localized in nucleolus; however, expression of KLHL7 facilitates a vulnerability of nucleolar integrity, followed by a decrease of TUT1 localization in nucleolus. On the other hand, pathogenic KLHL7 mutants, which causes an onset of RP, have little effect on both nucleolar integrity and TUT1 localization. Finally, KLHL7 increases TUT1 ubiquitination levels. Taken together, these results imply that KLHL7 is a novel regulator of nucleolus associated with TUT1 ubiquitination. Our study may provide a valuable information to elucidate a pathogenic mechanism of RP.
Collapse
Affiliation(s)
- Jaehyun Kim
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Fuminori Tsuruta
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; PhD Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
| | - Tomomi Okajima
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Sarasa Yano
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Ban Sato
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Tomoki Chiba
- Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; PhD Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
| |
Collapse
|
|
35
|
Prudent J, McBride HM. The mitochondria–endoplasmic reticulum contact sites: a signalling platform for cell death. Curr Opin Cell Biol 2017; 47:52-63. [DOI: 10.1016/j.ceb.2017.03.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 02/22/2017] [Accepted: 03/01/2017] [Indexed: 01/23/2023]
|
|
36
|
Kumar S, Sharma G, Chakraborty C, Sharma AR, Kim J. Regulatory functional territory of PLK-1 and their substrates beyond mitosis. Oncotarget 2017; 8:37942-37962. [PMID: 28415805 PMCID: PMC5514964 DOI: 10.18632/oncotarget.16290] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/03/2017] [Indexed: 12/04/2022] Open
Abstract
Polo-like kinase 1 (PLK-1) is a well-known (Ser/Thr) mitotic protein kinase and is considered as a proto-oncogene. As hyper-activation of PLK-1 is broadly associated with poor prognosis and cancer progression, it is one of the most extensively studied mitotic kinases. During mitosis, PLK-1 regulates various cell cycle events, such as spindle pole maturation, chromosome segregation and cytokinesis. However, studies have demonstrated that the role of PLK-1 is not only restricted to mitosis, but PLK-1 can also regulate other vital events beyond mitosis, including transcription, translation, ciliogenesis, checkpoint adaptation and recovery, apoptosis, chromosomes dynamics etc. Recent reviews have tried to define the regulatory role of PLK-1 during mitosis progression and tumorigenesis, but its' functional role beyond mitosis is still largely unexplored. PLK-1 can regulate the activity of many proteins that work outside of its conventional territory. The dysregulation of these proteins can cause diseases such as Alzheimer's disease, tumorigenesis etc. and may also lead to drug resistance. Thus, in this review, we discussed the versatile role of PLK-1 and tried to collect data to validate its' functional role in cell cycle regulation apart from mitosis.
Collapse
Affiliation(s)
- Shiv Kumar
- Department of Biochemistry, Institute of Cell Differentiation and Aging, Hallym University, College of Medicine, Chucheonsi, Gangwondo, Republic of Korea
| | - Garima Sharma
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University, College of Medicine, Chucheonsi, Gangwondo, Republic of Korea
| | - Chiranjib Chakraborty
- Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Ashish Ranjan Sharma
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University, College of Medicine, Chucheonsi, Gangwondo, Republic of Korea
| | - Jaebong Kim
- Department of Biochemistry, Institute of Cell Differentiation and Aging, Hallym University, College of Medicine, Chucheonsi, Gangwondo, Republic of Korea
| |
Collapse
|
|
37
|
Namuduri AV, Heras G, Mi J, Cacciani N, Hörnaeus K, Konzer A, Lind SB, Larsson L, Gastaldello S. A Proteomic Approach to Identify Alterations in the Small Ubiquitin-like Modifier (SUMO) Network during Controlled Mechanical Ventilation in Rat Diaphragm Muscle. Mol Cell Proteomics 2017; 16:1081-1097. [PMID: 28373296 DOI: 10.1074/mcp.m116.066159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 04/03/2017] [Indexed: 12/17/2022] Open
Abstract
The small ubiquitin-like modifier (SUMO) is as a regulator of many cellular functions by reversible conjugation to a broad number of substrates. Under endogenous or exogenous perturbations, the SUMO network becomes a fine sensor of stress conditions by alterations in the expression level of SUMO enzymes and consequently changing the status of SUMOylated proteins. The diaphragm is the major inspiratory muscle, which is continuously active under physiological conditions, but its structure and function is severely affected when passively displaced for long extents during mechanical ventilation (MV). An iatrogenic condition called Ventilator-Induced Diaphragm Dysfunction (VIDD) is a major cause of failure to wean patients from ventilator support but the molecular mechanisms underlying this dysfunction are not fully understood. Using a unique experimental Intensive Care Unit (ICU) rat model allowing long-term MV, diaphragm muscles were collected in rats control and exposed to controlled MV (CMV) for durations varying between 1 and 10 days. Endogenous SUMOylated diaphragm proteins were identified by mass spectrometry and validated with in vitro SUMOylation systems. Contractile, calcium regulator and mitochondrial proteins were of specific interest due to their putative involvement in VIDD. Differences were observed in the abundance of SUMOylated proteins between glycolytic and oxidative muscle fibers in control animals and high levels of SUMOylated proteins were present in all fibers during CMV. Finally, previously reported VIDD biomarkers and therapeutic targets were also identified in our datasets which may play an important role in response to muscle weakness seen in ICU patients. Data are available via ProteomeXchange with identifier PXD006085. Username: reviewer26663@ebi.ac.uk, Password: rwcP5W0o.
Collapse
Affiliation(s)
- Arvind Venkat Namuduri
- From the ‡Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE-17177, Sweden
| | - Gabriel Heras
- From the ‡Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE-17177, Sweden
| | - Jia Mi
- §Department of Chemistry-BMC, Analytical Chemistry and Science for Lab Laboratory, Uppsala University, Box 599, Uppsala, SE-75124, Sweden.,¶Medicine and Pharmacy Research Center, Binzhou Medical University, Laishan District, No. 346, Guanhai Road, Yantai, Shandong Province, 264003 China
| | - Nicola Cacciani
- From the ‡Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE-17177, Sweden
| | - Katarina Hörnaeus
- §Department of Chemistry-BMC, Analytical Chemistry and Science for Lab Laboratory, Uppsala University, Box 599, Uppsala, SE-75124, Sweden
| | - Anne Konzer
- §Department of Chemistry-BMC, Analytical Chemistry and Science for Lab Laboratory, Uppsala University, Box 599, Uppsala, SE-75124, Sweden
| | - Sara Bergström Lind
- §Department of Chemistry-BMC, Analytical Chemistry and Science for Lab Laboratory, Uppsala University, Box 599, Uppsala, SE-75124, Sweden
| | - Lars Larsson
- From the ‡Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE-17177, Sweden.,‖Department of Biobehavioral Health, The Pennsylvania State University, University Park, Pennsylvania 16801; and.,**Department of Clinical Neuroscience, Clinical Neurophysiology, Karolinska Institutet, Stockholm, SE-17177, Sweden
| | - Stefano Gastaldello
- From the ‡Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, SE-17177, Sweden;
| |
Collapse
|
|
38
|
Jin L, Shen K, Chen T, Yu W, Zhang H. SUMO-1 Gene Silencing Inhibits Proliferation and Promotes Apoptosis of Human Gastric Cancer SGC-7901 Cells. Cell Physiol Biochem 2017; 41:987-998. [DOI: 10.1159/000460836] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/28/2016] [Indexed: 01/07/2023] Open
Abstract
Background: It has been reported that blocking small ubiquitin-like modifier (SUMO) conjugation by silencing SUMO gene remarkably decreased tumor growth in vivo. However, few studies have examined the relationship between SUMO gene silencing and gastric cancer (GC). The study aims to explore the effects of SUMO-1 gene silencing on GC cell proliferation and apoptosis. Methods: GC cells were cultured and divided into 5 groups: the blank group (without any transfection or treatment), the empty vector group (transfected with empty vector), the shRNA-SUMO-1-1 group (transfected with shRNA-SUMO-1-1 plasmid), the shRNA-SUMO-1-2 group (transfected with shRNA-SUMO-1-2 plasmid), and the shRNA-SUMO-1-3 group (transfected with shRNA-SUMO-1-3 plasmid). Cell Counting Kit-8 (CCK-8) assay was performed to examine cell proliferation. Annexin V/PI staining combined with flow cytometry were used to detect cell apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were employed to measure the mRNA and protein expressions of SUMO-1, P53, Bcl-2 and c-myc, respectively. Results: SUMO-1 mRNA and protein expressions were decreased after transfecting with shRNA-SUMO-1. Compared with the blank group, the shRNA-SUMO-1-1 group presented a remarkable decreased proliferation of SGC-7901 cells. Significant increase in cell apoptosis rate was observed. Bcl-2, c-myc and P53 expressions were declined after transfecting with shRNA-SUMO plasmid. Conclusion: Our study provided evidence that SUMO-1 gene silencing could decrease proliferation and promote apoptosis in GC cells.
Collapse
|
|
39
|
Abstract
Reversible post-translational modification is a rapid and efficient system to control the activity of pre-existing proteins. Modifiers range from small chemical moieties, such as phosphate groups, to proteins themselves as the modifier. The patriarch of the protein modifiers is ubiquitin which plays a central role in protein degradation and protein targeting. Over the last 20 years, the ubiquitin family has expanded to include a variety of ubiquitin-related small modifier proteins that are all covalently attached to a lysine residue on target proteins via series of enzymatic reactions. Of these more recently discovered ubiquitin-like proteins, the SUMO family has gained prominence as a major regulatory component that impacts numerous aspects of cell growth, differentiation, and response to stress. Unlike ubiquitinylation which often leads to proteins turn over, sumoylation performs a variety of function such as altering protein stability, modulating protein trafficking, directing protein-protein interactions, and regulating protein activity. This chapter will introduce the basic properties of SUMO proteins and the general tenets of sumoylation.
Collapse
Affiliation(s)
- Van G Wilson
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, 8447 HWY 47, Bryan, TX, 77807-1359, USA.
| |
Collapse
|
|
40
|
Coppieters F, Ascari G, Dannhausen K, Nikopoulos K, Peelman F, Karlstetter M, Xu M, Brachet C, Meunier I, Tsilimbaris M, Tsika C, Blazaki S, Vergult S, Farinelli P, Van Laethem T, Bauwens M, De Bruyne M, Chen R, Langmann T, Sui R, Meire F, Rivolta C, Hamel C, Leroy B, De Baere E. Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. Am J Hum Genet 2016; 99:470-80. [PMID: 27486781 PMCID: PMC4974088 DOI: 10.1016/j.ajhg.2016.06.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 06/20/2016] [Indexed: 11/24/2022] Open
Abstract
Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals’ lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations.
Collapse
|
|
41
|
Gutteridge REA, Ndiaye MA, Liu X, Ahmad N. Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics. Mol Cancer Ther 2016; 15:1427-35. [PMID: 27330107 PMCID: PMC4936921 DOI: 10.1158/1535-7163.mct-15-0897] [Citation(s) in RCA: 295] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 04/06/2016] [Indexed: 01/06/2023]
Abstract
Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor volasertib has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed toward understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer. Mol Cancer Ther; 15(7); 1427-35. ©2016 AACR.
Collapse
Affiliation(s)
| | - Mary Ann Ndiaye
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin
| | - Xiaoqi Liu
- Department of Biochemistry, Purdue University, West Lafayette, Indiana
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin. William S. Middleton Memorial VA Hospital, Madison, Wisconsin.
| |
Collapse
|
|
42
|
Liebelt F, Vertegaal ACO. Ubiquitin-dependent and independent roles of SUMO in proteostasis. Am J Physiol Cell Physiol 2016; 311:C284-96. [PMID: 27335169 PMCID: PMC5129774 DOI: 10.1152/ajpcell.00091.2016] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 06/15/2016] [Indexed: 01/04/2023]
Abstract
Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.
