# F-actin disassembly by the oxidoreductase MICAL1 promotes mechano-dependent VWF-GPIbα interaction in platelets

## TL;DR

Platelet adhesion under high shear stress depends on actin disassembly, regulated by MICAL1, which enhances receptor function for clot formation.

## Contribution

MICAL1 is identified as a shear-activated oxidoreductase that promotes F-actin disassembly to enhance VWF-GPIbα interaction in platelets.

## Key findings

- Actin disassembly is critical for VWF-GPIbα binding under shear stress.
- MICAL1 promotes F-actin disassembly around the GPIb-IX-V complex, enabling its translocation to lipid rafts.
- MICAL1-deficient platelets show impaired adhesion and defective thrombus formation.

## Abstract

Mechano-dependent interactions are key to thrombus formation and hemostasis, enabling stable platelet adhesion to injured vessels. The interaction between von Willebrand factor (VWF) and the platelet receptor GPIb-IX-V is central to this process. While GPIbα connects to the actin cytoskeleton, whether actin dynamics are important for GPIbα function under hemodynamic, high shear conditions remains largely unknown. Here, we show that actin disassembly is critical for proper VWF-GPIbα binding under shear. Mechanistically, we identify the oxidoreductase MICAL1 as a shear-activated regulator that promotes local F-actin disassembly around the GPIb-IX-V complex. This enables its translocation to lipid rafts and reinforces VWF binding. MICAL1-deficient platelets display impaired adhesion, increased deformability under shear, and defective thrombus formation in vivo. Thus, MICAL1 drives shear-dependent actin remodeling that supports GPIb-IX-V mechanotransduction and platelet function. These findings uncover a role for actin oxidation in platelet adhesion, providing a connection between cytoskeletal redox control and platelet function during thrombus formation.

To stop bleeding from an injured vessel, platelets adhere and form a clot despite high shear stress from the flow. Here, the authors show that platelet actin disassembly is a key step that enables a receptor to translocate to membrane lipid rafts, enhancing its adhesive function under shear stress.