title: 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.
authors.affiliation: Departments of Biochemistry and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Jobe
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Ding
authors.forename: Hyojung
authors.initials: H
authors.lastname: Choo
authors.forename: David R
authors.initials: DR
authors.lastname: Archer
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Mi
authors.forename: Tongzhong
authors.initials: T
authors.lastname: Ju
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D055018:Hemangioblasts; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism*; D013921:Thrombocytopenia / Q000235:genetics*
chemical_list: C514310:Cosmc protein, mouse; D006023:Glycoproteins; D018832:Molecular Chaperones; D011134:Polysaccharides