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The FEBS Journal Oct 2015SUMOylation is a post-translational modification that regulates a multitude of cellular processes, including replication, cell-cycle progression, protein transport and... (Review)
Review
SUMOylation is a post-translational modification that regulates a multitude of cellular processes, including replication, cell-cycle progression, protein transport and the DNA damage response. Similar to ubiquitin, SUMO (small ubiquitin-like modifier) is covalently attached to target proteins in a reversible process via an enzymatic cascade. SUMOylation is essential for nearly all eukaryotic organisms, and deregulation of the SUMO system is associated with human diseases such as cancer and neurodegenerative diseases. Therefore, it is of great interest to understand the regulation and dynamics of this post-translational modification. Within the last decade, mass spectrometry analyses of SUMO proteomes have overcome several obstacles, greatly expanding the number of known SUMO target proteins. In this review, we briefly outline the basic concepts of the SUMO system, and discuss the potential of proteomic approaches to decipher SUMOylation patterns in order to understand the role of SUMO in health and disease.
Topics: Humans; Ligases; Peptide Hydrolases; Protein Processing, Post-Translational; Proteins; Proteomics; Small Ubiquitin-Related Modifier Proteins; Sumoylation
PubMed: 26185901
DOI: 10.1111/febs.13378 -
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 -
Signal Transduction and Targeted Therapy Nov 2023Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory...
Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Endothelial Cells; Extracellular Vesicles; Lung Neoplasms; Lymphatic Metastasis; Sumoylation; Transcription Factors; RNA, Circular
PubMed: 37925421
DOI: 10.1038/s41392-023-01685-0 -
Nature Communications Jan 2024Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are...
Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP's ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral immune response is suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation and a newly identified SUMO-interacting motif in SARS2-NP. Importantly, the widespread SARS2-NP R203K mutation gains a novel site of SUMOylation which further increases SARS2-NP's LLPS and immunosuppression. Notably, the SUMO E3 ligase TRIM28 is responsible for catalyzing SARS2-NP SUMOylation. An interfering peptide targeting the TRIM28 and SARS2-NP interaction was screened out to block SARS2-NP SUMOylation and LLPS, and consequently inhibit SARS-CoV-2 replication and rescue innate antiviral immunity. Collectively, these data support SARS2-NP SUMOylation is critical for SARS-CoV-2 virulence, and therefore provide a strategy to antagonize SARS-CoV-2.
Topics: Humans; Sumoylation; SARS-CoV-2; Nucleocapsid Proteins; Virulence; Virus Replication; COVID-19; Tripartite Motif-Containing Protein 28
PubMed: 38172120
DOI: 10.1038/s41467-023-44502-6 -
Biochimica Et Biophysica Acta Jan 2014Covalent posttranslational modification with SUMO (small ubiquitin-related modifier) modulates functions of a wide range of proteins in eukaryotic cells. Sumoylation... (Review)
Review
Covalent posttranslational modification with SUMO (small ubiquitin-related modifier) modulates functions of a wide range of proteins in eukaryotic cells. Sumoylation affects the activity, interaction properties, subcellular localization and the stability of its substrate proteins. The recent discovery of a novel class of ubiquitin ligases (E3), termed ULS (E3-S) or STUbL, that recognize sumoylated proteins, links SUMO modification to the ubiquitin/proteasome system. Here we review recent insights into the properties and function of these ligases and their roles in regulating sumoylated proteins. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
Topics: Animals; DNA Damage; DNA Repair; Genomic Instability; Humans; Proteolysis; SUMO-1 Protein; Saccharomyces cerevisiae; Schizosaccharomyces; Sumoylation; Ubiquitin-Protein Ligases; Yeasts
PubMed: 24018209
DOI: 10.1016/j.bbamcr.2013.08.022 -
Medicina 2019Post-translational modifications (PTMs) are covalent modifications in proteins during or after their synthesis. Among them, the best known are phosphorylation,... (Review)
Review
Post-translational modifications (PTMs) are covalent modifications in proteins during or after their synthesis. Among them, the best known are phosphorylation, methylation, acetylation, and also cleavage or binding of small peptides (ubiquitination, SUMOylation and NEDDylation). Often the protein is modified in multiple sites and these modifications are coordinated generating a PTMs crosstalk. Altered patterns of PTMs have been related to several pathologies. Currently, advances in mass spectrometry have made it possible to study multiple PTMs simultaneously. Oncology is one of the disciplines that incorporated these technologies for the need to better characterize tumors. In cancer, several alterations related to the ubiquitinlike PTMs have been described, such as SUMOylation. In particular, the interaction between different PTMs with SUMOylation has been studied in the context of the von Hippel Lindau (VHL) multitumoral syndrome, generating new putative biomarkers for the evolution of these tumors. RSUME or RWDD3, an enhancer of SUMOylation that acts on VHL and HIF proteins, shows a correlation with malignant parameters in this type of tumors, such as angiogenesis. Regulators of PTMs are becoming relevant as biomarkers in cancer.
Topics: Humans; Neoplasms; Phosphorylation; Protein Processing, Post-Translational; Proteome; Sumoylation; Transcription Factors; Ubiquitination
PubMed: 31864228
DOI: No ID Found -
Molecular Cell Aug 2018Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely recognized post-translational modification that targets a myriad of proteins in many... (Review)
Review
Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely recognized post-translational modification that targets a myriad of proteins in many processes. Great progress has been made in understanding the SUMO pathway enzymes, substrate sumoylation, and the interplay between sumoylation and other regulatory mechanisms in a variety of contexts. As these research directions continue to generate insights into SUMO-based regulation, several mechanisms by which sumoylation and desumoylation can orchestrate large biological effects are emerging. These include the ability to target multiple proteins within the same cellular structure or process, respond dynamically to external and internal stimuli, and modulate signaling pathways involving other post-translational modifications. Focusing on nuclear function and intracellular signaling, this review highlights a broad spectrum of historical data and recent advances with the aim of providing an overview of mechanisms underlying SUMO-mediated global effects to stimulate further inquiry into intriguing roles of SUMO.
Topics: Animals; Cell Nucleus; Humans; Intracellular Signaling Peptides and Proteins; Protein Processing, Post-Translational; SUMO-1 Protein; Signal Transduction; Sumoylation
PubMed: 30075142
DOI: 10.1016/j.molcel.2018.07.027 -
Cell Communication and Signaling : CCS Jul 2017Viruses exploit various cellular processes for their own benefit, including counteracting anti-viral responses and regulating viral replication and propagation. In the... (Review)
Review
Viruses exploit various cellular processes for their own benefit, including counteracting anti-viral responses and regulating viral replication and propagation. In the past 20 years, protein sumoylation has emerged as an important post-translational modification that is manipulated by viruses to modulate anti-viral responses, viral replication, and viral pathogenesis. The process of sumoylation is a multi-step cascade where a small ubiquitin-like modifier (SUMO) is covalently attached to a conserved ΨKxD/E motif within a target protein, altering the function of the modified protein. Here we review how viruses manipulate the cellular machinery at each step of the sumoylation process to favor viral survival and pathogenesis.
Topics: Animals; Humans; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin-Protein Ligase Complexes; Virus Diseases
PubMed: 28705221
DOI: 10.1186/s12964-017-0183-0 -
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 -
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