title: Ubiquitination of the Transcription Factor IRF-3 Activates RIPA, the Apoptotic Pathway that Protects Mice from Viral Pathogenesis.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Mailstop 1021, Toledo, OH 43614, USA. Electronic address: saurabh.chattopadhyay@utoledo.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Teodora
authors.initials: T
authors.lastname: Kuzmanovic
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Wetzel
authors.affiliation: Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Immunology, Cleveland Clinic, 9500 Euclid Avenue, NE20, Cleveland, OH 44195, USA. Electronic address: seng@ccf.org.
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003001:Cloning, Molecular; D005347:Fibroblasts / Q000276:immunology* / Q000821:virology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012327:RNA Virus Infections / Q000276:immunology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D015533:Transcriptional Activation; D054875:Ubiquitination; D000097905:Roundabout Proteins
chemical_list: D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins