Biomedical subjects
Publications and source records attributed to Benjamin R Tenoever.
Viruses trigger signaling pathways of innate immunity. In this issue, it is shown that the mitochondrial antiviral signaling protein is critical for intracellular detection signaling, but is dispensable for the activation of innate immunity via Toll-like receptors.
Viral infection results in the activation of multiple signaling pathways, but how these pathways are coordinated remains a mystery. Two studies, one published in this issue of Cell (Seth et al., 2005) and the other in Molecular Cell (Xu et al., 2005), identify a new intracellular signaling protein that is required for activating type I interferon expression in response to viral infection. In addition,Seth et al. (2005) show that the function of this protein, which they call MAVS, requires that it be localized to the mitochondria. This observation establishes an unexpected link between innate immunity and an organelle with evolutionary origins in aerobic bacteria.
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.