Viral apoptosis is induced by IRF-3-mediated activation of Bax.
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.
Chattopadhyay
Saurabh
S
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Marques
Joao T
JT
Yamashita
Michifumi
M
Peters
Kristi L
KL
Smith
Kevin
K
Desai
Avanti
A
Williams
Bryan R G
BR
Sen
Ganes C
GC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D051379:Mice; D021381:Protein Transport; D012330:RNA, Double-Stranded / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
C494826:BAX protein, human; C494827:Bax protein, mouse; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D012330:RNA, Double-Stranded; D051028:bcl-2-Associated X Protein; D014212:Tretinoin