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

Autor: Chattopadhyay S; 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., Kuzmanovic T; Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA., Zhang Y; Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA., Wetzel JL; Department of Molecular Genetics, Cleveland Clinic, Cleveland, OH 44195, USA., Sen GC; 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.
Jazyk: angličtina
Zdroj: Immunity [Immunity] 2016 May 17; Vol. 44 (5), pp. 1151-61. Date of Electronic Publication: 2016 May 10.
DOI: 10.1016/j.immuni.2016.04.009
Abstrakt: 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.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE