Abstract
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.
Highlights
Human glycyl-tRNA synthetase (GARS) is an essential component of the translation apparatus
Identification of 2 mRNA isoforms Both the human mitochondrial and cytosolic glycyl-tRNA synthetase (GARS) enzymes are encoded by the same gene (GARS), located on chromosome 7, and use 2 alternative initiation codons
One mRNA isoform was previously identified from fetal liver cDNA, showing the presence of a long 50-UTR (357 nucleotides upstream of the putative initiator codon for mitochondrial GARS synthesis) containing 3 other potential initiation codons.[17] (Fig. 1A)
Summary
Human glycyl-tRNA synthetase (GARS) is an essential component of the translation apparatus. GARS, like other mammalian aminoacyl-tRNA synthetases (aaRS) 1-3 is involved in functions beyond translation.[4] Most of these alternative functions were identified mainly through the discovery of several diseases linked to mutations in the corresponding gene or to the presence of antibodies against extracellular GARS. At least 13 dominant mutations in the GARS gene cause motor and sensory axon loss in the peripheral nervous system and lead to clinical phenotypes ranging from CharcotMarie-Tooth (CMT) type 2D neuropathy to a severe infantile form of spinal muscular atrophy type V.5-10. The links between GARS mutations, tissue-specificity, and pathological mechanisms remain unclear (reviewed in).[7] Several studies identified autoantibodies to 8 different aaRSs; among them, anti-GARS antibodies (anti-EJ) are mainly found in patients with inflammatory myopathy, polymyositis and dermatomyositis (reviewed in).[11] Yet information on their clinical impact is still limited. Together these observations suggest that, in mammals, GARS expression may be regulated in response to many different stimuli
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
