The Atg5-Atg12 conjugate associates with innate antiviral immune responses
The Atg5-Atg12 conjugate associates with innate antiviral immune responses
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DOI：
10.1073/pnas.0704014104
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发表时间：
2007-08-28
影响因子：
11.1
通讯作者：
Okuda, Kenji
中科院分区：
文献类型：
--
作者：
Jounai, Nao;Takeshita, Fumihiko;Okuda, Kenji
自噬是生理稳态的重要过程，但其在病毒感染中的作用才刚刚开始被阐明。我们在此表明 Atg5-Atg12 缀合物是自噬过程的关键调节因子，在先天抗病毒免疫反应中发挥着重要作用。 Atg5缺陷型小鼠胚胎成纤维细胞（MEF）对水泡性口炎病毒复制具有抵抗力，这主要是由于免疫刺激性RNA（isRNA）（例如病毒来源的双链或5'-磷酸化RNA）产生的I型干扰素过量产生。在 Atg7 缺陷的 MEF 中也观察到了类似的 isRNA 过度反应，其中 Atg5-Atg12 缀合受损。 Atg5 或 Atg12 的过度表达导致 Atg5-Atg12 缀合物形成并抑制 isRNA 介导的信号传导。分子相互作用研究表明，Atg5-Atg12 缀合物通过 caspase 募集结构域 (CARD) 与视黄酸诱导基因 I (RIG-I) 和 IFN-β 启动子刺激子 1 (IPS-1) 直接关联，从而负调节 I 型 IFN 产生途径。因此，与其促进杀菌过程的作用相反，自噬机制的一个组成部分似乎阻断先天抗病毒免疫反应，从而有助于RNA病毒在宿主细胞中的复制。
Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5-Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibroblasts (MEFs) were resistant to vesicular stomatitis virus replication, which was largely due to hyperproduction of type I interferons in response to immunostimulatory RNA (isRNA), such as virus-derived, double-stranded, or 5'-phosphorylated RNA. Similar hyperresponse to isRNA was also observed in Atg7-deficient MEFs, in which Atg5-Atg12 conjugation is impaired. Overexpression of Atg5 or Atg12 resulted in Atg5-Atg12 conjugate formation and suppression of isRNA-mediated signaling. Molecular interaction studies indicated that the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1) through the caspase recruitment domains (CARDs). Thus, in contrast to its role in promoting the bactericidal process, a component of the autophagic machinery appears to block innate antiviral immune responses, thereby contributing to RNA virus replication in host cells.