Cell Motility Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
J Cell Sci. 2014 Feb 1;127(Pt 3):673-85. doi: 10.1242/jcs.141366. Epub 2013 Nov 27.
Vaccinia virus enhances its cell-to-cell spread by inducing Arp2/3-dependent actin polymerisation. This process is initiated by Src- and Abl-mediated phosphorylation of the viral transmembrane protein A36, leading to recruitment of a signalling network consisting of Grb2, Nck, WIP and N-WASP. Nck is a potent activator of N-WASP-Arp2/3-dependent actin polymerisation. However, recent observations demonstrate that an interaction between Nck and N-WASP is not required for vaccinia actin tail formation. We found that Cdc42 cooperates with Nck to promote actin tail formation by stabilising N-WASP beneath the virus. Cdc42 activation is mediated by the Rho guanine-nucleotide-exchange factor (GEF) intersectin-1 (ITSN1), which is recruited to the virus prior to its actin-based motility. Moreover, Cdc42, ITSN1 and N-WASP function collaboratively in a feed-forward loop to promote vaccinia-induced actin polymerisation. Outside the context of infection, we demonstrate that ITSN1 also functions together with Cdc42, Nck and N-WASP during phagocytosis mediated by the Fc gamma receptor. Our observations suggest that ITSN1 is an important general regulator of Cdc42-, Nck- and N-WASP-dependent actin polymerisation.
痘病毒通过诱导 Arp2/3 依赖性肌动蛋白聚合来增强其细胞间传播。该过程由Src 和 Abl 介导的病毒跨膜蛋白 A36 的磷酸化启动，导致募集由 Grb2、Nck、WIP 和 N-WASP 组成的信号网络。Nck 是 N-WASP-Arp2/3 依赖性肌动蛋白聚合的有效激活剂。然而，最近的观察表明，Nck 和 N-WASP 之间的相互作用对于痘病毒肌动蛋白尾的形成不是必需的。我们发现 Cdc42 通过在病毒下方稳定 N-WASP 来与 Nck 合作促进肌动蛋白尾的形成。Cdc42 的激活是由 Rho 鸟嘌呤核苷酸交换因子 (GEF) intersectin-1 (ITSN1) 介导的，该因子在病毒基于肌动蛋白的运动之前被招募到病毒上。此外，Cdc42、ITSN1 和 N-WASP 在一个正反馈回路中协同作用，促进痘病毒诱导的肌动蛋白聚合。在感染的背景之外，我们证明在 Fcγ受体介导的吞噬作用中，ITSN1 也与 Cdc42、Nck 和 N-WASP 一起发挥作用。我们的观察表明，ITSN1 是 Cdc42、Nck 和 N-WASP 依赖性肌动蛋白聚合的重要通用调节剂。
