SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2
Open accessAbstract
Inflammation associates with peripheral insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. Inflammation induces the expression of SOCS proteins. We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy.
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Obesity-related insulin resistance could result from a diminution in IRS-1 in animals secondary to an increase in SOCS-3.
“obesity-related insulin resistance could result from a diminution in insulin receptor substrate-1 (IRS-1) in animals, secondary to an increase in suppressor of cytokine signaling 3 (SOCS-3), which binds to IRS-1 and leads to its ubiquitylation and proteolysis in experimental animals [5]”
From Bariatric surgery: remission of inflammation, cardiometabolic benefits, and common adverse effects (2020) · cites this paper as [5]
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- Authors
- Rui, L., Yuan, M., Frantz, D., Shoelson, S., & White, M. F.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- White, Morris F.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 277
- Issue
- 44
- Pages
- 42394-42398
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2069711307
- Cited by
- 904
- References
- 44
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 18 · 2023: 25 · 2022: 35 · 2021: 39 · 2020: 27 · 2019: 29 · 2018: 42 · 2017: 33 · 2016: 48 · 2015: 27 · 2014: 50 · 2013: 51 · 2012: 57
- FWCI
- 30.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- SOCS1, SOCS3, IRS-1, insulin receptor substrate 2, insulin signaling, ubiquitin-mediated proteolysis, SOCS box, inflammation, insulin resistance, impaired glucose tolerance, liver, diabetes mellitus
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Elongin, Animals, Carrier Proteins, Glucose, Homeostasis, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Phosphoproteins, Proteins, Repressor Proteins, Transcription Factors, Ubiquitin, Intracellular Signaling Peptides and Proteins, Suppressor of Cytokine Signaling Proteins, Mice, Insulin Receptor Substrate Proteins
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