Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis.

Abstract

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.

• Authors: John Hiscott, Nathalie Grandvaux, Sonia Sharma, Benjamin R Tenoever, Marc J Servant, Rongtuan Lin
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1010 Pg. 237-48 (Dec 2003) ISSN: 0077-8923 [Print] United States
• PMID: 15033728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• DNA-Binding Proteins
• IRF3 protein, human
• Interferon Regulatory Factor-3
• NF-kappa B
• Transcription Factors
• Interferons

Topics

• Amino Acid Sequence
• Apoptosis (physiology)
• DNA-Binding Proteins (genetics)
• Humans
• Interferon Regulatory Factor-3
• Interferons (physiology)
• Jurkat Cells
• Molecular Sequence Data
• NF-kappa B (physiology)
• Oligonucleotide Array Sequence Analysis
• Signal Transduction (physiology)
• Transcription Factors (genetics)
• Transcription, Genetic
• Viruses (pathogenicity)