Collapse
Affiliation(s)
- Frauke Liebelt
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Alfred C O Vertegaal
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
| |
Collapse
|
|
43
|
Kumar S, Sharma AR, Sharma G, Chakraborty C, Kim J. PLK-1: Angel or devil for cell cycle progression. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1865:190-203. [PMID: 26899266 DOI: 10.1016/j.bbcan.2016.02.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 02/01/2016] [Accepted: 02/16/2016] [Indexed: 12/31/2022]
Abstract
PLK-1 is a key player in the eukaryotic cell cycle. Cell cycle progression is precisely controlled by cell cycle regulatory kinases. PLK-1 is a mitotic kinase that actively regulates the G2/M transition, mitosis, mitotic exit, and cytokinesis. During cell cycle progression, PLK-1 controls various events related to the cell cycle maturation, directly and/or indirectly. On the contrary, aberrant expression of PLK-1 is strongly associated with tumorigenesis and its poor prognosis. The misexpression of PLK-1 causes the abnormalities including aneuploidy, mitotic defects, leading to tumorigenesis through inhibiting the p53 and pRB genes. Therefore, we reviewed the role of PLK-1 in the cell cycle progression and in the tumorigenesis either as a cell cycle regulator or on an attractive anti-cancer drug target.
Collapse
Affiliation(s)
- Shiv Kumar
- Department of Biochemistry, Institute of Cell Differentiation and Aging, Hallym University, College of Medicine, Chucheonsi, Gangwondo 200-704, Republic of Korea.
| | - Ashish Ranjan Sharma
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University, College of Medicine, Chucheonsi, Gangwondo 200-704, Republic of Korea.
| | - Garima Sharma
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University, College of Medicine, Chucheonsi, Gangwondo 200-704, Republic of Korea.
| | - Chiranjib Chakraborty
- Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida 203201, India.
| | - Jaebong Kim
- Department of Biochemistry, Institute of Cell Differentiation and Aging, Hallym University, College of Medicine, Chucheonsi, Gangwondo 200-704, Republic of Korea.
| |
Collapse
|
|
44
|
Abstract
SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes. Recently, Small Ubiquitin-related MOdifier (SUMO) modification has emerged as a fundamental route that may drive different steps of human tumorigenesis. Indeed, alteration in expression or activity of one of the different SUMO pathway components may completely subvert cellular properties through fine-tuning modulation of protein(s) involved in carcinogenic pathways, leading to altered cell proliferation, apoptosis resistance and metastatic potential. Here we describe some of the most interesting findings pointing to a clear link between SUMO pathway and human malignancies. Importantly, a putative role for SUMO enzymes to predict cancer behavior can be speculated, and thus the possible application of alterations in SUMO pathway components as tumor biomarkers is discussed.
Collapse
Affiliation(s)
- Domenico Mattoscio
- 1Department of Experimental Oncology, European Institute of Oncology@ IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy
| | - Susanna Chiocca
- 1Department of Experimental Oncology, European Institute of Oncology@ IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy
| |
Collapse
|
|
45
|
TOPORS, a Dual E3 Ubiquitin and Sumo1 Ligase, Interacts with 26 S Protease Regulatory Subunit 4, Encoded by the PSMC1 Gene. PLoS One 2016; 11:e0148678. [PMID: 26872363 PMCID: PMC4752349 DOI: 10.1371/journal.pone.0148678] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 01/20/2016] [Indexed: 11/19/2022] Open
Abstract
The significance of the ubiquitin-proteasome system (UPS) for protein degradation has been highlighted in the context of neurodegenerative diseases, including retinal dystrophies. TOPORS, a dual E3 ubiquitin and SUMO1 ligase, forms a component of the UPS and selected substrates for its enzymatic activities, such as DJ-1/PARK7 and APOBEC2, are important for neuronal as well as retinal homeostasis, respectively. TOPORS is ubiquitously expressed, yet its mutations are only known to result in autosomal dominant retinitis pigmentosa. We performed a yeast two-hybrid (Y2H) screen of a human retinal cDNA library in order to identify interacting protein partners of TOPORS from the retina, and thus begin delineating the putative disease mechanism(s) associated with the retina-specific phenotype resulting from mutations in TOPORS. The screen led to isolation of the 26 S protease regulatory subunit 4 (P26s4/ PSMC1), an ATPase indispensable for correct functioning of UPS-mediated proteostasis. The interaction between endogenous TOPORS and P26s4 proteins was validated by co-immuno-precipitation from mammalian cell extracts and further characterised by immunofluorescent co-localisation studies in cell lines and retinal sections. Findings from hTERT-RPE1 and 661W cells demonstrated that TOPORS and P26s4 co-localise at the centrosome in cultured cells. Immunofluorescent staining of mouse retinae revealed a strong P26s4 reactivity at the interface between retinal pigmented epithelium (RPE) layer and the photoreceptors outer segments (OS). This finding leads us to speculate that P26s4, along with TOPORS, may have a role(s) in RPE phagocytosis, in addition to contributing to the overall photoreceptor and retinal homeostasis via the UPS.
