Platelet biogenesis and functions require correct protein O-glycosylation

• Authors: Yingchun Wang, Emory University; Shawn Jobe, Emory University; Xiaokun Ding, Emory University; Hyojung Choo, Emory University; David Archer, Emory University; Rongjuan Mi, Emory University; Tongzhong Ju, Emory University; Richard Cummings, Emory University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 109, Number 40
• Publisher: National Academy of Sciences | 2012-10-02, Pages 16143-16148
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1073/pnas.1208253109
• Subjects: Chemistry, Biochemistry
• Keywords: platelet glycoproteins; T-synthase; Tn antigen

Abstract

Platelets express a variety of membrane and secreted glycoproteins, but the importance of glycosylation to platelet functions is poorly understood. To explore the importance of O-glycosylation, we generated mice with a targeted deletion of Cosmc in murine endothelial/hematopoietic cells (EHC) (EHC Cosmc−/y). X-linked Cosmc encodes an essential chaperone that regulates protein O-glycosylation. This targeted mutation resulted in lethal perinatal hemorrhage in the majority of mice, and the surviving mice displayed severely prolonged tail-bleeding times and macrothrombocytopenia. EHC Cosmc−/y platelets exhibited a marked decrease in GPIb-IX-V function and agonist-mediated integrin αIIbβ3 activation, associated with loss of interactions with von Willebrand factor and fibrinogen, respectively. Significantly, three O-glycosylated glycoproteins, GPIbα, αIIb, and GPVI normally on platelet surfaces that play essential roles in platelet functions, were partially proteolyzed in EHC Cosmc−/y platelets. These results demonstrate that extended O-glycans are required for normal biogenesis of the platelets as well as the expression and functions of their essential glycoproteins, and that variations in O-glycosylation may contribute to altered hemostasis.