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

Immunity. 2016 May 17;44(5):1151-61. doi: 10.1016/j.immuni.2016.04.009. Epub 2016 May 10.


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.

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • Cloning, Molecular
  • Fibroblasts / immunology*
  • Fibroblasts / virology
  • Humans
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism*
  • RNA Virus Infections / immunology*
  • Receptors, Cell Surface
  • Signal Transduction
  • Transcriptional Activation
  • Ubiquitination


  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Robo3 protein, mouse