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Journal of Cerebral Blood Flow and... Jan 2018Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been... (Review)
Review
Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been extensively studied in brain ischemia. Convincing evidence is now at hand to support the notion that a major increase in levels of SUMOylated proteins is capable of inducing tolerance to ischemic stress. Therefore, the SUMOylation pathway has emerged as a promising therapeutic target for neuroprotection in the face of brain ischemia. Despite this, it is prudent to acknowledge that there are many key questions still to be addressed in brain ischemia related to SUMOylation. Accordingly, herein, we provide a critical review of literature within the field to summarize current knowledge and in so doing highlight pertinent translational implications of the SUMOylation pathway in brain ischemia.
Topics: Brain Ischemia; Humans; Neuroprotection; Sumoylation
PubMed: 29148315
DOI: 10.1177/0271678X17742260 -
Neurobiology of Disease Nov 2023SUMOylation is a post-translational modification (PTM) that exerts a regulatory role in different cellular processes, including protein localization, aggregation, and...
SUMOylation is a post-translational modification (PTM) that exerts a regulatory role in different cellular processes, including protein localization, aggregation, and biological activities. It consists of the dynamic formation of covalent isopeptide bonds between a family member of the Small Ubiquitin Like Modifiers (SUMOs) and the target proteins. Interestingly, it is a cellular mechanism implicated in several neurodegenerative pathologies and potentially it could become a new therapeutic target; however, there are very few pharmacological tools to modulate the SUMOylation process. In this study, we have designed and tested the activity of a novel small cell-permeable peptide, COV-1, in a neuroblastoma cell line that specifically prevents protein SUMOylation. COV-1 inhibits UBC9-protein target interaction and efficiently decreases global SUMO-1ylation. Moreover, it can perturb RanGAP-1 perinuclear localization by inducing the downregulation of UBC9. In parallel, we found that COV-1 causes an increase in the ubiquitin degradation system up to its engulfment while enhancing the autophagic flux. Surprisingly, COV-1 modifies protein aggregation, and specifically it mislocalizes TDP-43 within cells, inducing its aggregation and co-localization with SUMO-1. These data suggest that COV-1 could be taken into future consideration as an interesting pharmacological tool to study the cellular cascade effects of SUMOylation prevention.
Topics: Sumoylation; DNA-Binding Proteins; Cell Line; Ubiquitin; Peptides
PubMed: 37918759
DOI: 10.1016/j.nbd.2023.106342 -
Nucleic Acids Research Feb 2021Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin...
Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.
Topics: Binding Sites; Chromatin; Gene Expression Regulation; HEK293 Cells; Humans; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Coactivator 1; Protein Interaction Mapping; Receptors, Glucocorticoid; Small Ubiquitin-Related Modifier Proteins; Sumoylation
PubMed: 33524141
DOI: 10.1093/nar/gkab032 -
Biochimica Et Biophysica Acta.... Jan 2024The nuclear factor kappaB (NF-κB) subunit p65, plays an important role in the progression of hepatocellular carcinoma (HCC). Phosphorylation of p65 is considered as an...
The nuclear factor kappaB (NF-κB) subunit p65, plays an important role in the progression of hepatocellular carcinoma (HCC). Phosphorylation of p65 is considered as an important mechanism for the positive regulation of NF-κB activity. According to our previous data, p65 can be SUMOylated by small ubiquitin-related modifier 1 (SUMO1) protein, and SUMO1 promotes p65 nuclear import and HCC progression. However, the effect of SUMO1-related p65 SUMOylation on NF-κB transcriptional activity and the relationship between phosphorylation and SUMOylation of p65 remain obscure. Here, we found that phosphorylated p65 level was increased in cancer tissues of HCC patients, and similar phenomenon was found for SUMO1 expression but not for SUMO2/3. Further clinical data showed a positive correlation between SUMO1 and phosphorylated p65. We also verified that overexpression of SUMO1 upregulated phosphorylated p65 levels. Next, we verified SUMO1-related p65 SUMOylation with in vitro SUMOylation assay, constructed mutants of p65 SUMOylation and phosphorylation, and found that SUMO1-related p65 SUMOylation promoted p65 nuclear import and increased NF-κB activity. Both SUMO1-related p65 SUMOylation and p65 phosphorylation (especially at S276 site) increased the viability and invasion of hepatoma cells, and decreased the apoptosis of hepatoma cells. At last, we found that the phosphorylation of p65 promoted the level of SUMO1-related p65 SUMOylation, and SUMO1-related p65 SUMOylation upregulated phosphorylated p65 (at S276 site). Our study contributes to the exploration of the oncogenic mechanism of p65, which is the important protein in HCC.
