Abstract

The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/−) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.

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Acknowledgements

Supported by the KRIBB Initiative Program (KGM4541622 to M.H.K.), the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning of Korea (NRF-2010-0029767 and 2014R1A2A1A01005971 to M.H.K.; NRF-M3A6A4-2010-0029785 to S.K.; and 2015020957 to J.-S.L.), the Korea Institute of Oriental Medicine (K12050 to J.-S.L.), the Ministry for Food, Agriculture, Forestry and Fisheries (315044031SB010 to J.-S.L.) and the Korea Health Industry Development Institute (HI14C3484 to C.L.).

Author information

Author notes

    • Eun-Young Lee
    •  & Hyun-Cheol Lee

    These authors equally contributed to this work.

Affiliations

  1. Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.

    • Eun-Young Lee
    • , Hyun-Kwan Kim
    • , Song Yee Jang
    • , Jungwon Hwang
    •  & Myung Hee Kim
  2. College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.

    • Hyun-Cheol Lee
    • , Hyun-Kwan Kim
    • , Jae-Hoon Kim
    • , Tae-Hwan Kim
    •  & Jong-Soo Lee
  3. Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea.

    • Seong-Jun Park
    •  & Cheolju Lee
  4. Laboratory Animal Resource Center, KRIBB, University of Science and Technology (UST), Daejeon, Korea.

    • Yong-Hoon Kim
    •  & Chul-Ho Lee
  5. Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.

    • Jong Hwan Kim
    •  & Seon-Young Kim
  6. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Abul Arif
    •  & Paul L Fox
  7. College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.

    • Young-Ki Choi
  8. Department of Biological Chemistry, UST, Daejeon, Korea.

    • Cheolju Lee
  9. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Jae U Jung
  10. Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.

    • Sunghoon Kim
  11. Biosystems and Bioengineering Program, UST, Daejeon, Korea.

    • Myung Hee Kim

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Contributions

E.-Y.L. and H.-C.L. performed most of the experiments with help from H.-K.K., S.Y.J., J.H., J.-H.K. and T.-H.K. S.-J.P. and C.L. performed mass spectrometry. Y.-H.K. and C.-H.L. performed immunohistochemical analysis. J.H.K., S.-Y.K. and Y.-K.C. performed RNA-seq analysis. A.A., J.U.J., P.L.F. and S.K. contributed to the discussion and provided critical reagents. E.-Y.L., J.-S.L. and M.H.K. designed the study and wrote the manuscript. All of the authors helped with data analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jong-Soo Lee or Myung Hee Kim.

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https://doi.org/10.1038/ni.3542

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