Molecular Regulation of Protein O‐Glycosylation and Relevance to Disease and Development

Abstract

Altered glycan expression is a hallmark of animal development and cellular differentiation, as well as being a hallmark of cancer. A common class of glycans is the mucin‐type O‐glycan linked via GalNAcα1‐Ser/Thr, a precursor that is recognized as the Tn antigen and is normally extended to form complex O‐glycans. O‐GalNAc glycans occur in many cell surface glycoproteins. We discovered a key gene involved normal extension of O‐GalNAc glycans is the T‐synthase, which encodes a β1,3‐ galactosyltransferase that generates the common T‐antigen Galβ1–3GalNAcα1‐Ser/Thr. Unexpectedly, expression of the T‐synthase is under the control of a unique molecular chaperone termed Cosmc, which is a resident endoplasmic reticulum chaperone whose sole client is the T‐synthase. Cosmc is encoded by an X‐linked gene (Xq24) in humans; acquired or engineered acquired mutations in Cosmc lead to a loss of T‐synthase due to its misfolding and subsequent degradation, and concomitant expression of the Tn antigen in all cells. We have developed genetically engineered mice lacking Cosmc that express Tn antigen in a tissue‐ and cell‐specific manner. Our studies show that a wide variety of glycoproteins require extended O‐GalNAc glycans for normal expression and localization, oligomerization, turnover, and stability, and suggest a new paradigm for the functions of O‐GalNAc glycans in regulating a wide variety of cellular processes.