Platelet biogenesis and functions require correct protein O-glycosylation

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.

Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk

“…We next assessed the consequence of Cosmc deletion and glycocalyx loss in the intestine, which results in profound pathology when deleted in other tissues (7,10). Beginning at 3 mo of age, male KOs exhibited multiple signs of inflammation, including weight loss ( Fig.…”

What Can Proteomics Tell Us About Platelets?

“…Even with state-of-the-art instrumentation, the extreme heterogeneity and complexity of glycosylation patterns render their analysis challenging, such that many studies focus on the enrichment and identification of glycosylated residues rather than on characterizing the glycan structures. Yet, glycosylation patterns may dramatically influence processes such as platelet biogenesis 146 and activation. 147 To date, only few dedicated glycoproteomics studies have been conducted on human platelets, 117,118,148 identifying several hundreds of N-glycosylation sites mainly on membrane proteins.…”

Promoters of Human Cosmc and T-synthase Genes Are Similar in Structure, Yet Different in Epigenetic Regulation

“…Therefore, a major mechanism for the expression of Tn antigen on cells is the loss of functional Cosmc, including both genetic mutations and epigenetic dysregulation of Cosmc (19,21). Knock-out of either T-synthase or Cosmc in mice causes embryonic lethality and Tn antigen expression (9,13), and specific deletion of T-synthase in endothelial and hematopoietic cells in mice causes defective lymphatic vessel formation (10) and loss of high endothelial venule integrity (28); specific disruption of either Cosmc (29) or T-synthase (30) in hematopoietic cells confers megathrombocytopenia and bleeding in mice.…”