title: Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase.
abstract: 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.
authors: State Key Laboratory of Genetic Engineering, School of Life Sciences, Medical College, Fudan University, Shanghai 20032, China.
authors: Wenqing
authors: W
authors: Jiang
authors: Shiwen
authors: S
authors: Wang
authors: Mengtao
authors: M
authors: Xiao
authors: Yan
authors: Y
authors: Lin
authors: Lisha
authors: L
authors: Zhou
authors: Qunying
authors: Q
authors: Lei
authors: Yue
authors: Y
authors: Xiong
authors: Kun-Liang
authors: KL
authors: Guan
authors: Shimin
authors: S
authors: Zhao
mesh_terms: D000107:Acetylation; D002460:Cell Line; D005943:Gluconeogenesis / Q000502:physiology*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000502:physiology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D055550:Protein Stability; D056565:Sirtuin 2 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology; D054875:Ubiquitination
chemical_list: C092009:BAG6 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; C474199:SIRT2 protein, human; D056565:Sirtuin 2; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP)