title: Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex.
abstract: The platelet glycoprotein Ib-IX-V complex (GPIb-IX-IV) is the receptor for VWF and is responsible for VWF-mediated platelet activation and aggregation. Loss of the GPIb-IX-V complex is pathogenic for Bernard-soulier Syndrome (BSS), which is characterized by macrothrombocytopenia and impaired platelet function. It remains unclear how the GPIb-IX-V complex is assembled and whether there is a role for a specific molecular chaperone in the process. In the present study, we report that the assembly of the GPIb-IX-V complex depends critically on a molecular chaperone in the endoplasmic reticulum (ER): gp96 (also known as grp94 and HSP90b1). gp96/grp94 deletion in the murine hematopoietic system results in thrombocytopenia, prolonged bleeding time, and giant platelets that are clinically indistinguishable from human BSS. Loss of gp96/grp94 in vivo and in vitro leads to the concomitant reduction in GPIb-IX complex expression due to ER-associated degradation. We further demonstrate that gp96/grp94 binds selectively to the GPIX subunit, but not to gpIbα or gpIbβ. Therefore, we identify the platelet GPIX subunit of the GPIb-IX-V complex as an obligate and novel client of gp96/grp94.
authors.affiliation: Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Staron
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Stojanovic
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
authors.forename: Robert
authors.initials: R
authors.lastname: Bona
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001606:Bernard-Soulier Syndrome / Q000378:metabolism / Q000503:physiopathology; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D001854:Bone Marrow Cells / Q000378:metabolism / Q000648:ultrastructure; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis; D006470:Hemorrhage / Q000378:metabolism / Q000503:physiopathology; D006487:Hemostasis; D008533:Megakaryocytes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D034741:RNA, Small Interfering; D013921:Thrombocytopenia / Q000378:metabolism / Q000503:physiopathology; D018183:Transplantation Chimera / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; C490097:Hsp90b1 protein, mouse; D019038:Platelet Glycoprotein GPIb-IX Complex; D021122:Protein Subunits; D034741:RNA, Small Interfering