Topics: Humans; Carcinoma, Hepatocellular; NF-kappa B; Phosphorylation; Liver Neoplasms; Sumoylation; Small Ubiquitin-Related Modifier Proteins; SUMO-1 Protein
PubMed: 37730133
DOI: 10.1016/j.bbamcr.2023.119595 -
Methods (San Diego, Calif.) Jul 2011Combinations of phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones comprise what is referred to as the "histone code". These marks... (Review)
Review
Combinations of phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones comprise what is referred to as the "histone code". These marks influence processes from transcription to DNA replication, where gaining access to DNA organized in chromatin is necessary. Much emphasis has been placed on the role of histone ubiquitylation and sumoylation during the process of transcription. Histone H2B is monoubiquitylated at lysine 123 in budding yeast and influences gene activation. All four of the core histones are sumoylated on their amino terminal tails in this organism, and this serves to negatively regulate gene expression. Because antibodies specific for ubiquitylated or sumoylated yeast histones are not commercially available, and these marks are highly sensitive to proteolysis in native cell extracts, special genetic and molecular tools have been developed to monitor these dynamic and often rare modifications in vivo. Here, we describe some of these tools, with emphasis on how they can be used for transcriptional studies.
Topics: Chromatin Immunoprecipitation; Chromatography, Affinity; Cloning, Molecular; Endopeptidases; Enzyme Assays; Fractional Precipitation; Histones; Polymerase Chain Reaction; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sumoylation; Ubiquitination
PubMed: 21310241
DOI: 10.1016/j.ymeth.2011.02.003 -
Trends in Biochemical Sciences Apr 2015Sumoylation has important roles during DNA damage repair and responses. Recent broad-scope and substrate-based studies have shed light on the regulation and significance... (Review)
Review
Sumoylation has important roles during DNA damage repair and responses. Recent broad-scope and substrate-based studies have shed light on the regulation and significance of sumoylation during these processes. An emerging paradigm is that sumoylation of many DNA metabolism proteins is controlled by DNA engagement. Such 'on-site modification' can explain low substrate modification levels and has important implications in sumoylation mechanisms and effects. New studies also suggest that sumoylation can regulate a process through an ensemble effect or via major substrates. Additionally, we describe new trends in the functional effects of sumoylation, such as bi-directional changes in biomolecule binding and multilevel coordination with other modifications. These emerging themes and models will stimulate our thinking and research in sumoylation and genome maintenance.
Topics: Animals; DNA Repair; Humans; Protein Processing, Post-Translational; SUMO-1 Protein; Sumoylation
PubMed: 25778614
DOI: 10.1016/j.tibs.2015.02.006 -
Cell Reports Apr 2023Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show...
Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show that mouse embryonic stem cells (ESCs) solely exposed to chemical inhibition of SUMOylation generate embryo-like structures comprising anterior neural and trunk-associated regions. HypoSUMOylation-instructed ESCs give rise to spheroids that self-organize into gastrulating structures containing cell types spatially and functionally related to embryonic and extraembryonic compartments. Alternatively, spheroids cultured in a droplet microfluidic device form elongated structures that undergo axial organization reminiscent of natural embryo morphogenesis. Single-cell transcriptomics reveals various cellular lineages, including properly positioned anterior neuronal cell types and paraxial mesoderm segmented into somite-like structures. Transient SUMOylation suppression gradually increases DNA methylation genome wide and repressive mark deposition at Nanog. Interestingly, cell-to-cell variations in SUMOylation levels occur during early embryogenesis. Our approach provides a proof of principle for potentially powerful strategies to explore early embryogenesis by targeting chromatin roadblocks of cell fate change.
Topics: Animals; Mice; Sumoylation; Embryo, Mammalian; Embryonic Stem Cells; Embryonic Development; Cell Differentiation; Mammals
PubMed: 37061916
DOI: 10.1016/j.celrep.2023.112380 -
Cells Oct 2020Sumoylation 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... (Review)
Review
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.
Topics: Animals; Cell Hypoxia; Humans; Models, Biological; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Stress, Physiological; Sumoylation
PubMed: 33114748
DOI: 10.3390/cells9112359 -
Frontiers in Immunology 2022SUMOylation is an important component of post-translational protein modifications (PTMs), and bladder cancer (BCa) is the ninth most common cancer around the world. But...
