Desialylation of O-glycans on glycoprotein Ibα drives receptor signaling and platelet clearance

During infection neuraminidase desialylates platelets and induces their rapid clearance from circulation. The underlying molecular basis, particularly the role of platelet glycoprotein (GP)Ib alpha therein, is not clear. Utilizing genetically altered mice, we report that the extracellular domain of GPIb alpha, but neither von Willebrand factor nor ADAM17 (a disintegrin and metalloprotease 17), is required for platelet clearance induced by intravenous injection of neuraminidase. Lectin binding to platelet following neuraminidase injection over time revealed that the extent of desialylation of O-glycans correlates with the decrease of platelet count in mice. Injection of alpha 2,3-neuraminidase reduces platelet counts in wild-type but not in transgenic mice expressing only a chimeric GPIb alpha that misses most of its extracellular domain. Neuraminidase treatment induces unfolding of the O-glycosylated mechanosensory domain in GPIb alpha as monitored by single-molecule force spectroscopy, increases the exposure of the ADAM17 shedding cleavage site in the mechanosensory domain on the platelet surface, and induces ligand-independent GPIb-IX signaling in human and murine platelets. These results suggest that desialylation of O-glycans of GPIb alpha induces unfolding of the mechanosensory domain, subsequent GPIb-IX signaling including amplified desialylation of N-glycans, and eventually rapid platelet clearance. This new molecular mechanism of GPIb alpha-facilitated clearance could potentially resolve many puzzling and seemingly contradicting observations associated with clearance of desialylated or hyposialylated platelet.

Automated summary

During infection, neuraminidase removes sialic acid from platelet GPIb alpha, leading to their rapid clearance. This mechanism may explain many puzzling and seemingly contradictory observations associated with clearance of desialylated or hyposialylated platelets.