Aminoacyl tRNA synthetases (ARS) catalyze the ligation of amino acids to cognate tRNAs. Chordate ARSs have evolved distinctive features absent from ancestral forms, including compartmentalization in a multisynthetase complex (MSC), noncatalytic peptide appendages, and ancillary functions unrelated to aminoacylation. Here, we show that glutamyl-prolyl-tRNA synthetase (GluProRS), a bifunctional ARS of the MSC, has a regulated, noncanonical activity that blocks synthesis of a specific protein. GluProRS was identified as a component of the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex by RNA affinity chromatography using the ceruloplasmin (Cp) GAIT element as ligand. In response to IFN-γ, GluProRS is phosphorylated and released from the MSC, binds the Cp 3′-untranslated region in an mRNP containing three additional proteins, and silences Cp mRNA translation. Thus, GluProRS has divergent functions in protein synthesis: in the MSC, its aminoacylation activity supports global translation, but translocation of GluProRS to an inflammation-responsive mRNP causes gene-specific translational silencing.
Bibliographical noteFunding Information:
This work was supported by grants HL29582, HL67725, and HL76491 from the NIH (to P.L.F.); by an AHA Predoctoral Fellowship, Ohio Valley Affiliate (to P.S.); and by a Scientist Development Grant from the AHA, National Affiliate (to B.M.). We appreciate the assistance of Ratan Maitra in the Lerner Research Institute Virus Core Facility for expression of NSAP1. We are grateful to Ira Wool and Paul Schimmel for helpful discussions. We acknowledge Gideon Dreyfuss for the generous gift of anti-hnRNP Q/R and SP2/O antibodies. None of the authors have any financial conflict of interest with the information in this manuscript.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)