O-GlcNAc regulates FoxO activation in response to glucose

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

Research output: Contribution to journalArticlepeer-review

Abstract

FoxO proteins are key transcriptional regulators of nutrient homeostasis and stress response. The transcription factor FoxO1 activates expression of gluconeogenic, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and also activates the expression of the oxidative stress response enzymes catalase and manganese superoxide dismutase. Hormonal and stress-dependent regulation of FoxO1 via acetylation, ubiquitination, and phosphorylation, are well established, but FoxOs have not been studied in the context of the glucose-derived O-linked β-N-acetylglucosamine (O-GlcNAc) modification. Here we show that O-GlcNAc on hepatic FoxO1 is increased in diabetes. Furthermore, O-GlcNAc regulates FoxO1 activation in response to glucose, resulting in the paradoxically increased expression of gluconeogenic genes while concomitantly inducing expression of genes encoding enzymes that detoxify reactive oxygen species. GlcNAcylation of FoxO provides a new mechanism for direct nutrient control of transcription to regulate metabolism and stress response through control of FoxO1 activity.

Original languageEnglish (US)
Pages (from-to)16283-16292
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number24
DOIs
StatePublished - Jun 13 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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