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Double-stranded RNA-induced antiviral gene expression in mammalian cells requires activation of IFN regulatory factor 3 (IRF3). In this study, we show that the IL-17R adaptor protein Act1/CIKS is involved in this process. Small interfering RNA-mediated knockdown of Act1 in primary human skin fibroblasts specifically attenuates expression of IFN-β and IFN-stimulated antiviral genes induced by a synthetic viral mimic, polyinosinic-polycytidylic acid. Ectopic expression of Act1 potentiates the IRF3-driven expression of a synthetic reporter construct as well as the induction of antiviral genes. We demonstrate that this effect is dependent on the ability of Act1 to functionally and physically interact with IκB kinase ε (IKKε), a known IRF3 kinase, and IRF3: 1) Act1 binds IKKε and IRF3; 2) Act1-induced IRF3 activation can be blocked specifically by coexpression of a catalytically inactive mutant of IKKε; and 3) mutants of IRF3, either lacking the C terminus or mutated at the key phosphorylation sites, important for its activation by IKKε, do not support Act1-dependent IRF3 activation. We also show that a zebrafish Act1 protein is able to trigger antiviral gene expression in human cells, which suggests an evolutionarily conserved function of vertebrate Act1 in the host defense against viruses. On the whole, our study demonstrates that Act1 is a component of antiviral signaling.

IL-17 Receptor Adaptor Protein Act1/CIKS Plays an Evolutionarily Conserved Role in Antiviral Signaling