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

T. Kurata, T. Brodiazhenko, SR. Alves Oliveira, M. Roghanian, Y. Sakaguchi, KJ. Turnbull, O. Bulvas, H. Takada, H. Tamman, A. Ainelo, R. Pohl, D. Rejman, T. Tenson, T. Suzuki, A. Garcia-Pino, GC. Atkinson, V. Hauryliuk

. 2021 ; 81 (15) : 3160-3170.e9. [pub] 20210625

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21025159
E-resources Online Full text

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Links

PubMed 34174184
DOI 10.1016/j.molcel.2021.06.005
Knihovny.cz E-resources

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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