Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity

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 discr...

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Vydáno v:Cell Ročník 161; číslo 7; s. 1606
Hlavní autoři: Nedialkova, Danny D, Leidel, Sebastian A
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 18.06.2015
Témata:
Animals
Caenorhabditis elegans - cytology
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Codon
Protein Aggregates
Protein Biosynthesis
Ribosomes - metabolism
RNA, Transfer - metabolism
Saccharomyces cerevisiae - cytology
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Stress, Physiological
Uridine - genetics
ISSN:1097-4172, 1097-4172
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2015.05.022