Analysis of a degron-containing reporter protein GFP-CL1 reveals a role for SUMO1 in cytosolic protein quality control

Wang, Wei; Lu, Jian R.; Yang, Wen-Jen; Spear, Eric D.; Michaelis, Susan; Matunis, Michael J.

doi:10.1016/j.jbc.2022.102851

Cited by 2 publications

(6 citation statements)

References 78 publications

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“…Furthermore, SUMO1 conjugation may also direct substrate targeting to downstream degradation machineries through SUMO–SIM interactions with PQC pathway components. Supporting this view, we found that GFP-CL1 is conjugated by SUMO1 and SUMO1 is required for efficient downstream ubiquitylation of the protein [ 6 ]. For the GFP-CL1 substrate, the observed effects of SUMO1 were restricted to the cytosol but not in the nucleus.…”

Section: Sumo-regulated Pqc Outside the Nucleusmentioning

confidence: 96%

“…and ubiquitin-mediated degradation, leading to enhanced stability of substrate proteins A good example for this scenario is paralogue-specific regulation of CFTR homeostasis as discussed in the next section. On the other hand, SUMO1-mediated enhancement in solubility may improve accessibility to other degradation pathways and thereby promote protein turnover, as demonstrated for GFP-CL1 [6]. How the cell regulates different impacts of SUMO1 modification on substrate protein quality control is unclear.…”

Section: A Generalized Model For Sumo1-and Sumo2/3-mediated Pqc Pathwaysmentioning

confidence: 99%

“…In addition to the well-defined roles of poly-SUMO2/3 and RNF4 in nuclear PQC, recent findings in our lab revealed that SUMO1 also imparts unique functions in cytosolic PQC. Using a well-characterized PQC model substrate, GFP-CL1, we found that SUMO1 uniquely promotes solubility and degradation of this unstable cytosolic protein, while SUMO2 does not [ 6 , 117 ]. Knockdown of RNF4 by siRNA revealed that SUMO1 promotes substrate degradation independently of RNF4.…”

Section: Sumo-regulated Pqc Outside the Nucleusmentioning

confidence: 99%

“…Second, SUMO can act on target proteins directly to regulate their solubility and stability, achieved through both direct conjugation and noncovalent SIM-association. This function is exemplified by protein degradation through the SUMO2/3–STUbL–UPS pathway and SUMO1-mediated changes in substrate solubility and aggregation propensities [ 6 , 35 ]. Furthermore, SUMO can also impact cellular PQC by directly regulating factors within PQC pathways, such as molecular chaperones and the proteasome [ 10 , 172 ].…”

Section: Summary and Future Directionmentioning

confidence: 99%

“…The prototypical STUbL, RNF4, was soon found to be involved in many of the previously identified nuclear functions of SUMO2/3, suggesting that mediating protein turnover can be a major function of these paralogues [ 5 ]. Recent studies have also revealed functions for SUMO1 in modulating protein solubility and stability without clear involvement of STUbLs [ 6 , 7 ]. Furthermore, sumoylation also directly regulates PQC factors, including molecular chaperones and components of the proteasome [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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

Wang,

Matunis

2023

Cells

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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.

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Section: Sumo-regulated Pqc Outside the Nucleusmentioning

confidence: 96%

Section: A Generalized Model For Sumo1-and Sumo2/3-mediated Pqc Pathwaysmentioning

confidence: 99%

Section: Sumo-regulated Pqc Outside the Nucleusmentioning

confidence: 99%

Section: Summary and Future Directionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang,

Matunis

2023

Cells

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The Ubiquitin-like Proteins of Saccharomyces cerevisiae

Sengupta

Pick

2023

Biomolecules

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In this review, we present a comprehensive list of the ubiquitin-like modifiers (Ubls) of Saccharomyces cerevisiae, a common model organism used to study fundamental cellular processes that are conserved in complex multicellular organisms, such as humans. Ubls are a family of proteins that share structural relationships with ubiquitin, and which modify target proteins and lipids. These modifiers are processed, activated and conjugated to substrates by cognate enzymatic cascades. The attachment of substrates to Ubls alters the various properties of these substrates, such as function, interaction with the environment or turnover, and accordingly regulate key cellular processes, including DNA damage, cell cycle progression, metabolism, stress response, cellular differentiation, and protein homeostasis. Thus, it is not surprising that Ubls serve as tools to study the underlying mechanism involved in cellular health. We summarize current knowledge on the activity and mechanism of action of the S. cerevisiae Rub1, Smt3, Atg8, Atg12, Urm1 and Hub1 modifiers, all of which are highly conserved in organisms from yeast to humans.

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Analysis of a degron-containing reporter protein GFP-CL1 reveals a role for SUMO1 in cytosolic protein quality control

Cited by 2 publications

References 78 publications

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

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

The Ubiquitin-like Proteins of Saccharomyces cerevisiae

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