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Glycobiology Advance Access published online on February 27, 2006
Glycobiology, doi:10.1093/glycob/cwj096
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© The Author 2006. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received January 18, 2006
Revised February 14, 2006
Accepted February 21, 2006

Article

Disrupting the enzyme complex regulating O-GlcNAcylation blocks signaling and development

Thomas R. Whisenhunt 1, Xiaoyong Yang 2, Damon B. Bowe 3, Andrew J. Paterson 4, Brian A Van Tine 5, and Jeffrey E. Kudlow 6 *

1 Department of Cell Biology; Medical Scientist Training Program University of Alabama at Birmingham Birmingham AL 35294
2 Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, CA 92037
3 Department of Pharmacology and Toxicology
4 Department of Medicine, Division of Endocrinology, Diabetes and Metabolism
5 Medical Scientist Training Program University of Alabama at Birmingham Birmingham AL 35294
6 Department of Cell Biology; Department of Pharmacology and Toxicology; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism

* To whom correspondence should be addressed.
Jeffrey E. Kudlow, E-mail: kudlow{at}uab.edu


  Abstract

Although the knowledge that nuclear and cytoplasmic proteins are modified with N-acetylglucosamine has existed for decades, little has been shown as to its function until recently. There are now substantial data highlighting the significance of proper regulation of this modification in multiple cellular processes. Currently only two enzymes are known that regulate this modification. O-GlcNAc Transferase (OGT) modifies protein substrates post-translationally by adding the N-acetylglucosamine. Bifunctional Nuclear/Cytoplasmic O-GlcNAcase and Acetyl Transferase (NCOAT) is responsible for cleaving the modification from target proteins. Here we demonstrate for the first time an unusual association of these two opposing enzymes into a single O-GlcNAczyme complex. NCOAT and OGT associate strongly through specific domains such that NCOAT accompanies OGT, with histone deacetylases, into transcription corepression complexes. Exclusion of NCOAT activities from OGT association blocks proper estrogen dependent cell signaling as well as mammary development in transgenic mice. This demonstrates that NCOAT is in a strategic position to rapidly counteract OGT and HDAC without requiring its recruitment.

Keywords: Corepressor/Estrogen/HAT/O-GlcNAcase/OGT.
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