Coordination between aminoacylation and editing to protect against proteotoxicity.
Nucleic Acids Res
; 51(19): 10606-10618, 2023 10 27.
Article
em En
| MEDLINE
| ID: mdl-37742077
ABSTRACT
Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that ligate amino acids to tRNAs, and often require editing to ensure accurate protein synthesis. Recessive mutations in aaRSs cause various neurological disorders in humans, yet the underlying mechanism remains poorly understood. Pathogenic aaRS mutations frequently cause protein destabilization and aminoacylation deficiency. In this study, we report that combined aminoacylation and editing defects cause severe proteotoxicity. We show that the ths1-C268A mutation in yeast threonyl-tRNA synthetase (ThrRS) abolishes editing and causes heat sensitivity. Surprisingly, experimental evolution of the mutant results in intragenic mutations that restore heat resistance but not editing. ths1-C268A destabilizes ThrRS and decreases overall Thr-tRNAThr synthesis, while the suppressor mutations in the evolved strains improve aminoacylation. We further show that deficiency in either ThrRS aminoacylation or editing is insufficient to cause heat sensitivity, and that ths1-C268A impairs ribosome-associated quality control. Our results suggest that aminoacylation deficiency predisposes cells to proteotoxic stress.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estresse Proteotóxico
/
Aminoacil-tRNA Sintetases
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article