title: Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity.
abstract: Proteins begin to fold as they emerge from translating ribosomes. The kinetics of ribosome transit along a given mRNA can influence nascent chain folding, but the extent to which individual codon translation rates impact proteome integrity remains unknown. Here, we show that slower decoding of discrete codons elicits widespread protein aggregation in vivo. Using ribosome profiling, we find that loss of anticodon wobble uridine (U34) modifications in a subset of tRNAs leads to ribosome pausing at their cognate codons in S. cerevisiae and C. elegans. Cells lacking U34 modifications exhibit gene expression hallmarks of proteotoxic stress, accumulate aggregates of endogenous proteins, and are severely compromised in clearing stress-induced protein aggregates. Overexpression of hypomodified tRNAs alleviates ribosome pausing, concomitantly restoring protein homeostasis. Our findings demonstrate that modified U34 is an evolutionarily conserved accelerator of decoding and reveal an unanticipated role for tRNA modifications in maintaining proteome integrity.
authors.affiliation: Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Von-Esmarch-Strasse 54, 48149 Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany.
authors.forename: Danny D
authors.initials: DD
authors.lastname: Nedialkova
authors.affiliation: Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Von-Esmarch-Strasse 54, 48149 Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany; Faculty of Medicine, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany. Electronic address: sebastian.leidel@mpi-muenster.mpg.de.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Leidel
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D003062:Codon; D066329:Protein Aggregates; D014176:Protein Biosynthesis; D012343:RNA, Transfer / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D014529:Uridine / Q000235:genetics
chemical_list: D003062:Codon; D066329:Protein Aggregates; D012343:RNA, Transfer; D014529:Uridine