Collapse
|
|
46
|
Henley JM, Craig TJ, Wilkinson KA. Neuronal SUMOylation: mechanisms, physiology, and roles in neuronal dysfunction. Physiol Rev 2014; 94:1249-85. [PMID: 25287864 PMCID: PMC4187031 DOI: 10.1152/physrev.00008.2014] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Protein SUMOylation is a critically important posttranslational protein modification that participates in nearly all aspects of cellular physiology. In the nearly 20 years since its discovery, SUMOylation has emerged as a major regulator of nuclear function, and more recently, it has become clear that SUMOylation has key roles in the regulation of protein trafficking and function outside of the nucleus. In neurons, SUMOylation participates in cellular processes ranging from neuronal differentiation and control of synapse formation to regulation of synaptic transmission and cell survival. It is a highly dynamic and usually transient modification that enhances or hinders interactions between proteins, and its consequences are extremely diverse. Hundreds of different proteins are SUMO substrates, and dysfunction of protein SUMOylation is implicated in a many different diseases. Here we briefly outline core aspects of the SUMO system and provide a detailed overview of the current understanding of the roles of SUMOylation in healthy and diseased neurons.
Collapse
Affiliation(s)
- Jeremy M Henley
- School of Biochemistry, University of Bristol, Bristol, United Kingdom
| | - Tim J Craig
- School of Biochemistry, University of Bristol, Bristol, United Kingdom
| | - Kevin A Wilkinson
- School of Biochemistry, University of Bristol, Bristol, United Kingdom
| |
Collapse
|
|
47
|
Wasik U, Filipek A. Non-nuclear function of sumoylated proteins. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:2878-2885. [PMID: 25110347 DOI: 10.1016/j.bbamcr.2014.07.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 07/11/2014] [Accepted: 07/30/2014] [Indexed: 12/16/2022]
Abstract
Post-translational modification by the SUMO moiety is now regarded as one of the key regulatory modifications in eukaryotic cells. Up to now, plenty of sumoylated proteins have been found to be involved in nuclear processes such as chromatin organization, transcription and DNA repair as well as in other cellular functions. Since the number of data concerning sumoylated proteins and their function outside the nucleus has grown rapidly, in this review we summarized the results describing the non-nuclear role of SUMO substrates. In particular, we focused on the role of sumoylation in the regulation of channel activity, receptor function, G-protein signaling, activity of enzymes, cytoskeletal organization, exocytosis, autophagy and mitochondrial dynamics.
Collapse
Affiliation(s)
- Urszula Wasik
- Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Anna Filipek
- Nencki Institute of Experimental Biology, Warsaw, Poland.
| |
Collapse
|
|
48
|
Heinonen S, Saarinen L, Naukkarinen J, Rodríguez A, Frühbeck G, Hakkarainen A, Lundbom J, Lundbom N, Vuolteenaho K, Moilanen E, Arner P, Hautaniemi S, Suomalainen A, Kaprio J, Rissanen A, Pietiläinen KH. Adipocyte morphology and implications for metabolic derangements in acquired obesity. Int J Obes (Lond) 2014; 38:1423-31. [PMID: 24549139 DOI: 10.1038/ijo.2014.31] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/23/2014] [Accepted: 01/27/2014] [Indexed: 11/09/2022]
Abstract
BACKGROUND Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear. METHODS We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A). RESULTS The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death. CONCLUSIONS Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.
