A widespread toxin-antitoxin system exploiting growth control via alarmone signalling
A widespread toxin-antitoxin system exploiting growth control via alarmone signalling
ABSTRACT Under stressful conditions, bacterial RelA-SpoT Homologue (RSH) enzymes synthesise the alarmone (p)ppGpp, a nucleotide messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and at high concentrations inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single domain Small Alarmone Synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA and SpoT. We have discovered that multiple SAS subfamilies can be encoded in broadly distributed conserved bicistronic operon architectures in bacteria and bacteriophages that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralisation by the protein products of six neighbouring antitoxin genes. The toxicity of Cellulomonas marina ToxSAS FaRel is mediated by alarmone accumulation combined with depletion of cellular ATP and GTP pools, and this is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system is a novel TA paradigm comprising multiple different antitoxins that exemplifies how ancient nucleotide-based signalling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
Jimmy Steffi、Cepauskas Albinas、Takada Hiraku、Tenson Tanel、Strahl Henrik、Hauryliuk Vasili、Saha Chayan Kumar、Oliveira Sofia Raquel Alves、Koh Alan、Atkinson Gemma C.、Garcia-Pino Abel、Stavropoulos Constantine、Kurata Tatsuaki
Department of Molecular Biology, Ume? University||Laboratory for Molecular Infection Medicine Sweden (MIMS), Ume? UniversityCellular and Molecular Microbiology, Facult¨| des Sciences, Universit¨| Libre de BruxellesDepartment of Molecular Biology, Ume? University||Laboratory for Molecular Infection Medicine Sweden (MIMS), Ume? UniversityUniversity of Tartu, Institute of TechnologyCentre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences Newcastle UniversityDepartment of Molecular Biology, Ume? University||Laboratory for Molecular Infection Medicine Sweden (MIMS), Ume? University||University of Tartu, Institute of TechnologyDepartment of Molecular Biology, Ume? UniversityUniversity of Tartu, Institute of TechnologyCentre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences Newcastle UniversityDepartment of Molecular Biology, Ume? UniversityCellular and Molecular Microbiology, Facult¨| des Sciences, Universit¨| Libre de Bruxelles||Walloon Excellence in Life Sciences and Biotechnology (WELBIO)Department of Molecular Biology, Ume? UniversityDepartment of Molecular Biology, Ume? University
分子生物学微生物学生物化学
Jimmy Steffi,Cepauskas Albinas,Takada Hiraku,Tenson Tanel,Strahl Henrik,Hauryliuk Vasili,Saha Chayan Kumar,Oliveira Sofia Raquel Alves,Koh Alan,Atkinson Gemma C.,Garcia-Pino Abel,Stavropoulos Constantine,Kurata Tatsuaki.A widespread toxin-antitoxin system exploiting growth control via alarmone signalling[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/575399.点此复制
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