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Review
. 2023 Dec 20;13(1):8.
doi: 10.3390/cells13010008.

Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases

Wei Wang  1 , Michael J Matunis  1
Affiliations
Review

Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases

Wei Wang et al. Cells. .

Abstract

Small ubiquitin-related modifiers (SUMOs) function as post-translational protein modifications and regulate nearly every aspect of cellular function. While a single ubiquitin protein is expressed across eukaryotic organisms, multiple SUMO paralogues with distinct biomolecular properties have been identified in plants and vertebrates. Five SUMO paralogues have been characterized in humans, with SUMO1, SUMO2 and SUMO3 being the best studied. SUMO2 and SUMO3 share 97% protein sequence homology (and are thus referred to as SUMO2/3) but only 47% homology with SUMO1. To date, thousands of putative sumoylation substrates have been identified thanks to advanced proteomic techniques, but the identification of SUMO1- and SUMO2/3-specific modifications and their unique functions in physiology and pathology are not well understood. The SUMO2/3 paralogues play an important role in proteostasis, converging with ubiquitylation to mediate protein degradation. This function is achieved primarily through SUMO-targeted ubiquitin ligases (STUbLs), which preferentially bind and ubiquitylate poly-SUMO2/3 modified proteins. Effects of the SUMO1 paralogue on protein solubility and aggregation independent of STUbLs and proteasomal degradation have also been reported. Consistent with these functions, sumoylation is implicated in multiple human diseases associated with disturbed proteostasis, and a broad range of pathogenic proteins have been identified as SUMO1 and SUMO2/3 substrates. A better understanding of paralogue-specific functions of SUMO1 and SUMO2/3 in cellular protein quality control may therefore provide novel insights into disease pathogenesis and therapeutic innovation. This review summarizes current understandings of the roles of sumoylation in protein quality control and associated diseases, with a focus on the specific effects of SUMO1 and SUMO2/3 paralogues.

Keywords: SUMO; cardiovascular disease; cystic fibrosis; neurodegenerative disease; protein quality control; proteostasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Sequence and structural comparison of ubiquitin and SUMO paralogues. (A) Protein sequence comparison of ubiquitin and SUMO paralogues. Analysis was performed using the COBALT multiple alignment tool. (B) Comparison of ubiquitin, SUMO1 and SUMO2/3 structures. Protein structures were generated using PDB files and the PyMOL program.
Figure 2
Figure 2
Schematics of sumoylation and ubiquitylation pathways. SUMO precursors are first cleaved by sentrin-specific proteases (SENPs) to expose a C-terminal di-glycine motif required for ATP-dependent activation by the E1 enzyme heterodimer. Activated SUMOs can then be transferred to the E2 conjugating enzyme, Ubc9, through a thioester bond. Finally, SUMOs are conjugated to a lysine residue within target protein, either directly or with the help of an E3 ligase. Sumoylation can be reversed by SUMO-specific isopeptidases, which deconjugate and recycle SUMOs from substrate proteins. Ubiquitylation happens in a similar manner but employs distinct sets of enzymes in each step. DUBs: deubiquitinases. Numbers shown below each reaction are the number of related enzymes identified in humans.
Figure 3
Figure 3
3D model of the secondary structure of a SIM motif (purple) in contact with the SUMO surface (green). Negative and positive charges indicate the SIM acidic region and SUMO basic patch, respectively. N and C indicate the N- and C-terminus of SUMO protein. PDB: 6V7P.
Figure 4
Figure 4
Overlaps of sumoylated and ubiquitylated substrates. (A) Overlap of currently identified ubiquitin and sumoylation sites by proteomic analyses. Figure was adapted from Trulsson and Vertegaal, 2021 [82]. Difference in numbers of identified sites and substrates may be due to varied depths of analyses for the two modifications. (B) Different co-modification patterns of SUMO and ubiquitin, where a protein can be modified by SUMO or ubiquitin on the same or different lysine residues (a), sequentially modified by SUMO or ubiquitin during biological processes or at different subcellular localization (b), modified by SUMO-ubiquitin hybrid chains (c). Dash line represents intracellular membranes.
Figure 5
Figure 5
Proposed mechanisms for SUMO1 versus SUMO2/3 functions in cellular PQC. While poly-SUMO2/3 modification works in concert with STUbL and the UPS to promote substrate degradation, SUMO1 conjugation promotes solubility of misfolded substrates and prevents aggregation in cooperation with cellular chaperones and other PQC factors. Effects of SUMO1 on protein solubility and aggregation status may lead to protective or deleterious cellular outcome based on different contexts and specific substrates. In other cases, SUMO1 modification may counteract functions of poly-SUMO2/3, leading to stabilization of substrate proteins.
Figure 6
Figure 6
Divergent effects of SUMO1 and SUMO2/3 in CFTR biogenesis and degradation. SUMO1 modification of CFTR promotes protein stability during biogenesis, while selective modification of mutant CFTR by poly-SUMO2/3 enhances degradation through the RNF4–UPS degradation pathway.
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References

    1. Su H., Wang X. The ubiquitin-proteasome system in cardiac proteinopathy: A quality control perspective. Cardiovasc. Res. 2010;85:253–262. doi: 10.1093/cvr/cvp287. - DOI - PMC - PubMed
    1. Gestwicki J.E., Garza D. Protein quality control in neurodegenerative disease. Prog. Mol. Biol. Transl. Sci. 2012;107:327–353. doi: 10.1016/B978-0-12-385883-2.00003-5. - DOI - PubMed
    1. Desterro J.M., Rodriguez M.S., Hay R.T. SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol. Cell. 1998;2:233–239. doi: 10.1016/S1097-2765(00)80133-1. - DOI - PubMed
    1. Tatham M.H., Geoffroy M.C., Shen L., Plechanovova A., Hattersley N., Jaffray E.G., Palvimo J.J., Hay R.T. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat. Cell Biol. 2008;10:538–546. doi: 10.1038/ncb1716. - DOI - PubMed
    1. Chang Y.C., Oram M.K., Bielinsky A.K. SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability. Int. J. Mol. Sci. 2021;22:5391. doi: 10.3390/ijms22105391. - DOI - PMC - PubMed

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