@article{efa6de76cbe941d0aa8f60be8337d67d,
title = "Queuosine-modified tRNAs confer nutritional control of protein translation",
abstract = "Global protein translation as well as translation at the codon level can be regulated by tRNA modifications. In eukaryotes, levels of tRNA queuosinylation reflect the bioavailability of the precursor queuine, which is salvaged from the diet and gut microbiota. We show here that nutritionally determined Q-tRNA levels promote Dnmt2-mediated methylation of tRNA Asp and control translational speed of Q-decoded codons as well as at near-cognate codons. Deregulation of translation upon queuine depletion results in unfolded proteins that trigger endoplasmic reticulum stress and activation of the unfolded protein response, both in cultured human cell lines and in germ-free mice fed with a queuosine-deficient diet. Taken together, our findings comprehensively resolve the role of this anticodon tRNA modification in the context of native protein translation and describe a novel mechanism that links nutritionally determined modification levels to effective polypeptide synthesis and cellular homeostasis.",
keywords = "cytosine-5 methylation, protein translation, queuosine, tRNA modifications, unfolded protein response",
author = "Francesca Tuorto and Carine Legrand and Cansu Cirzi and Giuseppina Federico and Reinhard Liebers and Martin M{\"u}ller and Ehrenhofer-Murray, {Ann E.} and Gunnar Dittmar and Gr{\"o}ne, {Hermann Josef} and Frank Lyko",
note = "Funding Information: We thank Dario Demartin and Nader Alerasool for their contribution during early stages of this project. We also thank Kurt Reifenberg for axenic mice; Larissa Ziegler, Tanja Musch, and Sylvia Kaden for technical support; Felix Bormann for bioinformatics assistance; Hans-Dieter Gerber and Gerhard Klebe for materials; the DKFZ light microscopy facility for instrument support; the DKFZ Protein Analysis Core Facility and Bernd He{\ss}ling for dimethyl-labeling measurements. We thank and Georg Stoecklin, Manuel Rodr{\'i}guez-Paredes, and Thomas G. Hofmann for valuable discussions and comments. We also thank Adele Bourmaud and Celine Jaunty of the Proteome and Genome Research laboratory for their support measuring the proteomic samples. This work was supported by grants from Deutsche Forschungsgemeinschaft (DFG) (SPP1784) to AEM and FL, and DFG TU5371-1 to FT. Additional support was provided by a DKFZ NCT3.0 Integrative Project in Cancer Research to FL. GD was supported by the PEARL/CPIL grant of the Luxembourg National Research Fund (FNR), and FT was supported by the Institute of Genetics and Biophysics A. Buzzati-Traverso, C.N.R., Italy. Funding Information: We thank Dario Demartin and Nader Alerasool for their contribution during early stages of this project. We also thank Kurt Reifenberg for axenic mice; Larissa Ziegler, Tanja Musch, and Sylvia Kaden for technical support; Felix Bormann for bioinformatics assistance; Hans-Dieter Gerber and Gerhard Klebe for materials; the DKFZ light microscopy facility for instrument support; the DKFZ Protein Analysis Core Facility and Bernd He?ling for dimethyl-labeling measurements. We thank and Georg Stoecklin, Manuel Rodr?guez-Paredes, and Thomas G. Hofmann for valuable discussions and comments. We also thank Adele Bourmaud and Celine Jaunty of the Proteome and Genome Research laboratory for their support measuring the proteomic samples. This work was supported by grants from Deutsche Forschungsgemeinschaft (DFG) (SPP1784) to AEM and FL, and DFG TU5371-1 to FT. Additional support was provided by a DKFZ NCT3.0 Integrative Project in Cancer Research to FL. GD was supported by the PEARL/CPIL grant of the Luxembourg National Research Fund (FNR), and FT was supported by the Institute of Genetics and Biophysics A. Buzzati-Traverso, C.N.R., Italy. Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license",
year = "2018",
month = sep,
day = "14",
doi = "10.15252/embj.201899777",
language = "English",
volume = "37",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "EMBO Press",
number = "18",
}