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

Abstract

SUMMARY 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 Linear Ubiquitin Assembly Complex Modulates Latent Membrane Protein 1 Activation of NF-κB and Interferon Regulatory Factor 7

“…In fact, in addition to NF-B activation downstream of pathogen-associated recognition receptors, LUBAC negatively regulates RIG-I-mediated innate immune responses by targeting RIG-I, TRIM25, and IRF3 for degradation (60,61) and by disrupting the TRAF3-MAVS complex (62). LUBAC also promotes IRF3 linear ubiquitination at two specific sites to activate the RLR-induced IRF-3-mediated pathway of apoptosis (63). Thus, LUBAC seems to be an important player in modulation of innate immune responses through different mechanisms.…”

Hitting the right button: MAVS-mediated defense against HAV infection

“…In search of the mechanism mediating MAVS-induced death, the authors found that HAV-induced death of infected hepatocytes depends on the transcription factors IRF3 and IRF7. Since HAVinduced liver damage is independent of IFNAR signaling, IRF3/7 may trigger death directly through its transcriptional activity on pro-apoptotic molecules like the BH3-only protein PMAIP1 [5] or in a transcription-independent fashion by interacting with mitochondrial Bax [6]. Hirai-Yuki et al provide compelling evidence in their study for the key role of MAVS in the control of hepatocyte infection with an RNA virus like HAV.…”

MAVS-dependent host species range and pathogenicity of human hepatitis A virus

“…S13). IRF3 can also induce apoptosis through a transcription-independent mechanism involving a direct interaction with mitochondrial Bax (34). However, this would not explain the rare apoptotic hepatocytes observed in Irf3 -deficient mice (fig.…”