| First Author | Wang Y | Year | 2021 |
| Journal | Haematologica | Volume | 106 |
| Issue | 1 | Pages | 220-229 |
| PubMed ID | 31974202 | Mgi Jnum | J:340093 |
| Mgi Id | MGI:7524463 | Doi | 10.3324/haematol.2019.240440 |
| Citation | Wang Y, et al. (2021) Desialylation of O-glycans on glycoprotein Ibalpha drives receptor signaling and platelet clearance. Haematologica 106(1):220-229 |
| abstractText | During infection neuraminidase desialylates platelets and induces their rapid clearance from circulation. The underlying molecular basis, particularly the role of platelet glycoprotein (GP)Ibalpha therein, is not clear. Utilizing genetically altered mice we report that the extracellular domain of GPIbalpha, 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 alpha2,3-neuraminidase reduces platelet counts in wild-type but not in transgenic mice expressing only a chimeric GPIbalpha that misses most of its extracellular domain. Neuraminidase treatment induces unfolding of the O-glycosylated mechanosensory domain in GPIbalpha 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 GPIbalpha 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 GPIbalpha-facilitated clearance could potentially resolve many puzzling and seemingly contradicting observations associated with clearance of desialylated or hyposialylated platelets. |
