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

Saurabh Chattopadhyay, Teodora Kuzmanovic, Ying Zhang, Jaime L. Wetzel, Ganes C. Sen

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

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. 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.

Original languageEnglish
Pages (from-to)1151-1161
Number of pages11
JournalImmunity
Volume44
Issue number5
DOIs
StatePublished - May 17 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc..

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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