Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA.
J Biol Chem. 2011 Jun 24;286(25):22227-34. doi: 10.1074/jbc.M111.228874. Epub 2011 May 3.
SIRT1 is involved in the pathogenesis of obesity, diabetes, and aging. However, it is not clear how SIRT1 activity is regulated by intracellular kinases in cells. In this study, we investigated SIRT1 phosphorylation and protein degradation in response to JNK1 activation in obese mice. Mouse SIRT1 is phosphorylated by JNK1 at Ser-46 (Ser-47 in human SIRT1), which is one of the four potential residues targeted by JNK1. The phosphorylation induces a brief activation of SIRT1 function and degradation of SIRT1 thereafter by the proteasome. Ubiquitination occurs in SIRT1 protein after the phosphorylation. Mutation of Ser-46 to alanine prevents the phosphorylation, ubiquitination, and degradation. In vivo, SIRT1 undergoes an extensive degradation in hepatocytes in obesity as a consequence of persistent activation of JNK1. The degradation leads to inhibition of SIRT1 function, which contributes to development of hepatic steatosis. The degradation disappears in obesity when JNK1 is inactivated in mice. JNK2 exhibits an opposite activity in the regulation of SIRT1 degradation. The JNK1-SIRT1 pathway provides a new molecular mechanism for the pathogenesis of hepatic steatosis in obesity.
SIRT1 参与肥胖、糖尿病和衰老的发病机制。然而，细胞内激酶如何调节 SIRT1 活性尚不清楚。在这项研究中，我们研究了肥胖小鼠中 JNK1 激活时 SIRT1 的磷酸化和蛋白降解。小鼠 SIRT1 可被 JNK1 在 Ser-46（人 SIRT1 中的 Ser-47）磷酸化，这是 JNK1 靶向的四个潜在残基之一。磷酸化诱导 SIRT1 功能短暂激活，随后通过蛋白酶体降解 SIRT1。磷酸化后 SIRT1 蛋白发生泛素化。将 Ser-46 突变为丙氨酸可阻止磷酸化、泛素化和降解。在肥胖的肝细胞中，由于 JNK1 的持续激活，SIRT1 经历广泛降解。这种降解导致 SIRT1 功能抑制，这有助于肝脂肪变性的发展。当小鼠中 JNK1 失活时，这种降解在肥胖中消失。JNK2 在 SIRT1 降解的调节中表现出相反的活性。JNK1-SIRT1 通路为肥胖症中肝脂肪变性的发病机制提供了新的分子机制。
