A role for the small GTPase Rac1 in vaccinia actin-based motility

Abstract

Vaccinia virus dissemination relies on the recruitment of the nucleation promoting factor N-WASP underneath cell-associated extracellular virus (CEVs) and subsequent recruitment and activation of the ARP2/3 complex, a major actin nucleator of the host cell. We have recently discovered that, in addition to the N-WASP/ARP2/3 pathway, vaccinia actin-based motility also relies on the small GTPase Rac1 and its downstream effector the formin-type actin nucleator FHOD1. Here we discuss the potential signaling mechanisms supporting the integration of the N-WASP/ARP2/3 and Rac1/FHOD1 pathways. We suggest the existence of a receptor tyrosine kinase family member that would integrate the Src-dependent activation of the N-WASP/ARP2/3 pathway and the GTP exchange factor-dependent activation of the Rac1/FHOD1 pathway.

Keywords: ARP2/3 complex; Dissemination; FHOD1; N-WASP; Rac1; actin-based motility; spread from cell to cell; vaccinia virus.

Figure 1. (A) Canonical model for vaccinia actin tail formation by the activation of the N-WASP/ARP2/3 pathway. Phosphorylation of the cytoplasmatic domain of A36 underneath CEVs (gray and white oval) by Src and Abl families of non-receptor tyrosine kinases mediates the recruitment of Nck1 and Grb2 adaptor proteins that in turn recruit a complex of WIP and N-WASP to activate the ARP2/3 complex promoting actin tail formation. (B) Vaccinia actin tail formation involves the activation of the Rac1/FHOD1 pathway. The small GTPase Rac1 is activated underneath CEVs by a yet unidentified guanine-nucleotide exchange factor (GEF). Downstream of Rac1, recruitment and activation of FHOD1 promotes vaccinia actin tail formation. Profilin stimulates formin activities of FHOD1. (C) A model for the integration of N-WASP/ARP2/3 and Rac1/FHOD1 pathways. A vaccinia protein exposed on the outer membrane of CEVs engages a yet unidentified receptor tyrosine kinase (RTKs) leading to the activation of Src and subsequent phosphorylation of A36, as well as the recruitment of a GEF for Rac1, thereby integrating the activities of the N-WASP/ARP2/3 and Rac1/FHOD1 pathways. N-WASP interacts with FHOD1 through an unknown mechanism (arrow).