SUMO: ligases, isopeptidases and nuclear pores

Melchior, Frauke; Schergaut, Marion; Pichler, Andrea

doi:10.1016/j.tibs.2003.09.002

Cited by 365 publications

(356 citation statements)

References 64 publications

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“…While SUMO-2/3 are 50% identical in sequence to SUMO-1 (Saitoh and Hinchey, 2000), only these SUMO-2/3 isoforms possess a consensus motif that can be utilized to form polymeric SUMO chains (Tatham et al, 2001). The machinery necessary for protein sumoylation is mostly nuclear (Melchior et al, 2003), although an increasing number of sumoylated proteins act outside the nucleus. These include cytosolic proteins such as a-catenin, SCG10, phosducin (Gocke et al, 2005;Klenk et al, 2006), and the membrane spanning or attached proteins GLUT1 and GLUT4 transporters (Giorgino et al, 2000), or the focal adhesion kinase (Kadaré et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Sumoylation and glycosylation probably contribute to increase the size of the smaller 24 kDa RGSZ2 protein to 43 kDa and above. It is probable that sumoylation of the RGS-Rz proteins occurred in the nucleus or in the nuclear pore complexes (Melchior et al, 2003), and that they were subsequently transported to the cell membrane. The presence of RGSZ2 and RGSZ1 in the nuclear fraction is consistent with this idea (Figure 3a).…”

Section: Sumoylation and Phosphorylation Of Rgs-rz Proteinsmentioning

confidence: 99%

“…The activation of SUMO precursors, their conjugation and their release from target proteins is mediated by a series of specific enzymes (Melchior et al, 2003). The attachment of multiple SUMO molecules to target proteins, polysumoylation, leads to the formation of chains and these multiple protein isoforms are detected as a ladder pattern by SDS-PAGE (Gocke et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Sumoylated RGS-Rz Proteins Act as Scaffolds for Mu-Opioid Receptors and G-Protein Complexes in Mouse Brain

Rodríguez-Muñoz

Bermúdez

Sánchez‐Blázquez

et al. 2006

Neuropsychopharmacol

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The RGSZ1 and RGSZ2 proteins, members of the RGS-Rz subfamily of GTPase-activating proteins (GAP), are involved in Mu-opioid receptor desensitization. The expression of these proteins, as well as of their main target the Gz protein, is virtually restricted to the nervous tissue. In synaptosomal membranes, these Rz proteins undergo post-translational modifications such as glycosylation and phosphorylation, and they may covalently attach to small ubiquitin-like modifier (SUMO) proteins. While RGSZ1 exists in conjugated and non-conjugated forms, RGSZ2 is mostly conjugated to SUMO-1, SUMO-2 and SUMO-3 proteins. These sumoylated forms of the GAPs readily associated with Mu-opioid receptors but they associated only poorly with Delta receptors. Furthermore, Gai2 and Gaz subunits co-precipitated with the sumoylated forms of RGSZ1/Z2 proteins, but to a lesser extent with the Ser phosphorylated SUMO-free form of RGSZ1. Upon Mu-opioid receptor activation, there is a strong increase in the association of Ga proteins with RGSZ2 proteins that persists for intervals longer than 24 h. This effect probably accounts for their role in Mu-opioid receptor desensitization. Only a moderate increase was observed with RGSZ1, the non-sumoylated form of which probably acts as an efficient GAP for these Ga subunits. Therefore, sumoylation regulates the biological activity of RGS-Rz proteins and it is likely that it serves to switch their behavior, from that of a GAP for activated Ga subunits to that of a scaffold protein for specific signaling proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Sumoylation and Phosphorylation Of Rgs-rz Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sumoylated RGS-Rz Proteins Act as Scaffolds for Mu-Opioid Receptors and G-Protein Complexes in Mouse Brain

Rodríguez-Muñoz

Bermúdez

Sánchez‐Blázquez

et al. 2006

Neuropsychopharmacol

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“…Posttranslational modification of proteins by the small ubiquitin-like modifier (SUMO) is an important regulatory mechanism that impinges on many cellular processes (Mü ller et al, 2001;Gill, 2003;Melchior et al, 2003;Seeler and Dejean, 2003;Verger et al, 2003;Johnson, 2004). SUMO conjugation regulates different protein functions including protein stability, subnuclear localization, DNA binding, and transcription (reviewed in Gill, 2003;Verger et al, 2003;Johnson, 2004;Hay, 2005).…”

Section: Introductionmentioning

confidence: 99%

SUMOylation of the Corepressor N-CoR Modulates Its Capacity to Repress Transcription

