Ubiquitination of the Transcription Factor IRF-3 Activates RIPA, the Apoptotic Pathway that Protects Mice from Viral Pathogenesis

• Published in: Immunity (Cambridge, Mass.) Vol. 44; no. 5; pp. 1151 - 1161
• Main Authors: Chattopadhyay, Saurabh, Kuzmanovic, Teodora, Zhang, Ying, Wetzel, Jaime L., Sen, Ganes C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2016; Elsevier Limited
• Subjects: Animals; Apoptosis; Cell Line; Cloning, Molecular; Enzymes; Experiments; Fibroblasts - immunology; Fibroblasts - virology; Humans; Infections; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Kinases; Lungs; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Mutation - genetics; Nerve Tissue Proteins - metabolism; Pathogenesis; Phosphorylation; Proteins; Receptors, Cell Surface; RNA Virus Infections - immunology; Rodents; Signal Transduction; Transcription factors; Transcriptional Activation; Ubiquitination; Viruses
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.04.009

The transcription factor IRF-3 mediates cellular antiviral response by inducing the expression of interferon and other antiviral proteins. In RNA-virus infected cells, IRF-3’s transcriptional activation is triggered primarily by RIG-I-like receptors (RLR), which can also activate the RLR-induced IRF-3-mediated pathway of apoptosis (RIPA). Here, we have reported that the pathway of IRF-3 activation in RIPA was independent of and distinct from the known pathway of transcriptional activation of IRF-3. It required linear polyubiquitination of two specific lysine residues of IRF-3 by LUBAC, the linear polyubiquitinating enzyme complex, which bound IRF-3 in signal-dependent fashion. To evaluate the role of RIPA in viral pathogenesis, we engineered a genetically targeted mouse, which expressed a mutant IRF-3 that was RIPA-competent but transcriptionally inert; this single-action IRF-3 could protect mice from lethal viral infection. Our observations indicated that IRF-3-mediated apoptosis of virus-infected cells could be an effective antiviral mechanism, without expression of the interferon-stimulated genes. [Display omitted] •RLR-signaling activates IRF-3 to trigger RIPA, the pro-apoptotic antiviral pathway•RIPA can protect the host in the absence of antiviral gene induction•RIPA requires ubiquitination of IRF-3 on specific lysines The antiviral effects of IRF-3 are known to involve transcription of interferon stimulated genes as well as inducing apoptosis in infected cells. Sen and colleagues report that these two antiviral pathways mediated by IRF-3 are independent and that the apoptotic pathway is sufficient to inhibit viral pathogenesis