Collapse
Affiliation(s)
- S Heinonen
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - L Saarinen
- Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, Biochemistry and Developmental Biology, Helsinki, Finland
| | - J Naukkarinen
- 1] Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland [2] FIMM, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - A Rodríguez
- Metabolic Research Laboratory, Clinica Universidad de Navarra, & CIBERobn, Instituto de Salud Carlos III, Pamplona, Spain
| | - G Frühbeck
- Metabolic Research Laboratory, Clinica Universidad de Navarra, & CIBERobn, Instituto de Salud Carlos III, Pamplona, Spain
| | - A Hakkarainen
- Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
| | - J Lundbom
- Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
| | - N Lundbom
- Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
| | - K Vuolteenaho
- The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
| | - E Moilanen
- The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland
| | - P Arner
- Lipid Laboratory, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - S Hautaniemi
- Research Programs Unit, Genome-Scale Biology and Institute of Biomedicine, Biochemistry and Developmental Biology, Helsinki, Finland
| | - A Suomalainen
- Research Program of Molecular Neurology and Department of Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - J Kaprio
- 1] FIMM, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland [2] Finnish Twin Cohort Study, Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki Finland [3] National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland
| | - A Rissanen
- Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland
| | - K H Pietiläinen
- 1] Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland [2] FIMM, Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland [3] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland
| |
Collapse
|
|
49
|
Luxton HJ, Barnouin K, Kelly G, Hanrahan S, Totty N, Neal DE, Whitaker HC. Regulation of the localisation and function of the oncogene LYRIC/AEG-1 by ubiquitination at K486 and K491. Mol Oncol 2014; 8:633-41. [PMID: 24529480 PMCID: PMC4013555 DOI: 10.1016/j.molonc.2014.01.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 01/13/2014] [Accepted: 01/14/2014] [Indexed: 11/30/2022] Open
Abstract
The pivotal role of LYRIC/AEG‐1 in malignant transformation, tumourigenesis and chemo‐resistance has previously been demonstrated in different cell types and sub‐cellular compartments. The localisation of LYRIC/AEG‐1 appears crucial to its function and is regulated by three lysine‐rich nuclear localisation signal regions, one of which was previously demonstrated to be modified by ubiquitin. Here we show that mutation of LYRIC/AEG‐1 at K486 and K491 results in a loss of ubiquitination. A K486/491R double mutant that is incapable of ubiquitination shows reduced binding to the NFκB subunit p65 or importin‐β resulting in a distinctive peri‐nuclear localisation of LYRIC/AEG‐1. We also provide evidence to suggest that TOPORS, an E3 ligase that also regulates p53 modification may be responsible for LYRIC/AEG‐1 ubiquitin modification. Overall we demonstrate that specific sites of LYRIC/AEG‐1 ubiquitination are essential for regulating LYRIC/AEG‐1 localisation and functionally interacting proteins.
LYRIC/AEG‐1 is an important oncogene. 2 specific lysine residues in exNLS‐2 are ubiquitinated. Deletion of both lysine residues changes localisation and interaction with p65. LYRIC/AEG‐1 interacts with TOPORS, a known E3 ligase.
Collapse
Affiliation(s)
- Hayley J Luxton
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Karin Barnouin
- Protein Analysis and Proteomics, Cancer Research UK London Research Institute, London WC2A 3LY, UK; Protein Analysis and Proteomics, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Potters Bar EN6 3LD, UK
| | - Gavin Kelly
- Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London WC2A 3LY, UK
| | - Sarah Hanrahan
- Protein Analysis and Proteomics, Cancer Research UK London Research Institute, London WC2A 3LY, UK
| | - Nick Totty
- Protein Analysis and Proteomics, Cancer Research UK London Research Institute, London WC2A 3LY, UK
| | - David E Neal
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Hayley C Whitaker
- Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
| |
Collapse
|
|
50
|
SIM-dependent enhancement of substrate-specific SUMOylation by a ubiquitin ligase in vitro. Biochem J 2014; 457:435-40. [DOI: 10.1042/bj20131381] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The present study demonstrates that the Saccharomyces cerevisiae ubiquitin ligase Rad18 can unexpectedly catalyse conjugation of SUMO to its target, PCNA, with high selectivity under in vitro conditions by means of a SUMO-interacting motif that is normally involved in substrate recognition.
Collapse
|