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Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity

Authors
 Joo-Man Park  ;  Tae-Hyun Kim  ;  Seong-Ho Jo  ;  Mi-Young Kim  ;  Yong-Ho Ahn 
Citation
 SCIENTIFIC REPORTS, Vol.5 : 17395, 2015 
Journal Title
 SCIENTIFIC REPORTS 
Issue Date
2015
MeSH
Acetylation ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism* ; Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism* ; Glucokinase/genetics ; Glucokinase/metabolism* ; Glucose/genetics ; Glucose/metabolism* ; HeLa Cells ; Humans ; Male ; Mice ; Mice, Obese ; Protein Processing, Post-Translational* ; Sirtuin 2/genetics ; Sirtuin 2/metabolism
Abstract
Glucokinase (GK), mainly expressed in the liver and pancreatic β-cells, is critical for maintaining glucose homeostasis. GK expression and kinase activity, respectively, are both modulated at the transcriptional and post-translational levels. Post-translationally, GK is regulated by binding the glucokinase regulatory protein (GKRP), resulting in GK retention in the nucleus and its inability to participate in cytosolic glycolysis. Although hepatic GKRP is known to be regulated by allosteric mechanisms, the precise details of modulation of GKRP activity, by post-translational modification, are not well known. Here, we demonstrate that GKRP is acetylated at Lys5 by the acetyltransferase p300. Acetylated GKRP is resistant to degradation by the ubiquitin-dependent proteasome pathway, suggesting that acetylation increases GKRP stability and binding to GK, further inhibiting GK nuclear export. Deacetylation of GKRP is effected by the NAD(+)-dependent, class III histone deacetylase SIRT2, which is inhibited by nicotinamide. Moreover, the livers of db/db obese, diabetic mice also show elevated GKRP acetylation, suggesting a broader, critical role in regulating blood glucose. Given that acetylated GKRP may affiliate with type-2 diabetes mellitus (T2DM), understanding the mechanism of GKRP acetylation in the liver could reveal novel targets within the GK-GKRP pathway, for treating T2DM and other metabolic pathologies.
Files in This Item:
T201504742.pdf Download
DOI
10.1038/srep17395
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Mi Young(김미영)
Ahn, Yong Ho(안용호) ORCID logo https://orcid.org/0000-0002-4133-0757
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156830
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