Nck- and N-WASP-dependent actin-based motility is conserved in divergent vertebrate poxviruses.

Vaccinia virus enhances its cell-to-cell spread by stimulating actin polymerization via Src- and Abl-mediated phosphorylation of the highly conserved orthopoxvirus protein A36. The Yatapoxvirus, Yaba-like disease virus (YLDV), also induces actin polymerization, although it lacks an obvious A36 ortholog. We found that the YLDV protein YL126 can functionally replace A36 to promote Nck- and N-WASP-dependent actin polymerization. At least five phosphorylated tyrosines in YL126, rather than a single residue as in A36, are able to recruit Nck to promote actin polymerization. As is the case for A36, YL126-mediated actin tail formation is enhanced by the recruitment of Grb2 via a single phosphorylated tyrosine in YL126. Furthermore, highly divergent YL126 orthologs in Yaba monkey tumor, lumpy skin disease, Shope fibroma, myxoma, and swine and squirrel poxviruses also stimulate Nck- and N-WASP-dependent actin polymerization, suggesting that actin-based motility represents a common mechanism to enhance the cell-to-cell spread of vertebrate poxviruses.