Here, we find cytoskeleton-associated protein 4 (CKAP4) is a novel receptor for Spike protein invasion, as evidenced by its specific interaction with Spike protein and receptor-binding domain of Spike protein. CKAP4 is widely expressed in various tissues and cells and acts as a ligand-specific membrane receptor. The report has shown elevation of CKAP4 membrane translocation in ECs weakens the integrity of endothelial adherence junction; however, little is known about the role of endothelial CKAP4 in coagulopathy. We found silencing endothelial CKAP4 abolished Spike protein-induced vWF secretion, FVIII-vWF binding, and platelet adhesion to ECs. Moreover, the role of CKAP4 in coagulopathy was further confirmed in human lung microvascular ECs. Thus, CKAP4 is a novel receptor for Spike protein recognition and binding, and essential for Spike protein-induced coagulopathy.
