SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2*

By Liangyou Rui, M. Yuan, Daniel F Frantz, S. Shoelson, M. White. Journal of Biological Chemistry, 2002

941 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/c2dbecc388a3128a2a35a4686dc7f4f2be06376a

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Citations in the corpus

Adipocytokines: mediators linking adipose tissue, inflammation and immunity (2006, background): “Other factors involved in the regulation of insulin resistance are IL-6 and various suppressor of cytokine signalling (SOCS) protein”
Inflammation and insulin resistance (2008, background): “Socs1 and Socs3, which are induced in inflammation, promote the ubiquitylation and subsequent degradation of IRS proteins [ 10 ] (Fig. 1).”
Inflammation, stress, and diabetes. (2005, neutral): “insulin signaling either by interfering with IRS-1 and IRS-2 tyrosine phosphorylation or by targeting IRS-1 and IRS-2 for proteosomal degradation (65, 68).”
Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms (2004, background): “Recently, White and coworkers have reported that SOCS-1 and SOCS-3 bind to IRS proteins and lead them to ubiquitin-mediated protein degradation in cultured cells and liver (39).”
From mice to men: insights into the insulin resistance syndromes. (2006, background): “For example, the suppressors of cytokine signaling (SOCS) proteins, which are induced by inflammatory cytokines, bind to the insulin receptor and block its signaling (133, 134).”
Energy Metabolism in the Liver (2014, positive): “SOCS3 inhibits insulin signaling by both promoting IRS protein degradation and uncoupling IRS proteins from insulin receptors (228, 263).”
Inflammation and metabolic disorders (2006, background): “In addition, suppressor of cytokine signalling (SOCS) proteins seem to inhibit insulin action at the level of insulin-receptor substrates, although through a different mechanis”
Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. (2005, background): “In this context, a recent study has shown that the cytokine signaling suppressors, SOCS-1 and -3, direct elements of the insulin signaling pathway to proteosomic degradation, and therefore, accelerate the rate of protein turnover (19).”
Adipokines Mediate Inflammation and Insulin Resistance (2013, background): “However, excess insulin suppresses the expression of IRS2, and SOCS1/3 induced by inflammatory adipokines such as TNF-α, IL-6, and IL-1β enhance the degradation of IRS1/2 through E3 ubiquitin ligase activation (Rui et al., 2002) (Figure 1).”
Critical nodes in signalling pathways: insights into insulin action (2006, background): “Second, some studies have shown that SOCS proteins might induce ubiquitin-mediated degradation of IRS1 and IRS2 (Ref”