Cheng KK, Lam KS, Wang Y, Wu D, Zhang M, Wang B, Li X, Hoo RL, Huang Z, Sweeney G, Xu A

Insulin inhibits hepatic glucose production through activation of the protein kinase Akt, and any defect in this pathway causes fasting hyperglycemia in type 2 diabetes. The adaptor protein APPL1 sensitizes hepatic insulin action on suppression of gluconeogenesis by binding to Akt. However, the mechanisms underlying the insulin-sensitizing actions of APPL1 ...

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remain elusive. Here we show that insulin induces lysine 63-linked ubiquitination of APPL1 in primary hepatocytes and in liver of C57 mice. Lysine 160 located within the BAR domain of APPL1 is the major site for its ubiquitination. Substitution of lysine 160 with arginine abolishes insulin-dependent ubiquitination and membrane localization of APPL1, and also diminishes membrane recruitment and activation of Akt, thereby abrogating the effects of APPL1 on alleviation of hepatic insulin resistance and glucose intolerance in obese mice. Further analysis identifies tumor necrosis factor receptor-associated factor 6 (TRAF6) as an E3 ubiquitin ligase for APPL1 ubiquitination. Suppression of TRAF6 expression attenuates insulin-mediated ubiquitination and membrane targeting of APPL1, leading to the impairment in insulin-stimulated Akt activation and inhibition of gluconeogenesis in hepatocytes. Thus, TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulating the membrane trafficking and activity of Akt.

Date: Aug. 05, 2013

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