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RelA-SpoT Homolog toxins pyrophosphorylate the CCA end of tRNA to inhibit protein synthesis

Kurata, Tatsuaki LU ; Brodiazhenko, Tetiana ; Alves Oliveira, Sofia Raquel ; Roghanian, Mohammad ; Sakaguchi, Yuriko ; Turnbull, Kathryn Jane ; Bulvas, Ondřej ; Takada, Hiraku ; Tamman, Hedvig and Ainelo, Andres , et al. (2021) In Molecular Cell 81(15). p.1-3170
Abstract

RelA-SpoT Homolog (RSH) enzymes control bacterial physiology through synthesis and degradation of the nucleotide alarmone (p)ppGpp. We recently discovered multiple families of small alarmone synthetase (SAS) RSH acting as toxins of toxin-antitoxin (TA) modules, with the FaRel subfamily of toxSAS abrogating bacterial growth by producing an analog of (p)ppGpp, (pp)pApp. Here we probe the mechanism of growth arrest used by four experimentally unexplored subfamilies of toxSAS: FaRel2, PhRel, PhRel2, and CapRel. Surprisingly, all these toxins specifically inhibit protein synthesis. To do so, they transfer a pyrophosphate moiety from ATP to the tRNA 3' CCA. The modification inhibits both tRNA aminoacylation and the sensing of cellular amino... (More)

RelA-SpoT Homolog (RSH) enzymes control bacterial physiology through synthesis and degradation of the nucleotide alarmone (p)ppGpp. We recently discovered multiple families of small alarmone synthetase (SAS) RSH acting as toxins of toxin-antitoxin (TA) modules, with the FaRel subfamily of toxSAS abrogating bacterial growth by producing an analog of (p)ppGpp, (pp)pApp. Here we probe the mechanism of growth arrest used by four experimentally unexplored subfamilies of toxSAS: FaRel2, PhRel, PhRel2, and CapRel. Surprisingly, all these toxins specifically inhibit protein synthesis. To do so, they transfer a pyrophosphate moiety from ATP to the tRNA 3' CCA. The modification inhibits both tRNA aminoacylation and the sensing of cellular amino acid starvation by the ribosome-associated RSH RelA. Conversely, we show that some small alarmone hydrolase (SAH) RSH enzymes can reverse the pyrophosphorylation of tRNA to counter the growth inhibition by toxSAS. Collectively, we establish RSHs as RNA-modifying enzymes.

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type
Contribution to journal
publication status
published
subject
in
Molecular Cell
volume
81
issue
15
pages
1 - 3170
publisher
Cell Press
external identifiers
  • pmid:34174184
  • scopus:85111582311
ISSN
1097-4164
DOI
10.1016/j.molcel.2021.06.005
language
English
LU publication?
yes
id
fa853344-3fde-409c-bffb-70f9ee73e428
date added to LUP
2021-08-15 12:48:33
date last changed
2024-06-29 15:25:32
@article{fa853344-3fde-409c-bffb-70f9ee73e428,
  abstract     = {{<p>RelA-SpoT Homolog (RSH) enzymes control bacterial physiology through synthesis and degradation of the nucleotide alarmone (p)ppGpp. We recently discovered multiple families of small alarmone synthetase (SAS) RSH acting as toxins of toxin-antitoxin (TA) modules, with the FaRel subfamily of toxSAS abrogating bacterial growth by producing an analog of (p)ppGpp, (pp)pApp. Here we probe the mechanism of growth arrest used by four experimentally unexplored subfamilies of toxSAS: FaRel2, PhRel, PhRel2, and CapRel. Surprisingly, all these toxins specifically inhibit protein synthesis. To do so, they transfer a pyrophosphate moiety from ATP to the tRNA 3' CCA. The modification inhibits both tRNA aminoacylation and the sensing of cellular amino acid starvation by the ribosome-associated RSH RelA. Conversely, we show that some small alarmone hydrolase (SAH) RSH enzymes can reverse the pyrophosphorylation of tRNA to counter the growth inhibition by toxSAS. Collectively, we establish RSHs as RNA-modifying enzymes.</p>}},
  author       = {{Kurata, Tatsuaki and Brodiazhenko, Tetiana and Alves Oliveira, Sofia Raquel and Roghanian, Mohammad and Sakaguchi, Yuriko and Turnbull, Kathryn Jane and Bulvas, Ondřej and Takada, Hiraku and Tamman, Hedvig and Ainelo, Andres and Pohl, Radek and Rejman, Dominik and Tenson, Tanel and Suzuki, Tsutomu and Garcia-Pino, Abel and Atkinson, Gemma Catherine and Hauryliuk, Vasili}},
  issn         = {{1097-4164}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{15}},
  pages        = {{1--3170}},
  publisher    = {{Cell Press}},
  series       = {{Molecular Cell}},
  title        = {{RelA-SpoT Homolog toxins pyrophosphorylate the CCA end of tRNA to inhibit protein synthesis}},
  url          = {{http://dx.doi.org/10.1016/j.molcel.2021.06.005}},
  doi          = {{10.1016/j.molcel.2021.06.005}},
  volume       = {{81}},
  year         = {{2021}},
}