Viral apoptosis is induced by IRF-3-mediated activation of Bax

Abstract

Upon infection with many RNA viruses, the cytoplasmic retinoic acid inducible gene-I (RIG-I) pathway activates the latent transcription factor IRF-3, causing its nuclear translocation and the induction of many antiviral genes, including those encoding interferons. Here, we report a novel and distinct activity of IRF-3, in virus-infected cells, that induces apoptosis. Using genetically defective mouse and human cell lines, we demonstrated that, although both pathways required the presence of RIG-I, IPS1, TRAF3 and TBK1, only the apoptotic pathway required the presence of TRAF2 and TRAF6 in addition. More importantly, transcriptionally inactive IRF-3 mutants, such as the one missing its DNA-binding domain, could efficiently mediate apoptosis. Apoptosis was triggered by the direct interaction of IRF-3, through a newly identified BH3 domain, with the pro-apoptotic protein Bax, their co-translocation to the mitochondria and the resulting activation of the mitochondrial apoptotic pathway. Thus, IRF-3 is a dual-action cytoplasmic protein that, upon activation, translocates to the nucleus or to the mitochondrion and triggers two complementary antiviral responses of the infected cell.

The New World arenavirus Tacaribe virus induces caspase-dependent apoptosis in infected cells

“…The activation of caspase 8 is, in this case, independent from death receptors on the cell surface (Balachandran et al, 1998;Gil & Esteban, 2000;Iordanov et al, 2005). Kolokoltsova et al (2014) showed JUNV-induced apoptosis in Huh7 and A549 cells, which was RIG-I-dependent and IFN-Iindependent, an observation that is consistent with the finding that some RNA viruses can trigger mitochondrial apoptosis via a RIG-I/MAVS-dependent pathway involving IRF3 (Chattopadhyay et al, 2010(Chattopadhyay et al, , 2011, and indeed this might also be the case for TCRV. However, whether apoptosis in TCRV-infected cells is mediated by PKR, RIG-I/ MAVS, other apoptotic sensors or additional caspaseindependent signalling pathways, remains to be further determined.…”

STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease

“…Therefore, it would be desirable to design molecules that would suppress the proapoptotic role and spare the Type-I IFN-inducing capability of IRF3. This could be theoretically possible, as the transcriptional and the proapoptotic domains of IRF3 are distinct and located on the opposite termini of the molecule (8).…”

“…The unexpected finding of inflammation-and Type-I IFN-independent role of IRF3 in alcohol-induced liver damage directed our attention to the recently described proapoptotic role of IRF3 (8). We hypothesized that IRF3 partners with Bax to translocate to mitochondria and initiate hepatocyte apoptosis.…”

“…Phosphorylated IRF3 induces IFN-β during viral infection, but may also contribute to inflammatory cytokine response to LPS (7). IRF3 also promotes apoptosis in virus-infected cells through association with proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] (8). To elucidate the mechanism by which IRF3 determines ALD, we asked three fundamental questions.…”

Tom70 imports antiviral immunity to the mitochondria

“…Silencing of Tom70 had no effect on mitochondrial localization of MAVS per se, but the distribution of MAVS appeared quite different when compared to wild-type cells ( Figure 4F in reference [7]). One Another potential function of Tom70 in mitochondrial import of IRF3 is apoptosis as it was suggested by the recent study from the laboratory of Ganes Sen, who identified a BH3-like domain in IRF3 that enables activated IRF3 to associate with the pro-apoptotic BCL-2 family member Bax [12]. The Bax-IRF3 interaction triggered its translocation to the mitochondria and activation of the intrinsic mitochondrial apoptotic pathway.…”