Elaborate uORF/IRES features control expression and localization of human glycyl-tRNA synthetase.
The canonical activity of glycyl-tRNA synthetase (GARS) is to charge glycine onto its cognate tRNAs. However, outside translation, GARS also participates in many other functions. A single gene encodes both the cytosolic and mitochondrial forms of GARS but 2 mRNA isoforms were identified. Using immunolocalization assays, in vitro translation assays and bicistronic constructs we provide experimental evidence that one of these mRNAs tightly controls expression and localization of human GARS. An intricate regulatory domain was found in its 5'-UTR which displays a functional Internal Ribosome Entry Site and an upstream Open Reading Frame. Together, these elements hinder the synthesis of the mitochondrial GARS and target the translation of the cytosolic enzyme to ER-bound ribosomes. This finding reveals a complex picture of GARS translation and localization in mammals. In this context, we discuss how human GARS expression could influence its moonlighting activities and its involvement in diseases.
a Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS ; IBMC ; 15 rue René Descartes; Strasbourg Cedex , France.
Jana
J
Alexandrova
a Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS ; IBMC ; 15 rue René Descartes; Strasbourg Cedex , France.
Caroline
C
Paulus
a Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS ; IBMC ; 15 rue René Descartes; Strasbourg Cedex , France.
Joëlle
J
Rudinger-Thirion
a Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS ; IBMC ; 15 rue René Descartes; Strasbourg Cedex , France.
Fabrice
F
Jossinet
a Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS ; IBMC ; 15 rue René Descartes; Strasbourg Cedex , France.
Magali
M
Frugier
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D018388:Codon, Terminator / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006032:Glycine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics*; D010442:Peptide Chain Initiation, Translational; D021381:Protein Transport; D012315:RNA Caps / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D018388:Codon, Terminator; D000067556:Internal Ribosome Entry Sites; D007527:Isoenzymes; D012315:RNA Caps; D012333:RNA, Messenger; D006032:Glycine-tRNA Ligase
IRES; aminoacyl-tRNA synthetase; post-transcriptional control; uORF