Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity
Program in Molecular Medicine
Animals; Cell Line; Dietary Fats; Enzyme Activation; Fatty Liver; Gene Knockout Techniques; Histone Deacetylases; Humans; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 8; Obesity; Phosphorylation; Rats; Sirtuin 1; Ubiquitination
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
DOI of Published Version
J Biol Chem. 2011 Jun 24;286(25):22227-34. doi: 10.1074/jbc.M111.228874. Epub 2011 May 3. Link to article on publisher's site
The Journal of biological chemistry
Gao, Zhanguo; Zhang, Jin; Kheterpal, Indu; Kennedy, Norman J.; Davis, Roger J.; and Ye, Jianping, "Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity" (2011). Davis Lab Publications. 36.