Members of the family of aminoacyl-tRNA synthetases (ARSs) are essential for the proper synthesis of proteins from mRNAs; however, they are also involved in nontranslational processes. Many of these nontranslational functions involve the assembly of a cytoplasmic multi-tRNA synthetase complex (MSC) consisting of eight tRNA synthetases, including glutamyl-prolyl-tRNA synthetase (EPRS). Through RNA sequencing analysis of bronchial epithelial cells, Lee et al. found that the abundances of EPRS mRNA and protein were increased in response to infection with the PR8 strain of influenza virus. Experiments with human and mouse macrophages and cell lines showed that the increased abundance of EPRS depended on the cytosolic viral RNA sensor RIG-I, but was independent of the antiviral cytokine interferon-β (IFN-β). Knockdown of EPRS in these cells led to increased viral replication and decreased production of IFN-β and the antiviral cytokine interleukin-6 (IL-6). Compared with infected wild-type mice, heterozygous Eprs+/– mice infected with PR8 had decreased amounts of antiviral cytokines and increased amounts of virus. In addition, the Eprs+/– mice showed decreased survival in response to infection with the virus VSV. Western blotting analysis and coimmunoprecipitation studies showed that viral infection of a macrophage cell line led to the phosphorylation of EPRS and its release from the MSC. Furthermore, in response to viral infection, MSC-free EPRS interacted with PCBP2, a protein that was previously implicated in the ubiquitylation and degradation of MAVS, an outer mitochondrial membrane protein that binds to RIG-I to mediate antiviral responses. The interaction between EPRS and PCBP2 did not require the catalytic activity of EPRS. Additional experiments showed that EPRS protected MAVS from PCBP2-mediated ubiquitylation and degradation to enhance the antiviral response. Together, these data suggest that the tRNA synthetase EPRS enhances the immune response to viral infection through a protein interaction mechanism rather than a mechanism involving protein translation.
E.-Y. Lee, H.-C. Lee, H.-K. Kim, S. Y. Jang, S.-J. Park, Y.-H. Kim, J. H. Kim, J. Hwang, J.-H. Kim, T.-H. Kim, A. Arif, S.-Y. Kim, Y.-K. Choi, C. Lee, C.-H. Lee, J. U. Jung, P. L. Fox, S. Kim, J.-S. Lee, M. H. Kim, Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity. Nat. Immunol. 17, 1252–1262 (2016). [PubMed]