Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN.
Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN.
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线粒体核穿梭FK506结合蛋白51与TRAF蛋白相互作用，并促进IFN型I型IFN的RIG-I样受体介导的表达。
DOI：
10.1371/journal.pone.0095992
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Inoue J
中科院分区：
文献类型：
--
作者：
Akiyama T;Shiraishi T;Qin J;Konno H;Akiyama N;Shinzawa M;Miyauchi M;Takizawa N;Yanai H;Ohashi H;Miyamoto-Sato E;Yanagawa H;Yong W;Shou W;Inoue J
病毒来源的双链RNA(DsRNAs)由维甲酸诱导基因(RIG)样受体(RLRs)在胞浆中感受。它们通过线粒体抗病毒信号(MAVS)蛋白介导的信号通路诱导I型干扰素和促炎细胞因子的表达。据报道，肿瘤坏死因子受体相关因子(TRAF)家族蛋白通过与MAV相互作用促进I型干扰素的RLR依赖性表达。然而，具体的监管机制仍不清楚。在这里，我们展示了FK506结合蛋白51(FKBP51)在调节依赖dsRNA的I型干扰素表达中的作用。FKBP51与TRAF6的结合首先通过“体外病毒”筛选得到证实，随后在HEK293T细胞中用免疫共沉淀法证实。TRAF6的TRAF-C结构域是其相互作用所必需的，尽管FKBP51不包含与TRAF-C结构域相互作用的共识基序。除TRAF6外，我们还发现FKBP51还与TRAF3相互作用。FKBP51缺失可降低dsRNA或新城疫病毒感染诱导的小鼠成纤维细胞I型干扰素的表达。与此一致，FKBP51的缺失减弱了dsRNA介导的IRF3和JNK的磷酸化和RelA的核转位。有趣的是，dsRNA刺激促进了FKBP51在线粒体中的积累。此外，FKBP51的过表达抑制了RLR依赖的转录激活，提示FKBP51在MAVS介导的信号通路中具有支架功能。总之，我们已经证明FKBP51与TRAF蛋白相互作用，并促进胞内dsRNA诱导的I型干扰素的表达。这些发现表明FKBP51在对病毒感染的先天性免疫反应中发挥了新的作用。
Virus-derived double-stranded RNAs (dsRNAs) are sensed in the cytosol by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs). These induce the expression of type I IFN and proinflammatory cytokines through signaling pathways mediated by the mitochondrial antiviral signaling (MAVS) protein. TNF receptor-associated factor (TRAF) family proteins are reported to facilitate the RLR-dependent expression of type I IFN by interacting with MAVS. However, the precise regulatory mechanisms remain unclear. Here, we show the role of FK506-binding protein 51 (FKBP51) in regulating the dsRNA-dependent expression of type I IFN. The binding of FKBP51 to TRAF6 was first identified by “in vitro virus” selection and was subsequently confirmed with a coimmunoprecipitation assay in HEK293T cells. The TRAF-C domain of TRAF6 is required for its interaction, although FKBP51 does not contain the consensus motif for interaction with the TRAF-C domain. Besides TRAF6, we found that FKBP51 also interacts with TRAF3. The depletion of FKBP51 reduced the expression of type I IFN induced by dsRNA transfection or Newcastle disease virus infection in murine fibroblasts. Consistent with this, the FKBP51 depletion attenuated dsRNA-mediated phosphorylations of IRF3 and JNK and nuclear translocation of RelA. Interestingly, dsRNA stimulation promoted the accumulation of FKBP51 in the mitochondria. Moreover, the overexpression of FKBP51 inhibited RLR-dependent transcriptional activation, suggesting a scaffolding function for FKBP51 in the MAVS-mediated signaling pathway. Overall, we have demonstrated that FKBP51 interacts with TRAF proteins and facilitates the expression of type I IFN induced by cytosolic dsRNA. These findings suggest a novel role for FKBP51 in the innate immune response to viral infection.
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