-
Open Biology Jul 2021SUMOylation dynamically conjugates SUMO molecules to the lysine residue of a substrate protein, which depends on the physiological state of the cell and the attached... (Review)
Review
SUMOylation dynamically conjugates SUMO molecules to the lysine residue of a substrate protein, which depends on the physiological state of the cell and the attached SUMO isoforms. A prominent role of SUMOylation in molecular pathways is to govern the cellular death process. Herein, we summarize the association between SUMOylation modification events and four types of cellular death processes: apoptosis, autophagy, senescence and pyroptosis. SUMOylation positively or negatively regulates a certain cellular death pattern depending on specific conditions including the attached SUMO isoforms, disease types, substrate proteins and cell context. Moreover, we also discuss the possible role of SUMOylation in ferroptosis and propose a potential role of the SUMOylated GPX4 in the regulation of ferroptosis. Mapping the exact SUMOylation network with cellular death contributes to develop novel SUMOylation-targeting disease therapeutic strategies.
Topics: Animals; Biomarkers; Cell Death; Ferroptosis; Gene Expression Regulation; Humans; Phospholipid Hydroperoxide Glutathione Peroxidase; Protein Processing, Post-Translational; Protein Transport; Sumoylation
PubMed: 34255975
DOI: 10.1098/rsob.210050 -
International Journal of Oncology Apr 2018SUMOylation is a reversible post-translational modification which has emerged as a crucial molecular regulatory mechanism, involved in the regulation of DNA damage... (Review)
Review
SUMOylation is a reversible post-translational modification which has emerged as a crucial molecular regulatory mechanism, involved in the regulation of DNA damage repair, immune responses, carcinogenesis, cell cycle progression and apoptosis. Four SUMO isoforms have been identified, which are SUMO1, SUMO2/3 and SUMO4. The small ubiquitin-like modifier (SUMO) pathway is conserved in all eukaryotes and plays pivotal roles in the regulation of gene expression, cellular signaling and the maintenance of genomic integrity. The SUMO catalytic cycle includes maturation, activation, conjugation, ligation and de-modification. The dysregulation of the SUMO system is associated with a number of diseases, particularly cancer. SUMOylation is widely involved in carcinogenesis, DNA damage response, cancer cell proliferation, metastasis and apoptosis. SUMO can be used as a potential therapeutic target for cancer. In this review, we briefly outline the basic concepts of the SUMO system and summarize the involvement of SUMO proteins in cancer cells in order to better understand the role of SUMO in human disease.
Topics: Animals; Humans; Neoplasms; Protein Processing, Post-Translational; Small Ubiquitin-Related Modifier Proteins; Sumoylation
PubMed: 29484374
DOI: 10.3892/ijo.2018.4280 -
Nature Communications Aug 2021The cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome. Various posttranslational modifications (PTMs), including...
The cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome. Various posttranslational modifications (PTMs), including phosphorylation and ubiquitination, control NLRP3 protein degradation and inflammasome activation; however, the function of small ubiquitin-like modifier (SUMO) modification (called SUMOylation) in controlling NLRP3 stability and subsequent inflammasome activation is unclear. Here, we show that the E3 SUMO ligase tripartite motif-containing protein 28 (TRIM28) is an enhancer of NLRP3 inflammasome activation by facilitating NLRP3 expression. TRIM28 binds NLRP3, promotes SUMO1, SUMO2 and SUMO3 modification of NLRP3, and thereby inhibits NLRP3 ubiquitination and proteasomal degradation. Concordantly, Trim28 deficiency attenuates NLRP3 inflammasome activation both in vitro and in vivo. These data identify a mechanism by which SUMOylation controls the cellular NLRP3 level and inflammasome activation, and reveal correlations and interactions of NLRP3 SUMOylation and ubiquitination during inflammasome activation.
Topics: Animals; Female; HEK293 Cells; Humans; Inflammasomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphorylation; Protein Processing, Post-Translational; Proteolysis; SUMO-1 Protein; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Tripartite Motif-Containing Protein 28; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitins
PubMed: 34373456
DOI: 10.1038/s41467-021-25033-4 -
Nature Communications Sep 2022DNA end resection is delicately regulated through various types of post-translational modifications to initiate homologous recombination, but the involvement of...
