Peptidyl tRNA hydrolase is required for robust prolyl-tRNA turnover in mycobacterium tuberculosis

Francesca G. Tomasi, Jessica T. P. Schweber, Satoshi Kimura, Junhao Zhu, Laura A. T. Cleghorn, Susan H. Davis, Simon R. Green, Matthew K. Waldor, Eric J. Rubin (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
40 Downloads (Pure)

Abstract

Enzymes involved in rescuing stalled ribosomes and recycling translation machinery are ubiquitous in bacteria and required for growth. Peptidyl tRNA drop-off is a type of abortive translation that results in the release of a truncated peptide that is still bound to tRNA (peptidyl tRNA) into the cytoplasm. Peptidyl tRNA hydrolase (Pth) recycles the released tRNA by cleaving off the unfinished peptide and is essential in most bacteria. We developed a sequencing-based strategy called copper sulfatebased tRNA sequencing (Cu-tRNAseq) to study the physiological role of Pth in Mycobacterium tuberculosis (Mtb). While most peptidyl tRNA species accumulated in a strain with impaired Pth expression, peptidyl prolyl-tRNA was particularly enriched, suggesting that Pth is required for robust peptidyl prolyl-tRNA turnover. Reducing Pth levels increased Mtb's susceptibility to tRNA synthetase inhibitors that are in development to treat tuberculosis (TB) and rendered this pathogen highly susceptible to macrolides, drugs that are ordinarily ineffective against Mtb. Collectively, our findings reveal the potency of Cu-tRNAseq for profiling peptidyl tRNAs and suggest that targeting Pth would open new therapeutic approaches for TB.

Original languageEnglish
Article numbere03469-22
Number of pages13
JournalMBio
Volume14
Issue number1
Early online date25 Jan 2023
DOIs
Publication statusPublished - 28 Feb 2023

Keywords

  • Mycobacterium tuberculosis
  • antibiotic resistance
  • bacterial genetics
  • ribosomes
  • tRNA
  • tRNA sequencing
  • translation

ASJC Scopus subject areas

  • Virology
  • Microbiology

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