Tiefenbach

Novac

Ducasse

et al. 2006

MBoC

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“…However, cotransfection of cells with a plasmid encoding SUMO-1 did not alter the expression level of the HA-fusion protein (unpublished data), most probably because overexpression of SUMO-1 is not sufficient to enhance sumoylation of ADAR1 in vivo. In fact, there is evidence that modification of proteins by SUMO is a tightly regulated process in the cell (Melchior et al, 2003;Marx, 2005).The labile nature of SUMO-1 modification due to the high activity of SUMO specific proteases and the absence of a mechanism to induce SUMO-1 modification in vivo do not facilitate the investigation of a direct effect of SUMO-1 on ADAR1 activity in the cell. We therefore decided to perform further studies using in vitro systems.…”

mentioning

confidence: 99%

SUMO-1 Modification Alters ADAR1 Editing Activity

Desterro

Keegan

Jaffray

et al. 2005

MBoC

106

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We identify ADAR1, an RNA-editing enzyme with transient nucleolar localization, as a novel substrate for sumoylation. We show that ADAR1 colocalizes with SUMO-1 in a subnucleolar region that is distinct from the fibrillar center, the dense fibrillar component, and the granular component. Our results further show that human ADAR1 is modified by SUMO-1 on lysine residue 418. An arginine substitution of K418 abolishes SUMO-1 conjugation and although it does not interfere with ADAR1 proper localization, it stimulates the ability of the enzyme to edit RNA both in vivo and in vitro. Moreover, modification of wild-type recombinant ADAR1 by SUMO-1 reduces the editing activity of the enzyme in vitro. Taken together these data suggest a novel role for sumoylation in regulating RNA-editing activity. INTRODUCTIONA defining feature of eukaryotic cells is the generation of protein diversity either posttranscriptionally by alternative splicing and RNA editing or posttranslationally by modification of amino acids in proteins. One of the most recently discovered posttranslational modification mechanism in eukaryotes involves the covalent attachment of the small ubiquitinlike modifier, SUMO, to target proteins. Modification of proteins by SUMO, or sumoylation, plays crucial regulatory roles in eukaryotes. Proteins known to be modified by SUMO include, among others, RanGAP1, PCNA, I B␣, p53, c-jun, topoisomerases, promyelocytic leukemia protein (PML), Sp100, and the mitogen-activated protein kinase kinase 1 (MEKK1). Many SUMO substrates are transcription factors and cofactors, or proteins implicated in DNA repair and replication (reviewed by Hay, 2001;Melchior et al., 2003;Seeler and Dejean, 2003;Hay, 2005). Although it is well established that SUMO can affect target protein function by altering its subcellular localization, activity, or stability, for many substrates the biological functions of sumoylation remain unknown.Sumoylation is a reversible and highly dynamic process that involves formation of an isopeptide bond between the C-terminus of SUMO and the ⑀-amino group of a lysine residue of the target protein. The most intensely studied human form of SUMO is the SUMO-1 protein, which is 48% identical to yeast Smt3 (Bayer et al., 1998;Mossessova and Lima, 2000). In vertebrates there are at least three additional proteins. SUMO-2 and SUMO-3 are ϳ45% identical to SUMO-1 (Saitoh and Hinchey, 2000), and SUMO-4 shows an 86% amino acid homology to SUMO-2 (Bohren et al., 2004). SUMO is conjugated to protein substrates via an ATP-dependent enzymatic pathway that is mechanistically similar to ubiquitination. The reaction requires a SUMO protease that removes four amino acids from the C-terminus of the 101-amino acid SUMO-1 precursor to generate the mature form; an heterodimeric SUMO-activating enzyme, SAE1/2; Ubc9, a SUMO-conjugating enzyme that ligates directly to its protein target; and an E3-like SUMO ligase (reviewed Melchior et al., 2003). Three SUMO E3s have been identified so far: the mammalian protein inhibitors of activated S...

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SUMO: ligases, isopeptidases and nuclear pores

Cited by 365 publications

References 64 publications

Sumoylated RGS-Rz Proteins Act as Scaffolds for Mu-Opioid Receptors and G-Protein Complexes in Mouse Brain

Sumoylated RGS-Rz Proteins Act as Scaffolds for Mu-Opioid Receptors and G-Protein Complexes in Mouse Brain

SUMOylation of the Corepressor N-CoR Modulates Its Capacity to Repress Transcription

SUMO-1 Modification Alters ADAR1 Editing Activity

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