Unaccompanied mechanosensory domain mediates low expression of glycoprotein Ibα: implications for Bernard‐Soulier syndrome. (22nd December 2019)

• Record Type: Journal Article
• Authors: Tao, Yue; Gan, Chi; Zhang, Xiaoqin; Liu, Lanbo; Zakas, Philip M.; Doering, Christopher B.; Mo, Xi; Li, Renhao
• Is Part Of: Journal of thrombosis and haemostasis. Volume 18:Number 2(2020)
• Page Start: 510
• Page End: 517
• Publication Date: 2019-12-22
• Subjects: Bernard‐Soulier syndrome -- glycoprotein Ib alpha -- glycoprotein Ib‐IX complex -- mechanosensory -- unfolded protein response; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14684
• Languages: English
• ISSNs: 1538-7933

Abstract

Abstract: Background: Disruption of protein folding or inter‐subunit interactions in the platelet glycoprotein (GP)Ib‐IX complex leads to its abnormally low expression in the plasma membrane, the hallmark of Bernard‐Soulier syndrome (BSS). Objective: To discover the molecular mechanism by which GPIbα in the absence of GPIbβ and GPIX subunits is targeted for rapid degradation. Method: The expression of GPIbα mutants with deletion or replacement of various domains were measured in transiently transfected Chinese hamster ovary cells. Results: We report evidence to suggest that induction of the unfolded protein response by the unaccompanied mechanosensory domain (MSD) is a major factor for intracellular degradation and low expression of GPIbα. Removal of the MSD produced the first GPIbα variant that, even in the absence of GPIbβ and GPIX, expressed at a level comparable to that of wild‐type GPIbα in the GPIb‐IX complex, while retaining its native ligand‐binding activity. Conclusion: Our finding has important implications on the molecular pathogenesis of BSS and the function of the GPIb‐IX complex.