Transcriptional and non-transcriptional functions of IRF3 in host defense

Abstract Innate immune response is the first line of host defense against microbial infection. Interferon Regulatory Factor 3 (IRF3), a critical transcription factor, is rapidly activated during virus infection to trigger numerous antiviral genes, including the interferons. Our studies have revealed that in addition to triggering these genes, IRF3 activates direct apoptosis of virus-infected cells by a newly discovered antiviral apoptotic pathway, RIPA (Chattopadhyay et al, Immunity 2016, EMBO J, 2010). In RIPA, IRF3 is differentially modified by linear polyubiquitination of two lysine residues. Moreover, a knock-in mouse strain, without the transcriptional activity of IRF3, can still mount antiviral response by its RIPA branch. Importantly, the use of pathway-specific mutants of IRF3 revealed that both transcriptional, and RIPA, branches contribute to the overall antiviral functions of IRF3. To investigate the contribution of the transcriptional branch of IRF3, we screened a shRNA library of the human ISGs. Our screen identified a small subset of novel IRF3-dependent genes, which exhibit antiviral functions in human and mouse cells. These newly-identified ISGs are protective against a wide range of clinically relevant human viruses, e.g. RSV, HPIV3, HSV-1, HCMV. In-depth investigation revealed that these ISGs regulate cellular autophagy pathway to control virus replication. The presentation will highlight how both pathways of IRF3 mount an optimum host response against viral as well as non-viral pathogenesis.