TY - JOUR
T1 - Ubiquitination of the Transcription Factor IRF-3 Activates RIPA, the Apoptotic Pathway that Protects Mice from Viral Pathogenesis
AU - Chattopadhyay, Saurabh
AU - Kuzmanovic, Teodora
AU - Zhang, Ying
AU - Wetzel, Jaime L.
AU - Sen, Ganes C.
N1 - Publisher Copyright:
© 2016 Elsevier Inc..
PY - 2016/5/17
Y1 - 2016/5/17
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2016.04.009
DO - 10.1016/j.immuni.2016.04.009
M3 - Article
C2 - 27178468
AN - SCOPUS:84967106620
SN - 1074-7613
VL - 44
SP - 1151
EP - 1161
JO - Immunity
JF - Immunity
IS - 5
ER -