Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Association Institut de Myologie, Centre de Recherche en Myologie, UMRS 974, Paris, France.
Sorbonne Université, Department of Physiology, Pitié-Salpêtrière Hospital, Paris, France.
J Cell Biol. 2020 Sep 7;219(9). doi: 10.1083/jcb.201912061.
Clathrin function directly derives from its coat structure, and while endocytosis is mediated by clathrin-coated pits, large plaques contribute to cell adhesion. Here, we show that the alternative splicing of a single exon of the clathrin heavy chain gene (CLTC exon 31) helps determine the clathrin coat organization. Direct genetic control was demonstrated by forced CLTC exon 31 skipping in muscle cells that reverses the plasma membrane content from clathrin plaques to pits and by promoting exon inclusion that stimulated flat plaque assembly. Interestingly, mis-splicing of CLTC exon 31 found in the severe congenital form of myotonic dystrophy was associated with reduced plaques in patient myotubes. Moreover, forced exclusion of this exon in WT mice muscle induced structural disorganization and reduced force, highlighting the contribution of this splicing event for the maintenance of tissue homeostasis. This genetic control on clathrin assembly should influence the way we consider how plasticity in clathrin-coated structures is involved in muscle development and maintenance.
网格蛋白的功能直接来源于其外壳结构，虽然胞吞作用是由网格蛋白包被凹陷介导的，但大斑有助于细胞黏附。在这里，我们表明网格蛋白重链基因（CLTC 外显子 31）的单一外显子的选择性剪接有助于确定网格蛋白外壳的组织。通过在肌肉细胞中强制跳过 CLTC 外显子 31 进行直接遗传控制，这将细胞质膜的内容物从网格蛋白斑转移到凹陷，并通过促进刺激扁平斑组装的外显子包含来实现。有趣的是，在严重先天性肌强直性营养不良中发现的 CLTC 外显子 31 的错剪接与患者肌管中斑的减少有关。此外，在 WT 小鼠肌肉中强制排除该外显子会导致结构紊乱和力量减弱，这突出表明这种剪接事件对组织稳态的维持有贡献。这种对网格蛋白组装的遗传控制应该会影响我们对网格蛋白包被结构可塑性如何参与肌肉发育和维持的认识。