BACKGROUND
SUMOylation is an important component of post-translational protein modifications (PTMs), and bladder cancer (BCa) is the ninth most common cancer around the world. But the comprehensive role of SUMOylation in shaping tumor microenvironment (TME) and influencing tumor clinicopathological features and also the prognosis of patients remains unclear.
METHODS
Using the data downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), we comprehensively evaluated the SUMOylation patterns of 570 bladder cancer samples, and systematically correlated these SUMOylation patterns with TME immune cell infiltrating characteristics. The SUMO score was constructed to quantify SUMOylation patterns of individuals using principal component analysis (PCA) algorithms.
RESULTS
Two distinct SUMOylation patterns and gene clusters were finally determined. Significant differences in the prognosis of patients were found among two different SUMOylation patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system named SUMO score to quantify the SUMOylation pattern of individuals with BCa, which was discovered to be tightly connected with tumor clinicopathological characteristics and could predict the prognosis of patients with BCa. Moreover, SUMO score was a considerable predictive indicator for the survival outcome independent of tumor mutation burden (TMB) and low SUMO score was related to better response to immunotherapy using PD-1 blockade. We also found that there existed a significant relationship between sensitivity to commonly used chemotherapy drugs and SUMO score. Finally, a nomograph based on five features, namely, SUMO score, age, gender, T category, and M category was constructed to predict the survival probability of patients with BCa in 1, 3, and 5 years, respectively.
CONCLUSIONS
Our work demonstrated and overviewed the complicated regulation mechanisms of SUMOylation in bladder cancer, and better understanding and evaluating SUMOylation patterns could be helpful in guiding clinical therapeutic strategy and improving the prognosis of patients with BCa.
Topics: Female; Gene Expression Regulation, Neoplastic; Humans; Male; Prognosis; Sumoylation; Tumor Microenvironment; Urinary Bladder Neoplasms
PubMed: 35418978
DOI: 10.3389/fimmu.2022.864156 -
The Journal of Biological Chemistry Nov 2023The hypoxia-inducible factor (HIF) is a master regulator of the cellular transcriptional response to hypoxia. While the oxygen-sensitive regulation of HIF-1α subunit...
The hypoxia-inducible factor (HIF) is a master regulator of the cellular transcriptional response to hypoxia. While the oxygen-sensitive regulation of HIF-1α subunit stability via the ubiquitin-proteasome pathway has been well described, less is known about how other oxygen-independent post-translational modifications impact the HIF pathway. SUMOylation, the attachment of SUMO (small ubiquitin-like modifier) proteins to a target protein, regulates the HIF pathway, although the impact of SUMO on HIF activity remains controversial. Here, we examined the effects of SUMOylation on the expression pattern of HIF-1α in response to pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) in intestinal epithelial cells. We evaluated the effects of SUMO-1, SUMO-2, and SUMO-3 overexpression and inhibition of SUMOylation using a novel selective inhibitor of the SUMO pathway, TAK-981, on the sensitivity of HIF-1α in Caco-2 intestinal epithelial cells. Our findings demonstrate that treatment with TAK-981 decreases global SUMO-1 and SUMO-2/3 modification and enhances HIF-1α protein levels, whereas SUMO-1 and SUMO-2/3 overexpression results in decreased HIF-1α protein levels in response to DMOG. Reporter assay analysis demonstrates reduced HIF-1α transcriptional activity in cells overexpressing SUMO-1 and SUMO-2/3, whereas pretreatment with TAK-981 increased HIF-1α transcriptional activity in response to DMOG. In addition, HIF-1α nuclear accumulation was decreased in cells overexpressing SUMO-1. Importantly, we showed that HIF-1α is not directly SUMOylated, but that SUMOylation affects HIF-1α stability and activity indirectly. Taken together, our results indicate that SUMOylation indirectly suppresses HIF-1α protein stability, transcriptional activity, and nuclear accumulation in intestinal epithelial cells.
Topics: Humans; Caco-2 Cells; Epithelial Cells; Hypoxia-Inducible Factor 1, alpha Subunit; Sumoylation; Intestinal Mucosa; Gene Expression Regulation; Enzyme Inhibitors; Small Ubiquitin-Related Modifier Proteins
PubMed: 37742924
DOI: 10.1016/j.jbc.2023.105280