9odx
Structure of Unc119B in complex with N-acetyl-S-geranylgeranyl-L-Cysteine
Structural highlights
FunctionU119B_MOUSE Myristoyl-binding protein that acts as a cargo adapter: specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated NPHP3 and plays a key role in localization of NPHP3 to the primary cilium membrane. Does not bind all myristoylated proteins. Probably plays a role in trafficking proteins in photoreceptor cells (By similarity). Publication Abstract from PubMedOBJECTIVES: A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown. METHODS: Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis. RESULTS: We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1. CONCLUSIONS: Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking, and identifies the mechanism of action of a new class of insulin sensitizers. Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue.,Mittal A, Buscaglia P, Srivastava D, Artemyev NO, Sebag JA Mol Metab. 2025 Aug 7;100:102230. doi: 10.1016/j.molmet.2025.102230. PMID:40754229[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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