Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis.
The ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated following virus infection and functions as a key activator of the immediate-early Type 1 interferon (IFN) genes. Using DNA microarray analysis (8,556 genes) in Jurkat T cells inducibly expressing constitutively active IRF-3, several target genes directly regulated by IRF-3 were identified. Among the genes upregulated by IRF-3 were transcripts for a subset of known IFN-stimulated genes (ISGs), including ISG56, which functions as an inhibitor of translation initiation. Phosphorylation of C-terminal Ser/Thr residues--(382)GGASSLENTVDLHISNSHPLSLTSDQY(408)-is required for IRF-3 activation. Using C-terminal point mutations and a novel phosphospecific antibody, Ser396 was characterized as the minimal phosphoacceptor site required in vivo for IRF-3 activation following Sendai virus (SeV) infection, expression of viral nucleocapsid, or double-stranded RNA (dsRNA) treatment. The identity of the virus-activated kinase (VAK) activity that targets and activates IRF-3 and IRF-7 has remained a critical missing link in the understanding of interferon signaling. We report that the IKK-related kinases-IKKepsilon/TBK-1-are components of VAK that mediate IRF-3 and IRF-7 phosphorylation and thus functionally link the NF-kappaB and IRF pathways in the development of the antiviral response.
Hiscott
John
J
Lady Davis Institute for Medical Research, Jewish General Hospital, Departments of Microbiology and Immunology and Medicine, McGill University, Montreal, Canada H3T 1E2. john.hiscott@mcgill.ca
Grandvaux
Nathalie
N
Sharma
Sonia
S
Tenoever
Benjamin R
BR
Servant
Marc J
MJ
Lin
Rongtuan
R
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007372:Interferons / Q000502:physiology*; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014780:Viruses / Q000472:pathogenicity*
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D014157:Transcription Factors; D007372:Interferons