p53 Transcriptionally Activates IRF9 to Enhance Antiviral Defense

Tumor suppressor p53 has been previously reported to be a downstream transcriptional target of type I interferon (IFN), but its role in antiviral immunity remains to be fully elucidated. We observed that infected mouse and human cells with functional p53 exhibited a significant decrease in early viral replication in the absence of apoptosis. This inhibition of viral replication was mediated by a p53-dependent enhancement of antiviral genes containing IFN stimulated response elements (ISREs). We established that this p53-dependent enhancement of IFN signaling is dependent, at least to a great extent, on the ability of p53 to transcriptionally activate IRF9. By doing so, p53 also contributed to the previously described autocrine feed back loop of IFN production, helping to establish an IFN-dependent antiviral state in bystander cells. Our findings demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independently of its functions as a pro-apoptotic and tumor suppressor gene.