Akiyama Taishin, Shiraishi Takuma, Qin Junwen, Konno Hiroyasu, Akiyama Nobuko, Shinzawa Miho, Miyauchi Maki, Takizawa Nobukazu, Yanai Hiromi, Ohashi Hiroyuki, Miyamoto-Sato Etsuko, Yanagawa Hiroshi, Yong Weidong, Shou Weinian, Inoue Jun-Ichiro
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Department of Developmental and Regenerative Biology, Key Laboratory for Regenerative Medicine, Ministry of Education and International Base of Collaboration for Science and Technology, the Ministry of Science and Technology and Guangdong Province, Jinan University, Guangzhou, China.
PLoS One. 2014 May 1;9(5):e95992. doi: 10.1371/journal.pone.0095992. eCollection 2014.
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.
病毒衍生的双链RNA（dsRNAs）在细胞质中被视黄酸诱导基因（RIG）-I样受体（RLRs）识别。这些受体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MAVS相互作用促进I型干扰素的RLR依赖性表达。然而，确切的调控机制仍不清楚。在这里，我们展示了FK506结合蛋白51（FKBP51）在调节dsRNA依赖性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”筛选鉴定，随后在HEK293T细胞中通过免疫共沉淀试验得到证实。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有基序。除了TRAF6，我们发现FKBP51还与TRAF3相互作用。在鼠成纤维细胞中，FKBP51的缺失降低了dsRNA转染或新城疫病毒感染诱导的I型干扰素的表达。与此一致的是，FKBP51的缺失减弱了dsRNA介导的IRF3和JNK的磷酸化以及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依赖性转录激活，表明FKBP51在MAVS介导的信号通路中具有支架功能。总体而言，我们证明了FKBP51与TRAF蛋白相互作用，并促进细胞质dsRNA诱导的I型干扰素的表达。这些发现表明FKBP51在病毒感染的固有免疫反应中具有新的作用。
