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A widespread toxin-antitoxin system exploiting growth control via alarmone signaling

S. Jimmy, CK. Saha, T. Kurata, C. Stavropoulos, SRA. Oliveira, A. Koh, A. Cepauskas, H. Takada, D. Rejman, T. Tenson, H. Strahl, A. Garcia-Pino, V. Hauryliuk, GC. Atkinson,

. 2020 ; 117 (19) : 10500-10510. [pub] 20200428

Language English Country United States

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

Persistent link   https://www.medvik.cz/link/bmc20025016

Grant support
BB/S00257X/1 Biotechnology and Biological Sciences Research Council - United Kingdom

Under stressful conditions, bacterial RelA-SpoT Homolog (RSH) enzymes synthesize the alarmone (p)ppGpp, a nucleotide second 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 asked whether analysis of the genomic context of SASs can indicate possible functional roles. Indeed, multiple SAS subfamilies are encoded in widespread conserved bicistronic operon architectures that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralization by the protein products of six neighboring antitoxin genes. The toxicity of Cellulomonas marina toxSAS FaRel is mediated by the accumulation of alarmones ppGpp and ppApp, and an associated depletion of cellular guanosine triphosphate and adenosine triphosphate pools, and is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system with its multiple different antitoxins exemplifies how ancient nucleotide-based signaling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.

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$a Under stressful conditions, bacterial RelA-SpoT Homolog (RSH) enzymes synthesize the alarmone (p)ppGpp, a nucleotide second messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and, at high concentrations, inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single-domain small alarmone synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA, and SpoT. We asked whether analysis of the genomic context of SASs can indicate possible functional roles. Indeed, multiple SAS subfamilies are encoded in widespread conserved bicistronic operon architectures that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralization by the protein products of six neighboring antitoxin genes. The toxicity of Cellulomonas marina toxSAS FaRel is mediated by the accumulation of alarmones ppGpp and ppApp, and an associated depletion of cellular guanosine triphosphate and adenosine triphosphate pools, and is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system with its multiple different antitoxins exemplifies how ancient nucleotide-based signaling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
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$a Saha, Chayan Kumar $u Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden.
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$a Kurata, Tatsuaki $u Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden.
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$a Stavropoulos, Constantine $u Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden.
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$a Oliveira, Sofia Raquel Alves $u Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
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$a Koh, Alan $u Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, NE2 4AX Newcastle upon Tyne, United Kingdom.
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$a Cepauskas, Albinas $u Cellular and Molecular Microbiology, Faculté des Sciences, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
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$a Takada, Hiraku $u Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden. Laboratory for Molecular Infection Medicine Sweden, Umeå University, SE-901 87 Umeå, Sweden.
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$a Rejman, Dominik $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, CZ-166 10 Prague 6, Czech Republic.
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$a Tenson, Tanel $u Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
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$a Strahl, Henrik $u Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, NE2 4AX Newcastle upon Tyne, United Kingdom.
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$a Garcia-Pino, Abel $u Cellular and Molecular Microbiology, Faculté des Sciences, Université Libre de Bruxelles, 6041 Gosselies, Belgium. Walloon Excellence in Life Sciences and Biotechnology, 1200 Brussels, Belgium.
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$a Hauryliuk, Vasili $u Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden; vasili.hauryliuk@umu.se gemma.atkinson@umu.se. Laboratory for Molecular Infection Medicine Sweden, Umeå University, SE-901 87 Umeå, Sweden. Institute of Technology, University of Tartu, 50411 Tartu, Estonia.
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