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PLoS One. 2014 May 1;9(5):e95992. doi: 10.1371/journal.pone.0095992. eCollection 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.

Author information

1
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
2
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.
3
Division of Interactome Medical Sciences, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
4
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
5
Pediatrics, Biochemistry and Molecular Biology, Medical and Molecular Genetics, Pharmacology and Toxicology, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

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.

PMID:
24788966
PMCID:
PMC4006813
DOI:
10.1371/journal.pone.0095992
[Indexed for MEDLINE]
Free PMC Article

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