title: Double-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development.
abstract: Aminoacyl-tRNA synthetases (aaRSs) constitute a family of ubiquitously expressed essential enzymes that ligate amino acids to their cognate tRNAs for protein synthesis. Recently, aaRS mutations have been linked to various human diseases; however, how these mutations lead to diseases has remained unclear. In order to address the importance of aminoacylation fidelity in multicellular organisms, we generated an amino-acid double-sieving model in Drosophila melanogaster using phenylalanyl-tRNA synthetase (PheRS). Double-sieving-defective mutations dramatically misacylate non-cognate Tyr, induce protein mistranslation and cause endoplasmic reticulum stress in flies. Mutant adults exhibit many defects, including loss of neuronal cells, impaired locomotive performance, shortened lifespan and smaller organ size. At the cellular level, the mutations reduce cell proliferation and promote cell death. Our results also reveal the particular importance of the first amino-acid recognition sieve. Overall, these findings provide new mechanistic insights into how malfunctioning of aaRSs can cause diseases.
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, Bern 3012, Switzerland.
authors.forename: Jiongming
authors.initials: J
authors.lastname: Lu
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, Bern 3012, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Bergert
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, Bern 3012, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Walther
authors.affiliation: Institute of Cell Biology, University of Bern, Baltzerstrasse 4, Bern 3012, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Suter
mesh_terms: D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D059865:Endoplasmic Reticulum Stress; D055786:Gene Knockout Techniques; D009154:Mutation; D010652:Phenylalanine-tRNA Ligase / Q000172:deficiency / Q000235:genetics*; D014176:Protein Biosynthesis
chemical_list: D029721:Drosophila Proteins; D010652:Phenylalanine-tRNA Ligase