Essential role of glycoprotein Ibα in platelet activation

• DOI: 10.1182/bloodadvances.2023012308
• Publication Date: 2024-05-03T19:03:11Z
• Authors: Rong Yan; Yue Xia; Kangxi Zhou; Jun Liu; Yueyue Sun; Chunyan He; Xinxin Ge; Mengnan Yang; Chenglin Sun; Liuxia Yuan; Shujun Li; Biao Yang; Fanbi Meng; Lijuan Cao; Changgeng Ruan; Kesheng Dai
• Keywords: Glycoprotein Ib; GPVI; Dense granule

Abstract Glycoprotein Ibα (GPIbα), the ligand-binding subunit of platelet GPIb-IX complex, interacts with von Willebrand factor (VWF) exposed at injured vessel wall, initiating adhesion, activation, hemostasis, and thrombus formation. The cytoplasmic tail GPIbα 14-3-3ζ, regulating VWF-GPIbα–elicited signal transduction VWF binding function GPIbα. However, we unexpectedly found that GPIbα–14-3-3ζ association, beyond VWF-dependent function, is essential for general activation. We myristoylated peptide C-terminus MPαC, a potential inhibitor, by itself induced aggregation, integrin αIIbβ3 granule secretion, phosphatidylserine (PS) exposure. Conversely, deletion in mouse platelets (10aa−/−) decreased PS exposure various physiological agonists. Phosphoproteome-based kinase activity profiling revealed significantly upregulated protein C (PKC) MPαC-treated platelets. MPαC-induced activation was abolished pan-PKC inhibitor PKCα deletion. Decreased PKC observed both resting agonist-stimulated 10aa−/− regulates sequestering 14-3-3ζ from PKCα. In vivo, impaired hemostasis formation protected against platelet-dependent pulmonary thromboembolism. Therefore, our findings demonstrate an role VWF–GPIbα axis.