Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN.

Taishin Akiyama,Weinian Shou,Hiroyasu Konno,Junwen Qin,Hiroyuki Ohashi,Takuma Shiraishi,Nobukazu Takizawa,Nobuko Akiyama,Etsuko Miyamoto-Sato,Jun-Ichiro Inoue,Weidong Yong,Hiroshi Yanagawa,Hiromi Yanai,Maki Miyauchi,Miho Shinzawa,Hiroyasu Nakano

doi:10.1371/journal.pone.0095992

Abstract

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.

Highlights

Recognition of nonself nucleic acids is crucial for the initiation and modulation of the innate immune pathways in response to viral infection [1,2,3,4]
We previously demonstrated that TRAF6 promotes the induction of type I IFN and proinflammatory cytokines upon sensing cytosolic double-stranded RNAs (dsRNAs) or DNA [22]
TRAF6 is reported to bind to mitochondrial antiviral signaling (MAVS) and IRF7 [38], the molecular mechanism by which TRAF6 activates the downstream signaling to regulate type I IFN expression remains unclear

Summary

Introduction

Recognition of nonself nucleic acids is crucial for the initiation and modulation of the innate immune pathways in response to viral infection [1,2,3,4]. The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs)–RIG-I, melanoma differentiation associated factor 5 (MDA-5), and laboratory of genetics and physiology 2 (LGP2)– function as cytosolic sensors of virus-derived dsRNAs [5,6,7,8]. RLRs that recognize dsRNAs activate the signaling pathways that drive the production of type I IFN, which induce antiviral responses by upregulating the expression of a wide variety of IFN-stimulated genes [1,2,3,4]. The activation of the atypical IKKs (i.e., TBK1 and IKKe) promotes the phosphorylation, homodimerization, and nuclear localization of IFN regulatory factor 3 (IRF3) and IRF7 [17,18]. The nuclear localization of these transcription factors promotes the transcription of the type I IFN and proinflammatory cytokines [19]

Methods

Results

Conclusion