Wenqing Jiang,1,2 Shiwen Wang,1,2 Mengtao Xiao,1,2 Yan Lin,2 Lisha Zhou,1,2 Qunying Lei,2,3 Yue Xiong,1,2,4
Kun-Liang Guan,2,3,5 and Shimin Zhao1,2,*
1State Key Laboratory of Genetic Engineering, School of Life Sciences
2Institutes of Biomedical Sciences
3Department of Biochemistry
Medical College, Fudan University, Shanghai 20032, China
4Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill,
NC 27599, USA
5Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA
*Correspondence: zhaosm@fudan.edu.cn
Molecular Cell 43, 33–44, IF:14.194 生物1区
SUMMARY
Protein acetylation has emerged as a major mechanism in regulating cellular metabolism. Whereas most glycolytic steps are reversible, the reaction catalyzed by pyruvate kinase is irreversible, and the reverse reaction requires phosphoenolpyruvate carboxykinase
(PEPCK1) to commit for gluconeogenesis. Here, we show that acetylation regulates the stability of the gluconeogenic rate-limiting enzyme
PEPCK1, thereby modulating cellular response to glucose. High glucose destabilizes PEPCK1 by stimulating its acetylation. PEPCK1 is acetylated by the P300 acetyltransferase, and this acetylation stimulates the interaction between PEPCK1 and UBR5, a HECT domain containing E3 ubiquitin ligase, therefore promoting PEPCK1 ubiquitinylation and degradation. Conversely, SIRT2 deacetylates and
stabilizes PEPCK1. These observations represent an example that acetylation targets a metabolic enzyme to a specific E3 ligase in response to metabolic condition changes. Given that increased levels of PEPCK are linked with type II diabetes, this study also identifies potential therapeutic targets for diabetes.