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

Ann N Y Acad Sci. 2003 Dec:1010:237-48. doi: 10.1196/annals.1299.042.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 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*


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