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Nat Immunol. 2016 Nov;17(11):1252-1262. doi: 10.1038/ni.3542. Epub 2016 Sep 5.

Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity.

Author information

1
Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
2
College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
3
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea.
4
Laboratory Animal Resource Center, KRIBB, University of Science and Technology (UST), Daejeon, Korea.
5
Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.
6
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
7
College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.
8
Department of Biological Chemistry, UST, Daejeon, Korea.
9
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
10
Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
11
Biosystems and Bioengineering Program, UST, Daejeon, Korea.

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.

PMID:
27595231
PMCID:
PMC5173487
DOI:
10.1038/ni.3542
[Indexed for MEDLINE]
Free PMC Article

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