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Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase

State Key Laboratory of Genetic Engineering, School of Life Sciences, Medical College, Fudan University, Shanghai 20032, China.
Molecular cell (Impact Factor: 14.46). 07/2011; 43(1):33-44. DOI: 10.1016/j.molcel.2011.04.028
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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.

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Available from: Shimin Zhao, Jul 04, 2015
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    • "In certain cases acetylation at sites within or adjacent to the active site prevents catalytic steps such as substrate binding (Lundby et al., 2012; Bharathi et al., 2013; Hebert et al., 2013; Still et al., 2013). In others, such as Pepck1, acetylation is reported to promote degradation of the enzyme (Zhao et al., 2010; Jiang et al., 2011). "
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    • "Other reports in yeast and mice under caloric - restricted conditions suggest that SIRT2 may also play a role in helping cells to cope with oxidative stress ( Lamming et al , 2005 ; Wang et al , 2007 ; Zhu et al , 2012 ) . To date , many substrates of SIRT2 have been identified , including a - tubulin ( North et al , 2003 ) , histone H3 / H4 ( Vaquero et al , 2006 ; Das et al , 2009 ) , FOXO3A ( forkhead box O transcription factor 3a ) ( Wang et al , 2007 ) , and PEPCK1 ( phosphoenolpyruvate carboxykinase 1 ) ( Jiang et al , 2011b ) . Among them , only FOXO3A can be indirectly linked to ROS scavenging : SIRT2 - dependent deacetylation of FOXO3A stimulates the expression of FOXO - targeting genes , thereby reducing cellular ROS and decreasing cell death ( Wang et al , 2007 ) . "
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    • "Other reports in yeast and mice under caloric - restricted conditions suggest that SIRT2 may also play a role in helping cells to cope with oxidative stress ( Lamming et al , 2005 ; Wang et al , 2007 ; Zhu et al , 2012 ) . To date , many substrates of SIRT2 have been identified , including a - tubulin ( North et al , 2003 ) , histone H3 / H4 ( Vaquero et al , 2006 ; Das et al , 2009 ) , FOXO3A ( forkhead box O transcription factor 3a ) ( Wang et al , 2007 ) , and PEPCK1 ( phosphoenolpyruvate carboxykinase 1 ) ( Jiang et al , 2011b ) . Among them , only FOXO3A can be indirectly linked to ROS scavenging : SIRT2 - dependent deacetylation of FOXO3A stimulates the expression of FOXO - targeting genes , thereby reducing cellular ROS and decreasing cell death ( Wang et al , 2007 ) . "
    [Show abstract] [Hide abstract]
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