Chicken STING Mediates Activation of the IFN Gene Independently of the RIG-I Gene
Chicken STING Mediates Activation of the IFN Gene Independently of the RIG-I Gene
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鸡蜇刺介导独立于 RIG-I 基因的 IFN 基因激活
DOI：
10.4049/jimmunol.1500638
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发表时间：
2015-10-15
影响因子：
4.4
通讯作者：
Sun, Jianhe
中科院分区：
文献类型：
--
作者：
Cheng, Yuqiang;Sun, Yingjie;Sun, Jianhe
干扰素基因刺激子(STING)是哺乳动物细胞中视黄酸诱导基因I(RIG-I)下游的一种接头，但在鸡中缺失RIG-I。我们发现鸡刺(ChSTING)是病毒触发的I型干扰素信号在RIG-I缺失的鸡细胞中的关键中介。在DF-1细胞中过表达chSTING抑制了新城疫病毒和禽流感病毒的复制，并激活了IRF-7和NF-kB来诱导I型IFN的表达。内源性chSTING的敲除消除了病毒触发的IRF-7和干扰素-β的激活，并增加了病毒产量。ChSTING是病毒触发的IRF-7激活途径和细胞抗病毒反应中的关键成分。ChSTING主要定位于内质网外膜，也见于线粒体膜。此外，chSTING的敲除可阻断多聚肌苷-多胞苷、多(脱氧腺苷-脱氧胸苷)酸和黑色素瘤分化相关基因5(MDA5)刺激的干扰素-β的诱导。免疫共沉淀实验表明，鸡MDA5可与chSTING相互作用，异位表达的鸡线粒体抗病毒信号蛋白可增强这种相互作用。综上所述，这些结果表明chSTING是鸡天然免疫信号的重要调节因子，可能参与了鸡细胞中的MDA5信号通路。这些结果有助于理解在进化过程中刺在先天免疫中的生物学作用。
Stimulator of IFN genes (STING) is an adaptor that functions downstream of retinoic acid-inducible gene I (RIG-I) in mammalian cells; however, RIG-I is absent in chickens. We identified chicken STING (chSTING) as a critical mediator of virus-triggered type I IFN signaling in RIG-I-null chicken cells. Overexpression of chSTING in DF-1 cells inhibited Newcastle disease virus and avian influenza virus (AIV) viral replication and activated IRF-7 and NF-kB to induce expression of type I IFNs. Knockdown of endogenous chSTING abolished virus-triggered activation of IRF-7 and IFN-beta and increased viral yield. chSTING was a critical component in the virus-triggered IRF-7 activation pathway and the cellular antiviral response. chSTING predominantly localized to the outer membrane of the endoplasmic reticulum and was also found in the mitochondrial membrane. Furthermore, knockdown of chSTING blocked polyinosinic-polycytidylic acid-, poly(deoxyadenylic-deoxythymidylic) acid-, and melanoma differentiation-associated gene 5 (MDA5)-stimulated induction of IFN-beta. Coimmunoprecipitation experiments indicated that chicken MDA5 could interact with chSTING, and this interaction was enhanced by ectopically expressed chicken mitochondrial antiviral-signaling protein. Together, these results indicated that chSTING is an important regulator of chicken innate immune signaling and might be involved in the MDA5 signaling pathway in chicken cells. These results help with understanding the biological role of STING in innate immunity during evolution.