Identification of Distinct Signaling Pathways Leading to the Phosphorylation of Interferon Regulatory Factor 3

Marc J. Servant, Benjamin ten Oever, Cecile LePage, Lucia Conti, Sandra Gessani, Ilkka Julkunen, Rongtuan Lin, John Hiscott
2000 Journal of Biological Chemistry  
Infection of host cells by viruses leads to the activation of multiple signaling pathways, resulting in the expression of host genes involved in the establishment of the antiviral state. Among the transcription factors mediating the immediate response to virus is interferon regulatory factor-3 (IRF-3) which is post-translationally modified as a result of virus infection. Phosphorylation of latent cytoplasmic IRF-3 on serine and threonine residues in the C-terminal region leads to dimerization,
more » ... s to dimerization, cytoplasmic to nuclear translocation, association with the p300/CBP coactivator, and stimulation of DNA binding and transcriptional activities. We now demonstrate that IRF-3 is a phosphoprotein that is uniquely activated via virus-dependent C-terminal phosphorylation. Paramyxoviridae including measles virus and rhabdoviridae, vesicular stomatitis virus, are potent inducers of a unique virus-activated kinase activity. In contrast, stress inducers, growth factors, DNA-damaging agents, and cytokines do not induce C-terminal IRF-3 phosphorylation, translocation or transactivation, but rather activate a MAPKKK-related signaling pathway that results in N-terminal IRF-3 phosphorylation. The failure of numerous well characterized pharmacological inhibitors to abrogate virus-induced IRF-3 phosphorylation suggests the involvement of a novel kinase activity in IRF-3 regulation by viruses. Virus infection of mammalian cells triggers multiple signal transduction cascades involved in the activation of a diverse set of immunoregulatory genes and proteins that together create the antiviral state, an intracellular environment that antagonizes virus replication. The type I interferon (IFN) 1 family is
doi:10.1074/jbc.m007790200 pmid:11035028 fatcat:akt4nybgifab3jhxfkwg6tlfq4