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

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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.

Original languageEnglish (US)
Article numbere95992
JournalPLoS ONE
Volume9
Issue number5
DOIs
StatePublished - May 1 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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. I. (2014). Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN. PLoS ONE, 9(5), [e95992]. https://doi.org/10.1371/journal.pone.0095992