Alternate isoforms of IRF7 Differentially Regulate Interferon Expression to Tune Response to Viral Infection

Abstract

Interferon Regulatory Factor 7 (IRF7), and its homologue IRF3, are master transcriptional regulators of the innate immune response. IRF7 binds to promoters of interferon {beta} (IFN{beta}) and several IFNs as a homodimer or as a heterodimer with IRF3 to drive expression of these type I IFNs, which in turn activate downstream signaling pathways to promote expression of antiviral genes. Here we demonstrate that alternative splicing of the first intron within the coding region of IRF7 is highly regulated across immune tissues and in response to immunologic signals including viral infection. Retention of this intron generates an alternative translation start site, resulting in a N-terminally extended form of the protein (exIRF7) with distinct function from the canonical version of IRF7 (cIRF7). We find that exIRF7 uniquely activates a gene expression program, including IFN{beta}, in response to innate immune triggers. Mechanistically, this enhanced activity of exIRF7 relative to cIRF7 is through increased homodimerization and association with IRF3 on DNA. Furthermore, the enhanced transcriptional activity of exIRF7 controls viral infection to a greater extent than cIRF7, demonstrating that alternative splicing of IRF7 is a previously unrecognized mechanism used by cells to tune the interferon response to control viral infections and other immune challenges. HighlightsO_LIIntron retention in the human IRF7 gene generates a distinct protein isoform that differs in the N-terminus. C_LIO_LIIRF7 intron retention is regulated in a stimuli- and cell-type specific manner. C_LIO_LIThe extended version of IRF7, produced by intron retention, exhibits enhanced transcriptional activation of type I interferon genes. C_LIO_LICells expressing the extended version of IRF7 are more resistant to viral infection. C_LI