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Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322

Correspondence to Richard D. Cummings: rdcummi{at}emory.edu; or Tongzhong Ju: tju{at}emory.edu

Regulatory pathways for protein glycosylation are poorly understood, but expression of branchpoint enzymes is critical. A key branchpoint enzyme is the T-synthase, which directs synthesis of the common core 1 O-glycan structure (T-antigen), the precursor structure for most mucin-type O-glycans in a wide variety of glycoproteins. Formation of active T-synthase, which resides in the Golgi apparatus, requires a unique molecular chaperone, Cosmc, encoded on Xq24. Cosmc is the only molecular chaperone known to be lost through somatic acquired mutations in cells. We show that Cosmc is an endoplasmic reticulum (ER)–localized adenosine triphosphate binding chaperone that binds directly to human T-synthase. Cosmc prevents the aggregation and ubiquitin-mediated degradation of the T-synthase. These results demonstrate that Cosmc is a molecular chaperone in the ER required for this branchpoint glycosyltransferase function and show that expression of the disease-related Tn antigen can result from deregulation or loss of Cosmc function.

Abbreviations used in this paper: CD: cytoplasmic domain; DSS, disuccinimidyl suberate; ERAD, ER-associated degradation; GalNAc, N-acetylgalactosamine; Gal-T, galactosyltransferase; GlcNAc, N-acetylglucosamine; HPC, human protein C; PNS, Postnuclear supernatant; TMD, transmembrane domain.

© 2008 Ju et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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