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

Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
The EMBO Journal (Impact Factor: 10.43). 04/2010; 29(10):1762-73. DOI: 10.1038/emboj.2010.50
Source: PubMed


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.

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Available from: Michifumi Yamashita, Jan 13, 2016
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    • "Initiation of apoptosis in response to viral infection [34] has been linked to RLH signaling independent of type I IFN pathway activation [35]–[39]. Specifically, IFN-I-independent, caspase-9, Apaf-1-dependent signaling trough RIG-I/MDA5-MAVS-mediated induction of Puma and Noxa transcription [36], [40]; or MAVS mediated IFN-I, IRF3, NF-ΚB-independent, caspase-3, -9-dependent [35]; or IFN-I, NF-ΚB-independent, RIG-I-TRAF3/TRAF2/TRAF6–mediated IRF3 interaction with Bax protein [38], [39] has been shown to activate mitochondrial apoptotic pathway in response to dsRNA or viral infection. We observed that infection with Candid#1 JUNV induces CPE in primate cell lines. "
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    ABSTRACT: Junin virus (JUNV) is the etiological agent of Argentine hemorrhagic fever (AHF), a human disease with a high case-fatality rate. It is widely accepted that arenaviral infections, including JUNV infections, are generally non-cytopathic. In contrast, here we demonstrated apoptosis induction in human lung epithelial carcinoma (A549), human hepatocarcinoma and Vero cells upon infection with the attenuated Candid#1 strain of, JUNV as determined by phosphatidylserine (PS) translocation, Caspase 3 (CASP3) activation, Poly (ADP-ribose) polymerase (PARP) cleavage and/or chromosomal DNA fragmentation. Moreover, as determined by DNA fragmentation, we found that the pathogenic Romero strain of JUNV was less cytopathic than Candid#1 in human hepatocarcinoma and Vero, but more apoptotic in A549 and Vero E6 cells. Additionally, we found that JUNV-induced apoptosis was enhanced by RIG-I signaling. Consistent with the previously reported role of RIG-I like helicase (RLH) signaling in initiating programmed cell death, we showed that cell death or DNA fragmentation of Candid#1-infected A549 cells was decreased upon siRNA or shRNA silencing of components of RIG-I pathway in spite of increased virus production. Similarly, we observed decreased DNA fragmentation in JUNV-infected human hepatocarcinoma cells deficient for RIG-I when compared with that of RIG-I-competent cells. In addition, DNA fragmentation detected upon Candid#1 infection of type I interferon (IFN)-deficient Vero cells suggested a type I IFN-independent mechanism of apoptosis induction in response to JUNV. Our work demonstrated for the first time apoptosis induction in various cells of mammalian origin in response to JUNV infection and partial mechanism of this cell death.
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    • "Besides IFN-β and IFN-α4 (IFN-α1 in human), IRF3 regulates a subset of other ISGs, including ISG54, ISG56, and RANTES independently of IFNAR signaling (Grandvaux et al., 2002). IRF3 can also induce apoptosis through association with pro-apoptotic Bax (Chattopadhyay et al., 2010). In unstimulated cells, IRF3 resides in the nucleus. "
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    • "MAVS acts as a platform to recruit several cytosolic protein kinase complexes to mitochondria, including I kappa B kinase and tank binding kinase-1, which phosphorylate IRF3, resulting in IRF3 translocation to the nucleus to bind to interferon-sensitive response elements (ISRE) and turn on interferon stimulated genes (ISGs) [13]. In addition, IRF3 translocates to mitochondria through its interaction with the pro-apoptotic protein Bax to activate the intrinsic apoptotic pathway [14]. This and the fact that MAVS is located predominantly on the outer mitochondrial membrane have highlighted the importance of mitochondria in host innate immune signaling [15]. "
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