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The stringent response and physiological roles of (pp)pGpp in bacteria

Nature Reviews Microbiology volume 19, pages 256–271 (2021)Cite this article

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Abstract

The stringent response is a stress signalling system mediated by the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) in response to nutrient deprivation. Recent research highlights the complexity and broad range of functions that these alarmones control. This Review provides an update on our current understanding of the enzymes involved in ppGpp, pppGpp and guanosine 5′-monophosphate 3′-diphosphate (pGpp) (collectively (pp)pGpp) turnover, including those shown to produce pGpp and its analogue (pp)pApp. We describe the well-known interactions with RNA polymerase as well as a broader range of cellular target pathways controlled by (pp)pGpp, including DNA replication, transcription, nucleotide synthesis, ribosome biogenesis and function, as well as lipid metabolism. Finally, we review the role of ppGpp and pppGpp in bacterial pathogenesis, providing examples of how these nucleotides are involved in regulating many aspects of virulence and chronic infection.

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Fig. 1: Synthesis and hydrolysis of (pp)pGpp by RSH enzymes.
Fig. 2: (p)ppGpp-mediated inhibition of purine nucleotide synthesis.
Fig. 3: ppGpp binding to RNA polymerase.
Fig. 4: Control of protein translation by (p)ppGpp.
Fig. 5: Roles of (p)ppGpp in bacterial pathogenicity.

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Acknowledgements

Work in R.M.C.’s laboratory is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (104110/Z/14/Z to R.M.C.), as well as a Lister Institute Research Prize 2018 (to R.M.C.).

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  1. The Florey Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, UK

    Sophie E. Irving, Naznin R. Choudhury & Rebecca M. Corrigan

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S.E.I. and R.M.C. substantially contributed to discussion of the content. All authors wrote the article and reviewed or edited the manuscript.

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Glossary

GTPase

A member of a family of enzymes that act as molecular switches by hydrolysing GTP to GDP.

Ferroptosis

A type of cell death characterized by the accumulation of iron and lipid peroxides.

Toxin–antitoxin systems

Genetic modules that encode both a toxin, which inhibits cell growth, and a cognate antitoxin, which neutralizes the toxin.

Secretion system

A protein complex that facilitate the secretion of proteins across the bacterial membrane.

Swarmer cells

One of two daughter cells following Caulobacter crescentus cell division that expresses a flagellum but in which replication is suppressed.

Stalk cells

Second type of Caulobacter crescentus daughter cell, which contains a stalk for surface attachment and is replication competent.

BALB/c mouse model

Albino, immunodeficient mouse strain that is used as a general purpose animal infection model.

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Irving, S.E., Choudhury, N.R. & Corrigan, R.M. The stringent response and physiological roles of (pp)pGpp in bacteria. Nat Rev Microbiol 19, 256–271 (2021). https://doi.org/10.1038/s41579-020-00470-y

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