Mechanisms, regulation and consequences of protein SUMOylation

Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, U.K.
Biochemical Journal (Impact Factor: 4.4). 06/2010; 428(2):133-45. DOI: 10.1042/BJ20100158
Source: PubMed


The post-translational modification SUMOylation is a major regulator of protein function that plays an important role in a wide range of cellular processes. SUMOylation involves the covalent attachment of a member of the SUMO (small ubiquitin-like modifier) family of proteins to lysine residues in specific target proteins via an enzymatic cascade analogous to, but distinct from, the ubiquitination pathway. There are four SUMO paralogues and an increasing number of proteins are being identified as SUMO substrates. However, in many cases little is known about how SUMOylation of these targets is regulated. Compared with the ubiquitination pathway, relatively few components of the conjugation machinery have been described and the processes that specify individual SUMO paralogue conjugation to defined substrate proteins are an active area of research. In the present review, we briefly describe the SUMOylation pathway and present an overview of the recent findings that are beginning to identify some of the mechanisms that regulate protein SUMOylation.

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    • "Here, we demonstrate that SUMOylation of p27, induced by the anti-mitogenic stimulus of TGFb, is necessary for the proper regulation of its functions. This evidence is in agreement with the knowledge that SUMOylation is a post-translational modification that finely regulates protein activity, stability, and localization (Geiss-Friedlander and Melchior, 2007; Wilkinson and Henley, 2010). Whether it represents a common modification downstream from other anti-mitogenic signals able to stabilize nuclear p27, such as serum deprivation or contact inhibition, will be the matter of future investigations. "
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    ABSTRACT: Exposure of normal and tumor-derived cells to TGFβ results in different outcomes, depending on the regulation of key targets. The CDK inhibitor p27(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle arrest. TGFβ treatment inhibits p27(Kip1) degradation and induces its nuclear translocation, through mechanisms that are still unknown. Recent evidences suggest that SUMOylation, a post-translational modification able to modulate the stability and subcellular localization of target proteins, critically modifies members of the TGFβ signaling pathway. Here, we demonstrate that p27(Kip1) is SUMOylated in response to TGFβ treatment. Using different p27(Kip1) point mutants, we identified lysine 134 (K134) as the residue modified by small ubiquitin-like modifier 1 (SUMO1) in response to TGFβ treatment. TGFβ-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27(Kip1). We observed that SUMOylation regulated p27(Kip1) binding to CDK2, thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187. Importantly, p27(Kip1) SUMOylation was necessary for proper cell cycle exit following TGFβ treatment. These data indicate that SUMOylation is a novel regulatory mechanism that modulates p27(Kip1) function in response to TGFβ stimulation. Given the involvement of TGFβ signaling in cancer cell proliferation and invasion, our data may shed light on an important aspect of this pathway during tumor progression.
    Journal of Molecular Cell Biology 10/2015; DOI:10.1093/jmcb/mjv056 · 6.77 Impact Factor
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    • ", 2012 ) . However , insights into its fundamental role in regulating metabolism are still in the nascent stages ( Wilkinson and Henley , 2010 ) . Our study elaborates on how SUMOylation influences this cellular process and defines the SUMOylation changes that occur to maintain homeostasis in conditions of metabolic stress . "
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    ABSTRACT: SUMOylation has been implicated in cellular stress adaptation, but its role in regulating liver kinase B1 (LKB1), a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), is unknown. Here, we show that energy stress triggers an increase in SUMO1 modification of LKB1, despite a global reduction in both SUMO1 and SUMO2/3 conjugates. During metabolic stress, SUMO1 modification of LKB1 lysine 178 is essential in promoting its interaction with AMPK via a SUMO-interacting motif (SIM) essential for AMPK activation. The LKB1 K178R SUMO mutant had defective AMPK signaling and mitochondrial function, inducing death in energy-deprived cells. These results provide additional insight into how LKB1-AMPK signaling is regulated during energy stress, and they highlight the critical role of SUMOylation in maintaining the cell's energy equilibrium. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 12(5). DOI:10.1016/j.celrep.2015.07.002 · 8.36 Impact Factor
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    • "SUMO deconjugation is performed by a family of cysteine proteases, generically named as SENPs. Six SENP members were first described (Wilkinson and Henley, 2010) and very recently three new members, DESI1, DESI2 and USPL1, have been added to the group of SUMO deconjugating enzymes (Schulz et al., 2012; Shin et al., 2012). The attachment of SUMO moieties to their substrate targets regulates many relevant physiological processes by modulating enzyme activity, activating transcription factors (TFs), shifting protein subcellular localizations, and eventually, determining their substrate fate. "
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    ABSTRACT: Sumoylation is a reversible post-translational modification that regulates different cellular processes by conjugation/deconjugation of SUMO moieties to target proteins. Most work on the functional relevance of SUMO has focused on cell cycle, DNA repair and cancer in cultured cells, but data on the inter-dependence of separate components of the SUMO pathway in highly specialized tissues, such as the retina, is still scanty. Nonetheless, several retinal transcription factors (TFs) relevant for cone and rod fate, as well as some circadian rhythm regulators, are regulated by sumoylation. Here we present a comprehensive survey of SUMO pathway gene expression in the murine retina by quantitative RT-PCR and in situ hybridization (ISH). The mRNA expression levels were quantified in retinas obtained under four different light/dark conditions, revealing distinct levels of gene expression. In addition, a SUMO pathway retinal gene atlas based on the mRNA expression pattern was drawn. Although most genes are ubiquitously expressed, some patterns could be defined in a first step to determine its biological significance and interdependence. The wide expression of the SUMO pathway genes, the transcriptional response under several light/dark conditions, and the diversity of expression patterns in different cell layers clearly support sumoylation as a relevant post-translational modification in the retina. This expression atlas intends to be a reference framework for retinal researchers and to depict a more comprehensive view of the SUMO-regulated processes in the retina. © 2015. Published by The Company of Biologists Ltd.
    Biology Open 01/2015; 4(2). DOI:10.1242/bio.201410645 · 2.42 Impact Factor
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