We live in a world full of viruses and our immune system fights against them to keep us healthy and disease-free (Fensterl et al., 2015). The immune system is divided into two broad categories – the innate and the adaptive, both of which are required to protect against virus infection. The innate immune system, which is kicked off very early during virus infection, is the first line of antiviral defense; whereas the adaptive immune system, activated later, is dependent on the innate immune system. Therefore, an appropriate activation of the innate immune system is critical for the elimination of viruses, from an organism, by both branches of the immune system.
Type I interferon (IFN) mediates the key innate immune response against a wide range of viruses. The IFN system is triggered at the onset of virus infection via cellular recognition of viral components. Mammalian cells are equipped with protein sensors, e.g. TLRs, RLRs, NLRs or cGAS/STING, which detect the incoming virus particles in the cytoplasm or inside specific cellular compartments and trigger intracellular signaling pathways. These signaling pathways lead to the induction of IFN through the action of the transcription factor, Interferon Regulatory Factor 3 (IRF3). IFN is secreted from infected cells, so that it can inhibit virus replication in the infected, as well as neighboring uninfected, cells through the action of many antiviral proteins, the products of IFN-stimulated genes (ISG). ISGs can be directly induced by activated IRF3 as well, without any involvement of IFN. IRF3, a cytosolic protein, is inactive in uninfected cells; virus infection activates it by causing phosphorylation of its specific serine residues and its translocation to the nucleus, where it binds to the promoters of the target genes (Lin et al., 1998 and Sato et al., 1998). Specific cellular proteins, e.g. HDAC6, β-catenin and PKC-β, are required for full transcriptional activity of IRF3 (Chattopadhyay et al., 2013a).
In addition to directly impairing virus replication, another effective protection mechanism used by multi-cellular organisms is to trigger suicide of the infected cell. Because only a few cells are initially infected, their premature death ensures that progeny viruses are too few to spread the infection efficiently. A critical discovery was made showing dual functions of IRF3 in virus infected cells: it not only induces antiviral genes but also triggers apoptotic cell death by the RLR-induced IRF3 mediated Pathway of Apoptosis (RIPA) (Fig. 1). Here, we discuss IRF3’s role in RIPA, the antiviral apoptotic pathway.