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

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


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.

MeSH terms

  • Amino Acyl-tRNA Synthetases / chemistry
  • Amino Acyl-tRNA Synthetases / genetics
  • Amino Acyl-tRNA Synthetases / metabolism*
  • Animals
  • Antiviral Agents / pharmacology
  • Disease Models, Animal
  • Disease Resistance / immunology*
  • Host-Pathogen Interactions / immunology*
  • Immunity, Innate
  • Mice
  • Mice, Knockout
  • Peptides / pharmacology
  • Phosphorylation
  • Protein Binding
  • RNA Virus Infections / immunology
  • RNA Virus Infections / metabolism
  • RNA Virus Infections / virology
  • RNA Viruses / drug effects
  • RNA Viruses / immunology
  • RNA-Binding Proteins / metabolism
  • Signal Transduction
  • Ubiquitination
  • Virus Diseases / immunology*
  • Virus Diseases / metabolism*
  • Virus Diseases / virology
  • Virus Replication


  • Antiviral Agents
  • PCBP2 protein, human
  • Peptides
  • RNA-Binding Proteins
  • Amino Acyl-tRNA Synthetases
  • prolyl T RNA synthetase