Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification

Lamoliatte, Frederic; McManus, Francis P.; Maarifi, Ghizlane; Chelbi-Alix, Mounira K.; Thibault, Pierre

doi:10.1038/ncomms14109

Cited by 123 publications

(131 citation statements)

References 54 publications

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“…In another context, PML-mediated sumoylation of misfolded proteins located inside PML bodies can facilitate their RNF4-mediated degradation to reduce the protein aggregates associated with neurodegenerative disease (Chu and Yang, 2011; Guo et al, 2014). These findings corroborate the observation that proteasomes can be targeted to PML bodies when their subunits are sumoylated (Lamoliatte et al, 2017), suggesting that multiple SUMO-based mechanisms act in concert to prevent undesired protein aggregation.…”

Section: Global Changes In Sumoylation Levelssupporting

confidence: 87%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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Summary 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.

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Section: Global Changes In Sumoylation Levelssupporting

confidence: 87%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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“…Moreover, the ubiquitin-E3-ligase, murine double minute 2 (MDM2), is a critical negative regulator of p53 in order to keep p53 tightly in normal cells (Lamoliatte et al 2017). Several studies also suggest that post-translational modification of both p53 and MDM2 regulate their interaction and the ability of MDM2 to target p53 for degradation (Sherr and Weber 2000;Shi and Gu 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Methylation of p53 stabilizes the protein (West and Gozani 2011), and various studies identify cross-talk between SUMO and other post-translational modifications (Lamoliatte et al 2017). Moreover, the ubiquitin-E3-ligase, murine double minute 2 (MDM2), is a critical negative regulator of p53 in order to keep p53 tightly in normal cells (Lamoliatte et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

Park

Jang

2018

Animal Cells and Systems

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The histone demethylase lysine-specific demethylase 4A (KDM4A/Jmjd2A) has diverse functions, including involvement in gene regulation and cell cycle, and plays an oncogenic role in cancer cells. The modulation of KDM4A through post-translational modifications remains unclear. Here, we show that small ubiquitin-like modifier (SUMO) 1-mediated modification of KDM4A was required for interaction with tumor suppressor p53. Our data revealed that KDM4A is mainly sumoylated at lysine residue 471. However, the SUMO modification resulted in little change in subcellular localization, demethylase activity, or protein stability of KMD4A. Intriguingly, coimmunoprecipitation data revealed that sumoylation-defective mutants of KDM4A had a lower binding ability with p53 compared to that of wild-type KDM4A, suggesting a positive role for sumoylation in the interaction between KDM4A and p53. Together, these data suggest that KDM4A is post-translationally modified by SUMO, and this sumoylation may be a novel regulatory switch for controlling the interplay between KDM4A and p53.ARTICLE HISTORY

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“…Comparison of the datasets allowed to identify and distinguish ISGylated sites from ubiquitin sites in vivo (Zhang et al, 2019). Similar approaches have already been used in several cell systems to identify different post-translational modifications such as, phosphorylation (Rush et al, 2005), ubiquitination (Xu et al, 2010a;Kim et al, 2011), acetylation (Weinert et al, 2011;Kori et al, 2017), methylation and SUMOylation (Impens et al, 2014;Lamoliatte et al, 2017).…”

Section: Identification Of Isg15 Substratesmentioning

confidence: 99%

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

2020

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The interferon (IFN)-stimulated gene product 15 (ISG15) represents an ubiquitin-like protein (Ubl), which in a process termed ISGylation can be covalently linked to target substrates via a cascade of E1, E2, and E3 enzymes. Furthermore, ISG15 exerts functions in its free form both, as an intracellular and as a secreted protein. In agreement with its role as a type I IFN effector, most functions of ISG15 and ISGylation are linked to the anti-pathogenic response. However, also key roles in other cellular processes such as protein translation, cytoskeleton dynamics, exosome secretion, autophagy or genome stability and cancer were described. Ubiquitin-specific protease 18 (USP18) constitutes the major ISG15 specific protease which counteracts ISG15 conjugation. Remarkably, USP18 also functions as a critical negative regulator of the IFN response irrespective of its enzymatic activity. Concordantly, lack of USP18 function causes fatal interferonopathies in humans and mice. The negative regulatory function of USP18 in IFN signaling is regulated by various protein-protein interactions and its stability is controlled via proteasomal degradation. The broad repertoire of physiological functions and regulation of ISG15 and USP18 offers a variety of potential intervention strategies which might be of therapeutic use. Due to the high mutation rates of pathogens which are often species specific and constantly give rise to a variety of immune evasion mechanisms, immune effector systems are under constant evolutionarily pressure. Therefore, it is not surprising that considerable differences in ISG15 with respect to function and sequence exist even among closely related species. Hence, it is essential to thoroughly evaluate the translational potential of results obtained in model organisms especially for therapeutic strategies. This review covers existing and conceptual assay systems to target and identify modulators of ISG15, ISGylation, USP18 function, and protein-protein interactions within this context. Strategies comprise mouse models for translational perspectives, cell-based and biochemical assays as well as chemical probes.

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Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification

Cited by 123 publications

References 54 publications

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

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