Abstract
Platelet adhesion and aggregation at sites of vascular injury is essential for hemostasis but may also cause thrombosis.1 Firm platelet adhesion is mediated by heterodimeric receptors of the β1- and β3-integrin families, which upon activation reversibly shift to a high-affinity state and efficiently bind their ligands, most notably components of the extracellular matrix and other receptors.2⇓-4 Binding of talin-1 (Tln1) and kindlins to the intracellular tail of the integrin β-subunit triggers the switch to the high-affinity state, whereas their dissociation results in integrin closure, the switch back to the low-affinity state.5⇓⇓-8 Tln1 and kindlins connect integrins to the actin cytoskeleton, thereby enabling the sensing and exertion of mechanical forces as well as regulating adhesion formation and turnover.9⇓⇓-12 Consistently, defects in actin-regulating proteins result in altered platelet and megakaryocyte integrin function.13⇓⇓⇓⇓⇓-19 Furthermore, we have recently shown a critical role of twinfilin 2a (Twf2a) and the cortical cytoskeleton in regulating platelet integrin turnover in a profilin 1 (Pfn1)–dependent manner.10 The small actin-binding protein Pfn1 is central for actin dynamics by mediating the nucleotide exchange on G-actin monomers, thereby promoting filament assembly with implications for platelet biogenesis.13,20 Megakaryocyte-specific Pfn1 deficiency resulted in microthrombocytopenia because of cytoskeletal alterations and accelerated platelet clearance (supplemental Figure 1).13 However, the precise role of Pfn1 for platelet function is unknown. Here, we report that the lack of Pfn1 in platelets (Pfn1fl/fl-Pf4Cre) perturbs the organization of the adhesion-dependent circumferential actin network and thereby results in accelerated integrin inactivation and hence impaired platelet function in vitro and in vivo.
Stritt, Simon