Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1
Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1
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DOI：
10.1038/ni1347
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发表时间：
2006-06-01
影响因子：
30.5
通讯作者：
Yamaoka, Shoji
中科院分区：
文献类型：
--
作者：
Saitoh, Tatsuya;Tun-Kyi, Adrian;Yamaoka, Shoji
双链RNA的识别激活干扰素调节因子3 （IRF3）依赖性抗病毒因子的表达。虽然已经研究了IRF3激活的分子机制，但还没有研究IRF3活性降低的机制。在这里，我们报道了IRF3的激活受到肽基脯氨酸异构酶Pin1的负调控。在双链RNA刺激后，IRF3的Ser339-Pro340基序的诱导磷酸化导致其与Pin1相互作用，最终导致IRF3的多泛素化，然后是蛋白酶体依赖性降解。通过RNA干扰或基因缺失抑制Pin1导致irf -3依赖性干扰素β产生增强，从而减少病毒复制。这些结果阐明了先前未知的通过Pin1负性调节IRF3活性来控制先天抗病毒反应的机制。
Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)-dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.