WDR81 represses IKK-mediated expression of pro-survival genes to regulate apoptosis.

Apoptosis is a common host response to virus infection. The extent and timing of apoptosis following infection is controlled by the balance between the strength of signals that activate death-inducing and survival-promoting pathways in cells. In many cell types, infection with mammalian orthoreovirus (reovirus) results in induction of cell death by apoptosis late in infection. In this study, we uncovered that WD repeat-containing protein 81 (WDR81) is required for apoptosis induction after reovirus infection. The requirement for WDR81 for apoptosis induction is not unique to reovirus because cells lacking WDR81 are also resistant to apoptosis induced by other agonists. We find that in cells deficient in WDR81, expression of several pro-survival genes is upregulated. The expression of these genes is controlled by the inhibitor of κB kinase (IKK) complex-nuclear factor of kB (NFκB) signaling pathway. When IKK signaling is blocked in WDR81-deficient cells, pro-survival gene expression is restored to normal levels, and the cells regain their susceptibility to cell death triggers. Our work uncovers a new function for WDR81 in controlling apoptosis. Additionally, it reveals a previously unknown link between an endosomally localized protein, WDR81, and IKK-NFκB signaling.IMPORTANCEVirus infection often results in the death of the infected cells. Cell death prior to generation of virus progeny limits the spread of infection to neighboring cells and therefore can be beneficial to the host. However, cell death might also cause tissue destruction and could contribute to viral disease. It is therefore important to understand how cell death is controlled. Here, we uncover a cell death-regulating role for WD repeat-containing protein 81 (WDR81)-a cellular protein that has not been previously implicated in affecting cell death. We find that when this protein is absent, cells express a much greater level of survival signals. These survival signals prevent efficient induction of cell death. By investigating how these survival signals are expressed, we reveal a new link between WDR81 and nuclear factor of kB (NFκB), a well-known cellular survival pathway.