Abstract

The host recognition of intracellular viral RNA and subsequent induction of cytokine signalling is tightly regulated at the cellular level and is a target for manipulation by viruses and therapeutics alike. Here we characterise C6orf106 as an evolutionarily-conserved inhibitor of the innate antiviral response. C6orf106 suppresses the synthesis of IFN-α/β and the pro-inflammatory TNF-α in response to the double-stranded RNA mimic poly(I:C) and to Sendai virus infection. Unlike canonical inhibitors of antiviral signalling, C6orf106 blocks IRF3 and, to a lesser extent, NF-κB activity without modulating their activation, nuclear translocation, cellular expression or degradation. Instead, C6orf106 interacts with IRF3 and inhibits IRF3 recruitment to type I IFN promoter sequences, whilst also reducing the nuclear levels of the coactivator proteins p300 and CBP. In summary we have defined C6orf106 as a negative regulator of antiviral immunity that blocks IRF3-dependent cytokine production via a non-canonical and poorly-defined mechanism. This work presents intriguing implications for antiviral immunity, autoimmune disorders and cancer.