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 (CHO) 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.
