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

Michael P. Housley, Namrata D. Udeshi, Joseph T. Rodgers, Jeffrey Shabanowitz, Pere Puigserver, Donald F. Hunt, Gerald Warren Hart

Research output: Contribution to journalArticle

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-1α, and the dynamic post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc). Here we identify novel post-translational modifications of PGC-1α, including O-GlcNAc, and describe a novel mechanism for how PGC-1α co-activates transcription by FoxOs. In liver, in cultured cells, and in vitro with recombinant proteins, PGC-1α 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-1α-O-GlcNAc transferase-mediated GlcNAcylation. Therefore, one mechanism by which PGC-1α can serve as a co-activator of transcription is by targeting the O-GlcNAc transferase to increase Glc-NAcylation of specific transcription factors important to nutrient/stress sensing and energy metabolism.

Original languageEnglish (US)
Pages (from-to)5148-5157
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number8
DOIs
StatePublished - Feb 20 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Housley, M. P., Udeshi, N. D., Rodgers, J. T., Shabanowitz, J., Puigserver, P., Hunt, D. F., & Hart, G. W. (2009). A PGC-1α-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. Journal of Biological Chemistry, 284(8), 5148-5157. https://doi.org/10.1074/jbc.M808890200