title: Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3.
abstract: 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, 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.
authors.affiliation: Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, H3T 1E2 Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Servant
authors.forename: B
authors.initials: B
authors.lastname: ten Oever
authors.forename: C
authors.initials: C
authors.lastname: LePage
authors.forename: L
authors.initials: L
authors.lastname: Conti
authors.forename: S
authors.initials: S
authors.lastname: Gessani
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
authors.forename: R
authors.initials: R
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D050838:Interferon Regulatory Factor-3; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018108:Respirovirus / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D018406:Virus Physiological Phenomena
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006133:Growth Substances; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D011494:Protein Kinases; D020930:MAP Kinase Kinase Kinases; D010744:Phosphoric Monoester Hydrolases