Interferon regulatory factor 1
regulation of transcription by RNA polymerase II
HCFC2 is needed for IRF1- and IRF2-dependent <i>Tlr3</i> transcription and for survival during viral infections.
Transcriptional regulation of numerous interferon-regulated genes, including <i>Toll-like receptor 3</i> (<i>Tlr3</i>), which encodes an innate immune sensor of viral double-stranded RNA, depends on the interferon regulatory factor 1 (IRF1) and IRF2 transcription factors. We detected specific abrogation of macrophage responses to polyinosinic-polycytidylic acid (poly(I:C)) resulting from three independent <i>N</i>-ethyl-<i>N</i>-nitrosourea-induced mutations in <i>host cell factor C2</i> (<i>Hcfc2</i>). <i>Hcfc2</i> mutations compromised survival during influenza virus and herpes simplex virus 1 infections. HCFC2 promoted the binding of IRF1 and IRF2 to the <i>Tlr3</i> promoter, without which inflammatory cytokine and type I IFN responses to the double-stranded RNA analogue poly(I:C) are reduced in mouse macrophages. HCFC2 was also necessary for the transcription of a large subset of other IRF2-dependent interferon-regulated genes. Deleterious mutations of <i>Hcfc2</i> may therefore increase susceptibility to diverse infectious diseases.