Platelet Rubicon Bidirectional Regulation of GPVI and Integrin αIIbβ3 Signaling Mitigates Stroke Infarction Without Compromising Hemostasis.

Abstract

Inhibiting the platelet glycoprotein VI (GPVI) receptor is a promising strategy for reducing cerebral ischemia-reperfusion injury (CIRI) without severe compromise of hemostasis, while targeting glycoprotein IIb/IIIa (integrin αIIbβ3) causes bleeding. The underlying cellular mechanism remains unclear. This study shows that megakaryocyte-platelet-specific deficiency of the autophagic protein Rubicon (Run domain protein as Beclin-1 interacting and cysteine-rich containing) accelerates stroke development and exacerbates cerebral hemorrhage. Rubicon interacts with Bruton's tyrosine kinase (Btk) to inhibit GPVI-mediated thrombus formation, while it prevents αIIbβ3-mediated selective autophagy and degradation of Btk to stabilize platelet thrombi. The expression of Rubicon in platelets is decreased in patients with acute ischemic-reperfusion injury. A cell-permeable peptide mimicking the Rubicon-Btk interaction significantly reduces cerebral infarction volume in a mouse model. As Rubicon is dispensable for hemostasis but crucial in the reperfusion stage of CIRI, peptides mimicking its effects may offer a selective and safe therapeutic strategy.