Proteome-Wide Identification of SUMO2 Modification Sites

Tammsalu, Triin; Matić, Ivan; Jaffray, Ellis; Ibrahim, Adel; Tatham, Michael H.; Hay, Ronald T.

doi:10.1126/scisignal.2005146

Cited by 185 publications

(252 citation statements)

References 60 publications

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“…In agreement with our observations, a proteome-wide analysis recently identified K422 of endogenous FKBP51 as a putative SUMOylated site, 40 thus strengthening our findings.…”

Section: Discussionsupporting

confidence: 92%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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“…In agreement with our observations, a proteome-wide analysis recently identified K422 of endogenous FKBP51 as a putative SUMOylated site, 40 thus strengthening our findings.…”

Section: Discussionsupporting

confidence: 92%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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“…The independent confirmation of SUMOylation of K136 by Tammsalu et al 37 , in addition to the absence of changes in the ubiquitylation of CDC73 K136 on MG132 treatment, support a role for SUMOylation in the nuclear retention of CDC73. This finding is consistent with a recent study on the E1 SUMOactivating enzyme SAE2, indicating that SUMOylation of several residues located within the NLS and adjacent to the NLS regions was required for the nuclear retention of SAE2, whereas the nonSUMOylatable form of SAE2 was rapidly exported to the cytoplasm 40 .…”

Section: Cdc73 Sumoylation Affects Its Nucleocytoplasmic Localizationmentioning

confidence: 59%

“…Indeed, a report published during the review of this manuscript identified K136, K301 and K385 as SUMOylated residues on CDC73 (ref. 37). It is noteworthy that a recent large-scale proteomics study performed on MG132-treated Jurkat cells identified 12 ubiquitylation sites on CDC73, of which 4 sites were identified in our study (K136, K161, K198 and K283) 38 .…”

Section: Cdc73 Sumoylation Affects Its Nucleocytoplasmic Localizationmentioning

confidence: 74%

Large-scale analysis of lysine SUMOylation by SUMO remnant immunoaffinity profiling

Lamoliatte¹,

et al. 2014

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Small ubiquitin-related modifiers (SUMO) are evolutionarily conserved ubiquitin-like proteins that regulate several cellular processes including cell cycle progression, intracellular trafficking, protein degradation and apoptosis. Despite the importance of protein SUMOylation in different biological pathways, the global identification of acceptor sites in complex cell extracts remains a challenge. Here we generate a monoclonal antibody that enriches for peptides containing SUMO remnant chains following tryptic digestion. We identify 954 SUMO3-modified lysine residues on 538 proteins and profile by quantitative proteomics the dynamic changes of protein SUMOylation following proteasome inhibition. More than 86% of these SUMOylation sites have not been reported previously, including 5 sites on the tumour suppressor parafibromin (CDC73). The modification of CDC73 at K136 affects its nuclear retention within PML nuclear bodies on proteasome inhibition. In contrast, a CDC73 K136R mutant translocates to the cytoplasm under the same conditions, further demonstrating the effectiveness of our method to characterize the dynamics of lysine SUMOylation.

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“…Phosphorylation is a prerequisite for SUMOylation, which in turn promotes polyubiquitylation as a third posttranslational modification and eventually leads to degradation of the protein at the end of S phase, when it is no longer needed. It would be interesting to overlap the targets of cyclindependent kinases with known SUMO substrates, specifically as recent advances in proteomic approaches allow us to identify both phosphorylation and SUMOylation sites [48][49][50][51][52]. This might lend insight into the substrates that are co-regulated by SUMOylation and CDKs.…”

Section: Sumoylation and Cyclin-dependent Kinases In Concertmentioning

confidence: 99%

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

Eifler

Vertegaal

2015

Trends in Biochemical Sciences

243

211

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SUMOylation plays critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancers were recently shown to be dependent on a functioning SUMOylation system, a finding that could potentially be exploited in anti-cancer therapies. KeywordsSUMO; mitosis; SUMOylation; cancer; cell cycle SUMO: a ubiquitin-like modifier that regulates nuclear processesThe complexity of eukaryotic proteomes is widely expanded by protein processing and a vast array of posttranslational modifications. The quick and reversible attachment of small modifiers is essential for all cellular processes and ensures dynamic and rapid responses to extracellular and intracellular stimuli. Apart from chemical modifications such as phosphorylation [1], glycosylation [2] and acetylation [3], small polypeptides can be attached to proteins, resulting in a change in the activity, localization, half-life or interactome of the target protein. Since the initial discovery of ubiquitin, the founding member of these small protein posttranslational modifications in 1975 [4], a large family of structurally related ubiquitin-like modifiers has been uncovered including SUMO, Nedd8, ISG15, FAT10, FUB1, UFM1, URM1, Atg12 and Atg8 [5][6][7][8]. The attachment of these small ubiquitin-like modifiers is catalysed by an enzymatic cascade consisting of an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), and can be reversed by specific and cell cycle control. It is therefore not surprising that SUMO signal transduction has been implicated in the development of several different cancer types, which could potentially be exploited in anti-cancer therapies. In this review we will focus on the role of SUMO in cell cycle regulation, specifically highlighting its physiological relevance and its deregulation in cancer. Recent progress includes the identification of many novel SUMO substrates with important roles in cell cycle progression using proteomic approaches, and the demonstration that different mouse cancer models are dependent on a functioning SUMOylation system. Switching of SUMOylation in these cancer models caused a proliferation block of the cancer cells, showing that SUMO conjugating enzymes are potential drug targets. Europe PMC Funders Group Twenty years of SUMO research in cell cycle controlSUMO was linked to cell cycle progression even before the identification of the small protein modifier itself. Twenty years ago, the yeast SUMO conjugating enzyme Ubc9 was first proposed to be a ubiquitin conjugating enzyme. Ubc9 was s...

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Proteome-Wide Identification of SUMO2 Modification Sites

Cited by 185 publications

References 60 publications

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

Large-scale analysis of lysine SUMOylation by SUMO remnant immunoaffinity profiling

SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer

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