Vaccinia virus protein A49 activates Wnt signalling by targetting the E3 ligase β-TrCP

Vaccinia virus (VACV) encodes multiple proteins inhibiting the NF-κB signalling pathway. One of these, A49, targets the E3 ubiquitin ligase β-TrCP, which is responsible for the ubiquitylation and consequential proteosomal degradation of IκBα and the release of the NF-κB heterodimer. β-TrCP is a pleiotropic enzyme ubiquitylating multiple cellular substrates, including the transcriptional activator β-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 β-catenin. The data presented show that the expression of A49 ectopically or during VACV infection causes accumulation of β-catenin, and that A49 triggering of Wnt signalling is dependent on binding β-TrCP. This is consistent with A49 blocking the ability of β-TrCP to recognise β-catenin and IκBα, and possibly other cellular targets. Thus, A49 targetting of β-TrCP affects multiple cellular pathways, including the NF-κB and Wnt signalling cascades.