Mechanistic insights into oxidation-driven actin dynamics in platelet physiology – ACTOMIC

Actin dynamics plays a long-described and critical role in platelet physiology, but how, mechanistically, this is achieved and regulated remains an important open question. Actin filament networks constantly assemble and disassemble via various actin-binding proteins but also via post-translational modifications (PTM). Methionine oxidation of F-actin is an emerging PTM that dramatically induces filament disassembly and is catalysed by MICAL family members. ACTOMIC aims at understanding the role of actin oxidation mediated by MICAL1 in platelet physiology. This ambitious project will benefit from the expertise of two teams forming an interdisciplinary and highly complementary consortium, with multi-scale approaches, from physiology in vivo to cellular and molecular levels. The proposal will involve unique and innovative mouse and human models. A strength of this project relies on strong preliminary results and on the implementation of several cutting-edge experimental approaches mastered by the consortium: mouse models (with thrombosis and bleeding models), spatial spinning-disk confocal microscopy, super-resolution microscopy, biomechanics and proteomic approaches. Furthermore, the functional impact on platelet physiology of a non-characterized MICAL1 variant recently associated with bleeding will be investigated. Revealing new regulators of the actin cytoskeleton in platelets will be important to obtain a better understanding of their physiology, and will guide future efforts to correct the platelet function in patients.