Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity.
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.
Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Eun-Young
EY
Lee
College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
Hyun-Cheol
HC
Lee
Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.|College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
Hyun-Kwan
HK
Kim
Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Song Yee
SY
Jang
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea.
Seong-Jun
SJ
Park
Laboratory Animal Resource Center, KRIBB, University of Science and Technology (UST), Daejeon, Korea.
Yong-Hoon
YH
Kim
Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.
Jong Hwan
JH
Kim
Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Jungwon
J
Hwang
College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
Jae-Hoon
JH
Kim
College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
Tae-Hwan
TH
Kim
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Abul
A
Arif
Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.
Seon-Young
http://orcid.org/0000-0002-1030-7730
SY
Kim
College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea.
Young-Ki
YK
Choi
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea.|Department of Biological Chemistry, UST, Daejeon, Korea.
Cheolju
C
Lee
Laboratory Animal Resource Center, KRIBB, University of Science and Technology (UST), Daejeon, Korea.
Chul-Ho
CH
Lee
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Jae U
JU
Jung
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Paul L
PL
Fox
Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
Sunghoon
S
Kim
College of Veterinary Medicine, Chungnam National University, Daejeon, Korea.
Jong-Soo
JS
Lee
Infection and Immunity Research Laboratory, Microbiomics and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.|Biosystems and Bioengineering Program, UST, Daejeon, Korea.
Myung Hee
MH
Kim
D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D012327:RNA Virus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D012328:RNA Viruses / Q000187:drug effects / Q000276:immunology; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D014777:Virus Diseases / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D014779:Virus Replication
C501903:PCBP2 protein, human; D010455:Peptides; D016601:RNA-Binding Proteins; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase