Speaker: Stéphane Vassilopoulos - Sorbonne Université, INSERM, Institute of Myology, Centre of Research in Myology, Paris
Title: Clathrin kaleidoscope: Structural diversity and its impact on neuromuscular diseases
Abstract: Clathrin is best known for its role in endocytosis, but emerging evidence reveals that it forms structurally diverse assemblies with specialized functions across cell types. In this talk, I will describe how clathrin organizes into distinct architectures at the plasma membrane, ranging from coated pits to flat plaques, and how this diversity contributes to neuromuscular and neuronal physiology.
Using platinum replica electron microscopy and correlative super-resolution imaging, we show that clathrin plaque formation in skeletal muscle is developmentally regulated by alternative splicing of clathrin, which alters lattice curvature and mechanical properties. Perturbing this splicing event disrupts muscle function in vivo and is relevant to myotonic dystrophy.
We further demonstrate that clathrin plaques act as mechanosensitive platforms at costameres, integrating actin dynamics, dynamin 2 (DNM2), and integrin signaling to control YAP/TAZ mechanotransduction. Pathogenic DNM2 mutations associated with centronuclear myopathy drive aberrant nuclear YAP/TAZ signaling in patient samples and mouse models, a defect that can be rescued by allele-specific DNM2 silencing.
Finally, I will present new evidence for a specialized clathrin-based endocytic architecture at the axon initial segment, embedded within the spectrin/actin scaffold and dynamically regulated by neuronal activity. Together, these findings redefine clathrin as a multifunctional structural and mechanosensitive scaffold with direct relevance to several neuromuscular diseases.
References:
Wernert F, Moparthi SB, Pelletier F, Lainé J, Simons E, Moulay G, Rueda F, Jullien N, Benkhelifa-Ziyyat S, Papandréou MJ, Leterrier C, Vassilopoulos S. The actin-spectrin submembrane scaffold restricts endocytosis along proximal axons. Science. 2024 Aug 23;385(6711):eado2032. doi: 10.1126/science.ado2032.
Vassilopoulos S, Montagnac G. Clathrin assemblies at a glance. J Cell Sci. 2024 Apr 15;137(8):jcs261674. doi: 10.1242/jcs.261674.
Moulay G, Lainé J, Lemaître M, Nakamori M, Nishino I, Caillol G, Mamchaoui K, Julien L, Dingli F, Loew D, Bitoun M, Leterrier C, Furling D, Vassilopoulos S. Alternative splicing of clathrin heavy chain contributes to the switch from coated pits to plaques. J Cell Biol. 2020 Sep 7;219(9):e201912061. doi: 10.1083/jcb.201912061.
Vassilopoulos S. Unconventional roles for membrane traffic proteins in response to muscle membrane stress. Curr Opin Cell Biol. 2020 Aug;65:42-49. doi: 10.1016/j.ceb.2020.02.007.
