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

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 gluc...

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Main Authors:	Park, Joo-Man, Kim, Tae-Hyun, Jo, Seong-Ho, Kim, Mi-Young, Ahn, Yong-Ho
Format:	Online
Language:	English
Published:	Nature Publishing Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664969/

id	pubmed-4664969
recordtype	oai_dc
spelling	pubmed-46649692015-12-03 Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity Park, Joo-Man Kim, Tae-Hyun Jo, Seong-Ho Kim, Mi-Young Ahn, Yong-Ho Article 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. Nature Publishing Group 2015-12-01 /pmc/articles/PMC4664969/ /pubmed/26620281 http://dx.doi.org/10.1038/srep17395 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Park, Joo-Man Kim, Tae-Hyun Jo, Seong-Ho Kim, Mi-Young Ahn, Yong-Ho
spellingShingle	Park, Joo-Man Kim, Tae-Hyun Jo, Seong-Ho Kim, Mi-Young Ahn, Yong-Ho Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
author_facet	Park, Joo-Man Kim, Tae-Hyun Jo, Seong-Ho Kim, Mi-Young Ahn, Yong-Ho
author_sort	Park, Joo-Man
title	Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
title_short	Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
title_full	Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
title_fullStr	Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
title_full_unstemmed	Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
title_sort	acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity
description	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.
publisher	Nature Publishing Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664969/
_version_	1613508045866795008

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

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