RelA-SpoT Homolog toxins pyrophosphorylate the CCA end of tRNA to inhibit protein synthesis
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34174184
DOI
10.1016/j.molcel.2021.06.005
PII: S1097-2765(21)00452-4
Knihovny.cz E-resources
- Keywords
- (p)ppApp, (p)ppGpp, RelA-SpoT Homolog, SAH, SAS, ribosome, tRNA modification, toxSAS, toxin-antitoxin, translation,
- MeSH
- Bacterial Toxins genetics metabolism pharmacology MeSH
- Phosphorylation drug effects MeSH
- Gram-Positive Asporogenous Rods chemistry metabolism MeSH
- Guanosine Pentaphosphate chemistry metabolism MeSH
- Protein Synthesis Inhibitors pharmacology MeSH
- Ligases chemistry genetics metabolism MeSH
- Protein Biosynthesis drug effects physiology MeSH
- Pyrophosphatases MeSH
- Ribosomes metabolism MeSH
- RNA, Transfer metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Bacterial Toxins MeSH
- guanosine 3',5'-polyphosphate synthetases MeSH Browser
- guanosine-3',5'-bis(diphosphate) 3'-pyrophosphatase MeSH Browser
- Guanosine Pentaphosphate MeSH
- Protein Synthesis Inhibitors MeSH
- Ligases MeSH
- Pyrophosphatases MeSH
- RNA, Transfer MeSH
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.
Department of Experimental Medical Science Lund University 221 00 Lund Sweden
Faculty of Life Sciences Kyoto Sangyo University Kamigamo Motoyama Kita ku Kyoto 603 8555 Japan
University of Tartu Institute of Technology 50411 Tartu Estonia
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