• Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation.

Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation.

Cell (2004-10-14)
Prabha Sampath, Barsanjit Mazumder, Vasudevan Seshadri, Carri A Gerber, Laurent Chavatte, Michael Kinter, Shu M Ting, J David Dignam, Sunghoon Kim, Donna M Driscoll, Paul L Fox

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-gamma, 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.

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