Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity

• Published in: Cell 2015-06, Vol.161 (7), p.1606-1618
• Main Authors: Nedialkova, Danny D., Leidel, Sebastian A.
• Format: Article
• Language: English
• Subjects: Animals; Caenorhabditis elegans - cytology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Codon; codons; gene expression; homeostasis; messenger RNA; Protein Aggregates; Protein Biosynthesis; proteome; ribosomes; Ribosomes - metabolism; RNA, Transfer - metabolism; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Stress, Physiological; transfer RNA; translation (genetics); uridine; Uridine - genetics
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.05.022

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. [Display omitted] •tRNA anticodon modification loss slows translation at cognate codons in vivo•Codon-specific translational pausing triggers protein misfolding in yeast and worms•Codon translation rates and protein homeostasis are restored by tRNA overexpression Optimal codon translation rates—ensured by the presence of nucleoside modifications in the tRNA anticodon—are critical for maintaining proteome integrity.