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J. Biol. Chem., Vol. 283, Issue 24, 16283-16292, June 13, 2008

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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, and Gerald W. Hart¹

From the Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, the Department of Cell Biology, Harvard Medical School and the Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and the Departments of ^¶Chemistry and ^||Pathology, University of Virginia, Charlottesville, Virginia 22904

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.

Received for publication, March 20, 2008 , and in revised form, April 17, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK61671 and HD13563 (to G. W. H.) and GM37537 (to D. F. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Recipient of a share of royalties on university sales of CTD110.6 antibody. To whom correspondence should be addressed. E-mail: gwhart{at}jhmi.edu.

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