Extracellular O-Glcnacylation

Abstract

O-linked β-N-acetylglucosamine (O-GlcNAc) attachment to extracellular protein domains is a recently identified type of O-glycosylation found in epidermal growth factor (EGF) repeat-containing proteins such as Notch receptors. This O-GlcNAc modification occurs in the secretory pathway by the action of the endoplasmic reticulum-resident O-GlcNAc transferase EOGT. In Drosophila, Dumpy, a membrane-tethered apical extracellular protein, was identified as a major O-GlcNAcylated protein in the cuticle. Moreover, O-GlcNAcylation by EOGT contributes to developmental processes that involve epithelial cell–matrix interaction. In mammals, extracellular O-GlcNAc was detected in TSP1, Hspg2, Nell1, Lama5, Pamr1, and Notch receptors. Further, mutations in EOGT were identified in patients with Adams–Oliver syndrome. However, the role of O-GlcNAc in the pathogenesis of Adams–Oliver syndrome and the effect of extracellular O-GlcNAc on protein function are not elucidated thus far. Considering a number of extracellular and transmembrane proteins potentially O-GlcNAcylated by EOGT, additional biological and biochemical studies are necessary to address the molecular basis of the contribution of extracellular O-GlcNAc to the pathogenesis of Adams–Oliver syndrome.