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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    • "Similar to ubiquitination, SUMOylation involves the covalent attachment of a member of SUMO (small ubiquitin-like modifier) family to lysine residues in specific target proteins. This PTM depends on an enzymatic cascade analogous to, but distinct from, the ubiquitination pathway [112]. Unlike ubiquitination, SUMOylation does not target proteins for degradation but regulates a wide variety of functions including protein stability, nuclear-cytosolic shuttling and transcription. "
    [Show abstract] [Hide abstract] ABSTRACT: Post-translational modifications increase proteome functionality for managing all aspects of normal cell biology. They are based on the covalent attachment of functional groups, leading to phosphorylation, acetylation, glycosylation, acylation, ubiquitination, SUMOylation and oxidation of protein targets. Post-translational modifications occur at any step of protein life cycle, modulating in time and space protein folding, subcellular localization and activity. Aberrant post-translational modifications of one or more culprit proteins may lead to neurodegeneration, as shown in paradigmatic neurological disorders such as Alzheimer’s, Parkinson’s and prion diseases. In this review, we report the most important post-translational modifications found in neurodegenerative disorders, illustrating the pathophysiological mechanisms in which they are involved. This work highlights the lack of a global framework of post-translational modifications in terms of complexity and regulation. Therefore, in the next future many efforts are required to describe the interplay existing between post-translational modifications and their combinatorial patterns on protein targets.
    Full-text · Article · Dec 2015 · AIMS Biophysics
    • "Notably, SUMO2/3 but not SUMO1 contain the consensus sequence, and mixed SUMO chains with a terminal SUMO1 have been reported (Rodriguez et al. 2001). Sumoylation is a dynamic process that can be reversed through the activity of sentrin-specific proteases (SENPs) by the cleavage of the isopeptide bond between the SUMO moiety and the substrate (Mukhopadhyay & Dasso 2007, Yeh 2009, Hannoun et al. 2010, Wilkinson & Henley 2010). A diverse set of SUMO target proteins has been identified in somatic cells, including factors that regulate transcription, replication, DNA repair, RNA metabolism, translation, and cellular transport. "
    [Show abstract] [Hide abstract] ABSTRACT: Recent findings suggest diverse and potentially multiple roles of small ubiquitin-like modifier (SUMO) in testicular function and spermatogenesis. However, SUMO targets remain uncharacterized in the testis due to the complex multicellular nature of testicular tissue, the inability to maintain and manipulate spermatogenesis in vitro, and the technical challenges involved in identifying low-abundance endogenous SUMO targets. In this study, we performed cell-specific identification of sumoylated proteins using concentrated cell lysates prepared with de-sumoylation inhibitors from freshly purified spermatocytes and spermatids. One-hundred and twenty proteins were uniquely identified in the spermatocyte and/or spermatid fractions. The identified proteins are involved in the regulation of transcription, stress response, microRNA biogenesis, regulation of major enzymatic pathways, nuclear-cytoplasmic transport, cell-cycle control, acrosome biogenesis, and other processes. Several proteins with important roles during spermatogenesis were chosen for further characterization by co-immunoprecipitation, co-localization, and in vitro sumoylation studies. GPS-SUMO Software was used to identify consensus and non-consensus sumoylation sites within the amino acid sequences of the proteins. The analyses confirmed the cell-specific sumoylation and/or SUMO interaction of several novel, previously uncharacterized SUMO targets such as CDK1, RNAP II, CDC5, MILI, DDX4, TDP-43, and STK31. Furthermore, several proteins that were previously identified as SUMO targets in somatic cells (KAP1 and MDC1) were identified as SUMO targets in germ cells. Many of these proteins have a unique role in spermatogenesis and during meiotic progression. This research opens a novel avenue for further studies of SUMO at the level of individual targets.
    No preview · Article · Dec 2015 · Reproduction
    • "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. "
    [Show abstract] [Hide abstract] 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.
    No preview · Article · Oct 2015 · Journal of Molecular Cell Biology
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