Medical College of Wisconsin
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Desialylation of O-glycans on glycoprotein Ibα drives receptor signaling and platelet clearance. Haematologica 2021 Jan 01;106(1):220-229

Date

01/25/2020

Pubmed ID

31974202

Pubmed Central ID

PMC7776245

DOI

10.3324/haematol.2019.240440

Scopus ID

2-s2.0-85085201488 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

During infection neuraminidase desialylates platelets and induces their rapid clearance from circulation. The underlying molecular basis, particularly the role of platelet glycoprotein (GP)Ibα therein, is not clear. Utilizing genetically altered mice we report that the extracellular domain of GPIbα, 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 platelets 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 α2,3-neuraminidase reduces platelet counts in wild-type but not in transgenic mice expressing only a chimeric GPIbα that misses most of its extracellular domain. Neuraminidase treatment induces unfolding of the O-glycosylated mechanosensory domain in GPIbα 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 GPIbα 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 GPIbα-facilitated clearance could potentially resolve many puzzling and seemingly contradicting observations associated with clearance of desialylated or hyposialylated platelets.

Author List

Wang Y, Chen W, Zhang W, Lee-Sundlov MM, Casari C, Berndt MC, Lanza F, Bergmeier W, Hoffmeister KM, Zhang XF, Li R

Author

Karin Hoffmeister MD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Mice
Platelet Count
Platelet Glycoprotein GPIb-IX Complex
Polysaccharides
Signal Transduction
von Willebrand Factor