Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation.
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.
Department of Cell Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Prabha
P
Sampath
Barsanjit
B
Mazumder
Vasudevan
V
Seshadri
Carri A
CA
Gerber
Laurent
L
Chavatte
Michael
M
Kinter
Shu M
SM
Ting
J David
JD
Dignam
Sunghoon
S
Kim
Donna M
DM
Driscoll
Paul L
PL
Fox
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D002846:Chromatography, Affinity; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D046911:Macromolecular Substances; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D046911:Macromolecular Substances; D012261:Ribonucleoproteins; C026452:messenger ribonucleoprotein; D007371:Interferon-gamma; D002570:Ceruloplasmin; D000604:Amino Acyl-tRNA Synthetases; C415462:glutamyl-prolyl-tRNA synthetase