Institute of Biotechnology and Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, Finland.
Université de Paris, CNRS, Institut Jacques Monod, Paris, France.
Nat Cell Biol. 2021 Feb;23(2):147-159. doi: 10.1038/s41556-020-00629-y. Epub 2021 Feb 8.
Coordinated polymerization of actin filaments provides force for cell migration, morphogenesis and endocytosis. Capping protein (CP) is a central regulator of actin dynamics in all eukaryotes. It binds to actin filament (F-actin) barbed ends with high affinity and slow dissociation kinetics to prevent filament polymerization and depolymerization. However, in cells, CP displays remarkably rapid dynamics within F-actin networks, but the underlying mechanism remains unclear. Here, we report that the conserved cytoskeletal regulator twinfilin is responsible for CP's rapid dynamics and specific localization in cells. Depletion of twinfilin led to stable association between CP and cellular F-actin arrays, as well as to its retrograde movement throughout leading-edge lamellipodia. These were accompanied by diminished F-actin turnover rates. In vitro single-filament imaging approaches revealed that twinfilin directly promotes dissociation of CP from filament barbed ends, while enabling subsequent filament depolymerization. These results uncover a bipartite mechanism that controls how actin cytoskeleton-mediated forces are generated in cells.
肌动蛋白丝的协调聚合为细胞迁移、形态发生和胞吞作用提供了力。盖帽蛋白 (CP) 是所有真核生物中肌动蛋白动力学的核心调节剂。它以高亲和力和缓慢的离解动力学结合到肌动蛋白丝 (F-actin) 的棘突末端，以防止纤维聚合和解聚。然而，在细胞中，CP 在 F-actin 网络中表现出显著的快速动力学，但潜在的机制尚不清楚。在这里，我们报告说，保守的细胞骨架调节剂 twinfilin 负责 CP 的快速动力学和细胞内的特异性定位。twinfilin 的耗竭导致 CP 与细胞 F-actin 排列稳定结合，以及其在前缘片状伪足中的逆行运动。这伴随着 F-actin 周转率的降低。体外单丝成像方法表明，twinfilin 直接促进 CP 从丝状棘突末端解离，同时允许随后的丝状解聚。这些结果揭示了一种二分机制，控制细胞中如何产生肌动蛋白细胞骨架介导的力。
