PACT Facilitates RNA-Induced Activation of MDA5 by Promoting MDA5 Oligomerization.
PACT Facilitates RNA-Induced Activation of MDA5 by Promoting MDA5 Oligomerization.
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PACT通过促进MDA5寡聚化促进RNA诱导的MDA5激活。
DOI：
10.4049/jimmunol.1601493
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发表时间：
2017-09-01
期刊：
影响因子：
--
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中科院分区：
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MDA 5是dsRNA和某些RNA病毒（如脑心肌炎病毒）的RIG-I样细胞质传感器，用于启动先天性抗病毒应答中的IFN信号级联。MDA 5对dsRNA的亲和力很低，在未知的细胞共激活因子存在下，其活性变得最佳。在这篇文章中，我们报告了dsRNA结合蛋白PACT在介导MDA 5依赖的I型IFN应答中的重要辅激活因子功能。病毒诱导的和聚肌胞苷酸诱导的MDA 5活化在PACT敲除细胞中严重受损，在PACT敲除细胞中减弱，但当PACT过表达时，它们增强。PACT增强了IRF 3依赖的I型IFN的产生，随后dsRNA诱导的MDA 5活化。相反，PACT对MDA 5介导的NF-κB活化没有影响。PACT对MDA 5的作用需要dsRNA相互作用，并促进dsRNA诱导的MDA 5寡聚化。PACT对寡聚化和细丝组装缺陷的MDA 5突变体几乎没有刺激作用。PACT与MDA 5共定位在细胞质中并增强MDA 5向dsRNA配体的募集。综上所述，这些发现表明PACT作为RIG-I以及MDA 5的必需细胞共活化剂发挥作用，并且它促进RNA诱导的MDA 5寡聚体的形成。
MDA5 is a RIG-I–like cytoplasmic sensor of dsRNA and certain RNA viruses, such as encephalomyocarditis virus, for the initiation of the IFN signaling cascade in the innate antiviral response. The affinity of MDA5 toward dsRNA is low, and its activity becomes optimal in the presence of unknown cellular coactivators. In this article, we report an essential coactivator function of dsRNA-binding protein PACT in mediating the MDA5-dependent type I IFN response. Virus-induced and polyinosinic-polycytidylic acid–induced activation of MDA5 were severely impaired in PACT-knockout cells and attenuated in PACT-knockdown cells, but they were potentiated when PACT was overexpressed. PACT augmented IRF3-dependent type I IFN production subsequent to dsRNA-induced activation of MDA5. In contrast, PACT had no influence on MDA5-mediated activation of NF-κB. PACT required dsRNA interaction for its action on MDA5 and promoted dsRNA-induced oligomerization of MDA5. PACT had little stimulatory effect on MDA5 mutants deficient for oligomerization and filament assembly. PACT colocalized with MDA5 in the cytoplasm and potentiated MDA5 recruitment to the dsRNA ligand. Taken together, these findings suggest that PACT functions as an essential cellular coactivator of RIG-I, as well as MDA5, and it facilitates RNA-induced formation of MDA5 oligomers.
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