MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Cell. 2018 Jul 12;174(2):325-337.e14. doi: 10.1016/j.cell.2018.05.020. Epub 2018 Jun 7.
Multiple proteins act co-operatively in mammalian clathrin-mediated endocytosis (CME) to generate endocytic vesicles from the plasma membrane. The principles controlling the activation and organization of the actin cytoskeleton during mammalian CME are, however, not fully understood. Here, we show that the protein FCHSD2 is a major activator of actin polymerization during CME. FCHSD2 deletion leads to decreased ligand uptake caused by slowed pit maturation. FCHSD2 is recruited to endocytic pits by the scaffold protein intersectin via an unusual SH3-SH3 interaction. Here, its flat F-BAR domain binds to the planar region of the plasma membrane surrounding the developing pit forming an annulus. When bound to the membrane, FCHSD2 activates actin polymerization by a mechanism that combines oligomerization and recruitment of N-WASP to PI(4,5)P, thus promoting pit maturation. Our data therefore describe a molecular mechanism for linking spatiotemporally the plasma membrane to a force-generating actin platform guiding endocytic vesicle maturation.
多种蛋白质在哺乳动物网格蛋白介导的胞吞作用（CME）中协同作用，从质膜生成胞吞小泡。然而，控制哺乳动物 CME 期间肌动蛋白细胞骨架的激活和组织的原则尚未完全了解。在这里，我们表明 FCHSD2 蛋白是 CME 期间肌动蛋白聚合的主要激活剂。FCHSD2 缺失会导致配体摄取减少，这是由于陷口成熟速度减慢所致。支架蛋白 intersectin 通过不寻常的 SH3-SH3 相互作用将 FCHSD2 募集到胞吞陷口。在这里，其平坦的 F-BAR 结构域与围绕正在发育的陷口的质膜的平面区域结合形成一个环。当与膜结合时，FCHSD2 通过一种将寡聚化和 N-WASP 募集到 PI(4,5)P 结合起来的机制激活肌动蛋白聚合，从而促进陷口成熟。因此，我们的数据描述了一种将质膜与产生力的肌动蛋白平台连接起来的分子机制，指导胞吞小泡成熟。
