Eun-Young Lee1,12, Hyun-Cheol Lee2,12, Hyun-Kwan Kim1,2, Song Yee Jang1, Seong-Jun Park3, Yong-Hoon Kim4, Jong Hwan Kim5, Jungwon Hwang1, Jae-Hoon Kim2, Tae-Hwan Kim2, Abul Arif6, Seon-Young Kim5, Young-Ki Choi7, Cheolju Lee3,8, Chul-Ho Lee4, Jae U Jung9, Paul L Fox6, Sunghoon Kim10, Jong-Soo Lee2 & Myung Hee Kim1,11
1Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea. 2College of Veterinary Medicine, Chungnam National University, Daejeon, Korea. 3Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea. 4Laboratory Animal Resource Center, KRIBB, University of Science and Technology (UST), Daejeon, Korea. 5Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea. 6Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. 7College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea. 8Department of Biological Chemistry, UST, Daejeon, Korea. 9Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 10Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea. 11Biosystems and Bioengineering Program, UST, Daejeon, Korea. 12These authors equally contributed to this work.
Correspondence to : Jong-Soo Lee or Myung Hee Kim
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.