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Role of endocytic proteins in mechanotransduction and impact on autosomal dominant centronuclear myopathy

Abstract : Clathrin and dynamin 2 (DNM2), two key proteins of intracellular membrane trafficking, are co-expressed at specialized adhesion and force transmitting sites of muscle fibers called costameres. These assemblies link the plasma membrane to the extracellular matrix and to the contractile units of muscle. Importantly, mutations in their components cause several distinct myopathies. At the plasma membrane, clathrin forms large flat lattices interacting with costameric cytoskeleton. Clathrin depletion leads to defective costamere formation and induces an impairment of contractile properties. In addition, it has been shown that DNM2 mutations cause autosomal dominant centronuclear myopathy (CNM). In this project, I set out to investigate the interaction between clathrin plaques and the surrounding cytoskeleton with a particular emphasis on DNM2 contribution. I show that actin filaments surrounding mechanically sensitive clathrin plaques anchor a three-dimensional web of muscle-specific intermediate filaments and sequestrate YAP/TAZ, two nucleocytoplasmic shuttling proteins involved in muscle cell proliferation and differentiation. Importantly, my work demonstrates costameric defects in vivo in an heterozygous knock-in mouse model harboring the most frequent CNM mutation. By virtue of shaping both clathrin lattices and branched actin filaments, and by forming a complex with TAZ, DNM2 takes center stage as a central regulator of YAP/TAZ-mediated mechanotransduction and intermediate filament organization. This role may be the Achilles’ heel of several tissues and its dysfunction may lead to other diseases where the fine coupling between adhesion and force transduction is perturbed.
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Agathe Franck. Role of endocytic proteins in mechanotransduction and impact on autosomal dominant centronuclear myopathy. Cellular Biology. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS453⟩. ⟨tel-02926061⟩

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