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 journalArticle

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

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Nutrients
Chemical activation
Gene Expression
Glucose
Food
Acetylation
Glucose-6-Phosphatase
Phosphoenolpyruvate
Phosphorylation
Gene encoding
Oxidative stress
Acetylglucosamine
Ubiquitination
Enzymes
Transcription
Medical problems
Metabolism
Catalase
Superoxide Dismutase
Reactive Oxygen Species

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Housley, M. P., Rodgers, J. T., Udeshi, N. D., Kelly, T. J., Shabanowitz, J., Hunt, D. F., ... Hart, G. W. (2008). O-GlcNAc regulates FoxO activation in response to glucose. Journal of Biological Chemistry, 283(24), 16283-16292. https://doi.org/10.1074/jbc.M802240200

O-GlcNAc regulates FoxO activation in response to glucose. / Housley, Michael P.; Rodgers, Joseph T.; Udeshi, Namrata D.; Kelly, Timothy J.; Shabanowitz, Jeffrey; Hunt, Donald F.; Puigserver, Pere; Hart, Gerald Warren.

In: Journal of Biological Chemistry, Vol. 283, No. 24, 13.06.2008, p. 16283-16292.

Research output: Contribution to journalArticle

Housley, MP, Rodgers, JT, Udeshi, ND, Kelly, TJ, Shabanowitz, J, Hunt, DF, Puigserver, P & Hart, GW 2008, 'O-GlcNAc regulates FoxO activation in response to glucose', Journal of Biological Chemistry, vol. 283, no. 24, pp. 16283-16292. https://doi.org/10.1074/jbc.M802240200
Housley MP, Rodgers JT, Udeshi ND, Kelly TJ, Shabanowitz J, Hunt DF et al. O-GlcNAc regulates FoxO activation in response to glucose. Journal of Biological Chemistry. 2008 Jun 13;283(24):16283-16292. https://doi.org/10.1074/jbc.M802240200
Housley, Michael P. ; Rodgers, Joseph T. ; Udeshi, Namrata D. ; Kelly, Timothy J. ; Shabanowitz, Jeffrey ; Hunt, Donald F. ; Puigserver, Pere ; Hart, Gerald Warren. / O-GlcNAc regulates FoxO activation in response to glucose. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 24. pp. 16283-16292.
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