VapCs of Mycobacterium Tuberculosis Cleave RNAs Essential for Translation

Nucleic Acids Res. 2016 Nov 16;44(20):9860-9871. doi: 10.1093/nar/gkw781. Epub 2016 Sep 5.

Abstract

The major human pathogen Mycobacterium tuberculosis can survive in the host organism for decades without causing symptoms. A large cohort of Toxin-Antitoxin (TA) modules contribute to this persistence. Of these, 48 TA modules belong to the vapBC (virulence associated protein) gene family. VapC toxins are PIN domain endonucleases that, in enterobacteria, inhibit translation by site-specific cleavage of initiator tRNA. In contrast, VapC20 of M. tuberculosis inhibits translation by site-specific cleavage of the universally conserved Sarcin-Ricin loop (SRL) in 23S rRNA. Here we identify the cellular targets of 12 VapCs from M. tuberculosis by applying UV-crosslinking and deep sequencing. Remarkably, these VapCs are all endoribonucleases that cleave RNAs essential for decoding at the ribosomal A-site. Eleven VapCs cleave specific tRNAs while one exhibits SRL cleavage activity. These findings suggest that multiple vapBC modules contribute to the survival of M. tuberculosis in its human host by reducing the level of translation.

MeSH terms

  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • Genes, rRNA
  • Host-Pathogen Interactions*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / metabolism*
  • Phylogeny
  • Protein Binding
  • Protein Biosynthesis*
  • RNA Stability
  • RNA, Transfer, Met / chemistry
  • RNA, Transfer, Met / metabolism*
  • Tuberculosis / genetics*
  • Tuberculosis / microbiology*

Substances

  • Bacterial Proteins
  • Bacterial Toxins
  • RNA, Transfer, Met
  • VapC protein, Mycobacterium smegmatis