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PMID: 19103600 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A PGC-1alpha-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose.

The Journal of biological chemistry ·Vol. 284 ·No. 8 ·2009-02-20 ·Pages 5148-57

Housley MP, Udeshi ND, Rodgers JT, Shabanowitz J, Puigserver P, Hunt DF, Hart GW

Abstract

Metabolic and stress response gene regulation is crucial for the survival of an organism to a changing environment. Three key molecules that sense nutrients and broadly affect gene expression are the FoxO transcription factors, the transcriptional co-activator PGC-1alpha, and the dynamic post-translational modification, O-linked beta-N-acetylglucosamine (O-GlcNAc). Here we identify novel post-translational modifications of PGC-1alpha, including O-GlcNAc, and describe a novel mechanism for how PGC-1alpha co-activates transcription by FoxOs. In liver, in cultured cells, and in vitro with recombinant proteins, PGC-1alpha binds to O-GlcNAc transferase and targets the enzyme to FoxOs, resulting in their increased GlcNAcylation and increased transcriptional activity. Furthermore, glucose-enhanced activation of FoxO1 occurs via this PGC-1alpha-O-GlcNAc transferase-mediated GlcNAcylation. Therefore, one mechanism by which PGC-1alpha can serve as a co-activator of transcription is by targeting the O-GlcNAc transferase to increase GlcNAcylation of specific transcription factors important to nutrient/stress sensing and energy metabolism.

MeSH Terms
Acetylglucosamine/genetics,metabolism Acylation/physiology Cell Line Energy Metabolism/physiology Forkhead Box Protein O1 Forkhead Transcription Factors/genetics,metabolism Heat-Shock Proteins/genetics,metabolism Humans Multienzyme Complexes/genetics,metabolism N-Acetylglucosaminyltransferases/genetics,metabolism Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Protein Processing, Post-Translational/physiology Transcription Factors/genetics,metabolism Transcription, Genetic/physiology
Chemicals
FOXO1 protein, human Forkhead Box Protein O1 Forkhead Transcription Factors Heat-Shock Proteins Multienzyme Complexes PPARGC1A protein, human Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Transcription Factors N-Acetylglucosaminyltransferases Acetylglucosamine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Housley Michael P
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Udeshi Namrata D
Rodgers Joseph T
Shabanowitz Jeffrey
Puigserver Pere
Hunt Donald F
Hart Gerald W
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M808890200
Published
2009-02-20
Epub
2008-00-22
Pages
5148-57
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2643526
Subset
IM
Grants
NIGMS NIH HHS · R01 GM037537 · United States
NICHD NIH HHS · HD13563 · United States
NIGMS NIH HHS · GM37537 · United States
NIDDK NIH HHS · DK61671 · United States
External Links
PubMed source DOI: 10.1074/jbc.M808890200 PMC Full Text View journal details
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