DNA end resection is delicately regulated through various types of post-translational modifications to initiate homologous recombination, but the involvement of SUMOylation in this process remains incompletely understood. Here, we show that MRE11 requires SUMOylation to shield it from ubiquitin-mediated degradation when resecting damaged chromatin. Upon DSB induction, PIAS1 promotes MRE11 SUMOylation on chromatin to initiate DNA end resection. Then, MRE11 is deSUMOylated by SENP3 mainly after it has moved away from DSB sites. SENP3 deficiency results in MRE11 degradation failure and accumulation on chromatin, causing genome instability. We further show that cancer-related MRE11 mutants with impaired SUMOylation exhibit compromised DNA repair ability. Thus, we demonstrate that MRE11 SUMOylation in coordination with ubiquitylation is dynamically controlled by PIAS1 and SENP3 to facilitate DNA end resection and maintain genome stability.
Topics: Chromatin; Cysteine Endopeptidases; DNA; DNA Breaks, Double-Stranded; DNA Repair; Genomic Instability; Homeostasis; Humans; MRE11 Homologue Protein; Protein Inhibitors of Activated STAT; Sumoylation; Ubiquitination
PubMed: 36050397
DOI: 10.1038/s41467-022-32920-x -
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer.The Journal of Clinical Investigation May 2022Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved...
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell-mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Topics: Antigen Presentation; Histocompatibility Antigens Class I; Humans; Immune Evasion; Neoplasms; Sumoylation
PubMed: 35499080
DOI: 10.1172/JCI152383 -
Science Advances Jan 2021Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here,...
Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor κB activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the IκB kinase (IKK) complex and selectively enhanced IKKα degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKKα and NBR1 to promote IKKα degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.
Topics: Animals; Annexin A1; Autophagy; Brain Ischemia; I-kappa B Kinase; Mice; Microglia; Sumoylation
PubMed: 33523920
DOI: 10.1126/sciadv.abc5539 -
Development (Cambridge, England) Mar 2020In essentially all eukaryotes, proteins can be modified by the attachment of small ubiquitin-related modifier (SUMO) proteins to lysine side chains to produce branched... (Review)
Review
In essentially all eukaryotes, proteins can be modified by the attachment of small ubiquitin-related modifier (SUMO) proteins to lysine side chains to produce branched proteins. This process of 'SUMOylation' plays essential roles in plant and animal development by altering protein function in spatially and temporally controlled ways. In this Primer, we explain the process of SUMOylation and summarize how SUMOylation regulates a number of signal transduction pathways. Next, we discuss multiple roles of SUMOylation in the epigenetic control of transcription. In addition, we evaluate the role of SUMOylation in the etiology of neurodegenerative disorders, focusing on Parkinson's disease and cerebral ischemia. Finally, we discuss the possibility that SUMOylation may stimulate survival and neurogenesis of neuronal stem cells.
Topics: Animals; Growth and Development; Humans; Nerve Degeneration; Neurodegenerative Diseases; Neurogenesis; Plant Development; Protein Processing, Post-Translational; Signal Transduction; Sumoylation
PubMed: 32188601
DOI: 10.1242/dev.175703 -
Theranostics 2023SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus,...
SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic. and SUMOylation assays were used to determine the SUMOylation levels of MORC2. Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation. The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through and functional assays. Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms. Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner. MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1). Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28. MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair. At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair. Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs. Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR. We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway.
Topics: Humans; Female; Sumoylation; Chromatin Assembly and Disassembly; Drug Resistance, Neoplasm; Breast Neoplasms; DNA Repair; DNA Damage; Chromatin; Transcription Factors
PubMed: 36793866
DOI: 10.7150/thno.79688 -
Science Translational Medicine Sep 2021SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1)...
SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8 T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.
Topics: Immunity; Sumoylation
PubMed: 34524860
DOI: 10.1126/scitranslmed.aba7791 -
International Journal of Molecular... Jul 2022Since the discovery of the small ubiquitin-like modifier (SUMO) protein in 1995, SUMOylation has been considered a crucial post-translational modification in diverse... (Review)
Review
Since the discovery of the small ubiquitin-like modifier (SUMO) protein in 1995, SUMOylation has been considered a crucial post-translational modification in diverse cellular functions. In neurons, SUMOylation has various roles ranging from managing synaptic transmitter release to maintaining mitochondrial integrity and determining neuronal health. It has been discovered that neuronal dysfunction is a key factor in the development of major depressive disorder (MDD). PubMed and Google Scholar databases were searched with keywords such as 'SUMO', 'neuronal plasticity', and 'depression' to obtain relevant scientific literature. Here, we provide an overview of recent studies demonstrating the role of SUMOylation in maintaining neuronal function in participants suffering from MDD.
Topics: Depressive Disorder, Major; Humans; Neurons; Protein Processing, Post-Translational; Small Ubiquitin-Related Modifier Proteins; Sumoylation
PubMed: 35887370
DOI: 10.3390/ijms23148023