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Convergence of the NF‐κB and Interferon Signaling Pathways in the Regulation of Antiviral Defense and Apoptosis
Author(s) -
HISCOTT JOHN,
GRANDVAUX NATHALIE,
SHARMA SONIA,
TENOEVER BENJAMIN R.,
SERVANT MARC J.,
LIN RONGTUAN
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1299.042
Subject(s) - interferon regulatory factors , interferon , sendai virus , biology , signal transduction , phosphorylation , irf1 , kinase , irf3 , jurkat cells , gene , microbiology and biotechnology , iκb kinase , virology , transcription factor , virus , nf κb , t cell , immunology , genetics , immune system
A bstract : 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 GGA SS LENTVDLHI S N S HPL S L TS DQY 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—IKKε/TBK‐1—are components of VAK that mediate IRF‐3 and IRF‐7 phosphorylation and thus functionally link the NF‐κB and IRF pathways in the development of the antiviral response.