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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Immunity, Innate
  • Interferon Type I / genetics*
  • Interferon Type I / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Newcastle disease virus / genetics
  • Newcastle disease virus / immunology
  • Newcastle disease virus / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Protein Transport
  • RNA, Double-Stranded / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism*
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism*


  • Interferon Type I
  • RNA, Double-Stranded
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 5

Grant support

This work was supported by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science (T.A.); a Grant-in-Aid for Challenging Exploratory Research (T.A.); a grant for the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (J-i.I.); a Grant-in-Aid for Scientific Research on Innovative Areas from MEXT (J-i.I.); and a contract research fund for the Program of Japan Initiative for Global Research Network on Infectious Diseases from MEXT (J-i.I.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.