Identification of a Novel in Vivo Virus-targeted Phosphorylation Site in Interferon Regulatory Factor-3 (IRF3)
Identification of a Novel in Vivo Virus-targeted Phosphorylation Site in Interferon Regulatory Factor-3 (IRF3)
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DOI：
10.1074/jbc.m109.084822
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发表时间：
2010-08-06
影响因子：
4.8
通讯作者：
Anthonsen, Marit W.
中科院分区：
文献类型：
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作者：
Bergstroem, Bjarte;Johnsen, Ingvild B.;Anthonsen, Marit W.
转录因子干扰素调节因子-3（IRF 3）调节I型干扰素-β的表达，并且在抗病毒免疫中起重要作用。尽管IRF 3具有生物学重要性，但其体内磷酸化模式尚未报道。在这项研究中，我们已经确定了IRF 3中的残基在体内被仙台病毒感染后磷酸化。我们发现，仙台病毒诱导的C-末端残基Thr（390）和Ser（396）的磷酸化，除了Ser（385）或Ser（386）。此外，Ser（173）和Ser（175）被组成性磷酸化。Ser（396）以前被认为是IRF 3激活激酶TBK 1（TANK结合激酶-1）的主要靶点，而Thr（390）以前没有参与IRF 3调节。突变研究表明，Thr（390）的磷酸化促进Ser（396）的磷酸化和与辅激活因子cAMP反应元件结合蛋白的结合。综上所述，我们的结果表明IRF 3受到多个相互依赖的磷酸化，我们确定Thr（390）作为一个新的体内磷酸化位点，调节TBK 1靶向Ser（396）的磷酸化状态。
The transcription factor interferon regulatory factor-3 (IRF3) regulates expression of type I interferon-beta and plays an important role in antiviral immunity. Despite the biological importance of IRF3, its in vivo phosphorylation pattern has not been reported. In this study, we have identified residues in IRF3 that are phosphorylated in vivo after infection with Sendai virus. We found that Sendai virus induced phosphorylation of the C-terminal residues Thr(390) and Ser(396), in addition to either Ser(385) or Ser(386). Moreover, Ser(173) and Ser(175) were constitutively phosphorylated. Ser(396) has previously been suggested to be the major target of the IRF3-activating kinase TBK1 (TANK-binding kinase-1), whereas Thr(390) has not previously been implicated in IRF3 regulation. Mutagenesis studies indicated that phosphorylation of Thr(390) promotes Ser(396) phosphorylation and binding to the coactivator cAMP-response element-binding protein. Taken together, our results show that IRF3 is subject to multiple interdependent phosphorylations, and we identify Thr(390) as a novel in vivo phosphorylation site that modulates the phosphorylation status of TBK1-targeted Ser(396).