Editors' ChoiceApoptosis

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Science Signaling  01 Jun 2010:
Vol. 3, Issue 124, pp. ec161
DOI: 10.1126/scisignal.3124ec161

The double-stranded RNA (dsRNA) that is produced in virally infected cells triggers multiple responses aimed at limiting viral spread. Among these are activation of the transcription factor IRF-3 (interferon regulatory factor 3), which occurs after detection of the viral dsRNA by a member of the RIG-1–like helicases (RLHs) and RLH interaction at the mitochondria with the adaptor MAVS, various members of the TRAF family of ubiquitin ligases, and the kinase TBK1. In addition to inducing antiviral genes, IRF-3 also stimulates the production of proapoptotic proteins and thus can trigger death of the infected cells. Chattopadhyay et al. identified a transcription-independent mechanism by which IRF-3 can mediate apoptosis. After demonstrating that IRF-3 was necessary for apoptosis of either infected cells or cells exposed to polyinosine-polycytosine [poly(I:C)] by analyzing specific knockout mouse embryo fibroblasts, the authors showed that poly(I:C)- or virus-induced apoptosis required RLH RIG-1, MAVS, TRAF3, TRAF2, TRAF6, and TBK1. Surprisingly, reconstitution of IRF-3–deficient cells with IRF-3 mutants that lacked transcriptional activity restored apoptosis in response to poly(I:C). Inhibition or knockdown of caspase-9, but not caspase-8, blocked poly(I:C)–induced apoptosis, suggesting that death was mediated by the intrinsic mitochondrial apoptosis pathway. Indeed, IRF-3 not only translocated to the nucleus in response to poly(I:C) but also translocated to the mitochondria (based on cell fractionation assays). Virus-infected cells exhibited an interaction between IRF-3 and the proapoptotic protein Bax, and this interaction was lost if point mutations were introduced into IRF-3 in its putative BH3 domain, a domain known to mediate protein interactions and that is often found in proteins that regulate apoptosis. The activation of Bax in response to poly(I:C), detected with a conformation-specific antibody, was lost in IRF-3–deficient cells, and, conversely, cells deficient in Bax failed to undergo virus- or poly(I:C)–induced apoptosis. In vitro mitochondrial cytochrome c release assays performed with Bax (from extracts of either wild-type or Bax-deficient cells) showed that addition of IRF-3 was sufficient to promote cytochrome c release. Thus, IRF-3 has a dual function in the antiviral response—initiating a transcriptional response and directly mediating apoptosis at the mitochondria (see Vince and Tschopp for commentary).

S. Chattopadhyay, J. T. Marques, M. Yamashita, K. L. Peters, K. Smith, A. Desai, B. R. G. Williams, G. C. Sen, Viral apoptosis is induced by IRF-3-mediated activation of Bax. EMBO J. 29, 1762–1773 (2010). [PubMed]

J. E. Vince, J. Tschopp, IRF-3 partners Bax in a viral-induced dance macabre. EMBO J. 29, 1627–1628 (2010). [PubMed]

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