Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3
Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3
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DOI：
10.1074/jbc.m007790200
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发表时间：
2001-01-05
影响因子：
4.8
通讯作者：
Hiscott, J
中科院分区：
文献类型：
--
作者：
Servant, MJ;ten Oever, B;Hiscott, J
病毒感染宿主细胞可激活多种信号通路，导致参与抗病毒状态建立的宿主基因表达。在介导对病毒的即时反应的转录因子中，干扰素调节因子-3 （IRF-3）在病毒感染后被翻译后修饰。c端丝氨酸和苏氨酸残基上的潜在胞质IRF-3磷酸化导致二聚化，胞质向核易位，与p300/CBP共激活子关联，并刺激DNA结合和转录活性。我们现在证明IRF-3是一种通过病毒依赖的c端磷酸化唯一激活的磷蛋白。副粘病毒科包括麻疹病毒和横纹肌病毒科，水疱性口炎病毒，是一种独特的病毒激活激酶活性的有效诱导剂。相反，应激诱导剂、生长因子、dna损伤剂和细胞因子不会诱导c端IRF-3磷酸化、易位或反激活，而是激活mapkkk相关的信号通路，导致n端IRF-3磷酸化。许多已知的药物抑制剂无法消除病毒诱导的IRF-3磷酸化，这表明一种新的激酶活性参与了病毒对IRF-3的调节。
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.