Coordination between aminoacylation and editing to protect against proteotoxicity

Author:

Zhang Hong1,Murphy Parker1,Yu Jason1,Lee Sukyeong23,Tsai Francis T F2345,van Hoof Ambro6,Ling Jiqiang1ORCID

Affiliation:

1. Department of Cell Biology and Molecular Genetics, The University of Maryland , College Park , MD  20742 , USA

2. Department of Biochemistry and Molecular Biology, Baylor College of Medicine , Houston , TX  77030 , USA

3. Advanced Technology Core for Macromolecular X-ray Crystallography, Baylor College of Medicine , Houston , TX  77030 , USA

4. Department of Molecular and Cellular Biology, Baylor College of Medicine , Houston , TX  77030 , USA

5. Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston , TX  77030 , USA

6. Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston , Houston , TX  77030 , USA

Abstract

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.

Funder

National Institute of General Medical Sciences

Welch Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference61 articles.

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