Abstract
Vaccinia virus (VACV) encodes multiple proteins inhibiting the NF-kB signalling pathway. One of these, A49, targets the E3 ubiquitin ligase b-TrCP, which is responsible for the ubiquitylation and consequential proteosomal degradation of IkBa and the release of the NF-kB heterodimer. b-TrCP is a pleiotropic enzyme ubiquitylating multiple cellular substrates, including the transcriptional activator b-catenin. Here we demonstrate that A49 can activate the Wnt signalling pathway, a critical pathway that is involved in cell cycle and cell differentiation, and is controlled by b-catenin. The data presented show that the expression of A49 ectopically or during VACV infection causes accumulation of b-catenin, and that A49 triggering of Wnt signalling is dependent on binding b-TrCP. This is consistent with A49 blocking the ability of b-TrCP to recognize b-catenin and IkBa, and possibly other cellular targets. Thus, A49 targeting of b-TrCP affects multiple cellular pathways, including the NF-kB and Wnt signalling cascades.