Curated Papers > Recent high-impact research in "synthetic biology" (IF≥30, last 5 years)

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

Literature Information

DOI	10.1038/s41579-020-00470-y
PMID	33149273
Journal	Nature reviews. Microbiology
Impact Factor	103.3
JCR Quartile	Q1
Publication Year	2021
Times Cited	194
Keywords	stringent response, ppGpp, bacterial pathogenesis, nutrient deprivation, cell signaling
Literature Type	Journal Article, Research Support, Non-U.S. Gov't, Review
ISSN	1740-1526
Pages	256-271
Issue	19(4)
Authors	Sophie E Irving, Naznin R Choudhury, Rebecca M Corrigan

TL;DR

This review explores the intricate roles of the alarmones ppGpp and pppGpp in the stringent response to nutrient stress, highlighting their involvement in various cellular processes such as DNA replication, transcription, and virulence in bacterial pathogenesis. By detailing the enzymes responsible for their turnover and their interactions with RNA polymerase, the study underscores the significance of (pp)pGpp in regulating bacterial survival and chronic infection.

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stringent response · ppGpp · bacterial pathogenesis · nutrient deprivation · cell signaling

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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Primary Questions Addressed

1. How do (pp)pGpp levels specifically influence the regulation of DNA replication in bacteria?
2. What are the potential therapeutic implications of targeting (pp)pGpp pathways in bacterial infections?
3. In what ways do the interactions between (pp)pGpp and RNA polymerase affect transcriptional regulation during stress responses?
4. Can you elaborate on the role of (pp)pGpp in ribosome biogenesis and its impact on protein synthesis under nutrient-limited conditions?
5. How does the signaling role of (pp)pGpp differ between various bacterial species in response to environmental stresses?

Key Findings

1. Research Background and Objectives

The stringent response is a critical bacterial stress signaling mechanism activated during nutrient deprivation, primarily mediated by the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp). Understanding the physiological roles of these alarmones is essential for elucidating how bacteria adapt to stress conditions and regulate various cellular processes. This review aims to synthesize recent advancements in the knowledge of (pp)pGpp synthesis and degradation, the enzymes involved in these processes, and the broader implications of these molecules on bacterial physiology and pathogenesis.

2. Main Methods and Findings

The review integrates findings from a variety of studies focusing on the enzymatic pathways responsible for the turnover of (pp)pGpp, including the synthesis of guanosine 5'-monophosphate 3'-diphosphate (pGpp) and its analogue (pp)pApp. It discusses the interactions of (pp)pGpp with RNA polymerase and identifies additional cellular pathways influenced by these alarmones. Key functions highlighted include:

• Regulation of DNA replication and transcription processes.
• Modulation of nucleotide synthesis.
• Control over ribosome biogenesis and function.
• Impact on lipid metabolism.

The review also emphasizes the role of ppGpp and pppGpp in bacterial pathogenesis, illustrating how these molecules influence virulence and contribute to chronic infections.

3. Core Conclusions

The findings underscore the multifaceted roles of (pp)pGpp in bacterial physiology, extending beyond traditional views of transcriptional regulation to include critical involvement in DNA replication, ribosome function, and metabolic processes. The review establishes that these alarmones are integral to the bacterial response to environmental stressors and are pivotal in modulating virulence factors, thereby influencing the pathogenic potential of bacteria.

4. Research Significance and Impact

This review significantly advances the understanding of how bacteria adapt to nutrient stress and manage cellular processes through (pp)pGpp signaling. By elucidating the complex interactions of (pp)pGpp with various cellular pathways, this research has profound implications for developing novel antibacterial strategies. Targeting (pp)pGpp synthesis or signaling pathways could provide new avenues for combating bacterial infections, particularly those involving antibiotic resistance and chronic disease states. The insights gained from this work could also foster further research into the intricate regulatory networks within bacterial cells, contributing to the broader field of microbial physiology and pathogenesis.

References

1. Bacterial lifestyle shapes stringent response activation. - Cara C Boutte;Sean Crosson - Trends in microbiology (2013)
2. (p)ppGpp: still magical? - Katarzyna Potrykus;Michael Cashel - Annual review of microbiology (2008)
3. The RelA/SpoT homolog (RSH) superfamily: distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life. - Gemma C Atkinson;Tanel Tenson;Vasili Hauryliuk - PloS one (2011)
4. From (p)ppGpp to (pp)pGpp: Characterization of Regulatory Effects of pGpp Synthesized by the Small Alarmone Synthetase of Enterococcus faecalis. - Anthony O Gaca;Pavel Kudrin;Cristina Colomer-Winter;Jelena Beljantseva;Kuanqing Liu;Brent Anderson;Jue D Wang;Dominik Rejman;Katarzyna Potrykus;Michael Cashel;Vasili Hauryliuk;José A Lemos - Journal of bacteriology (2015)
5. The Ps and Qs of alarmone synthesis in Staphylococcus aureus. - Ning Yang;Shujie Xie;Nga-Yeung Tang;Mei Yee Choi;Ying Wang;Rory M Watt - PloS one (2019)
6. Identification and Functional Characterization of Small Alarmone Synthetases in Corynebacterium glutamicum. - Matthias Ruwe;Jörn Kalinowski;Marcus Persicke - Frontiers in microbiology (2017)
7. Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance. - Shuo Yang;Meijie Tian;Yulong Dai;Shengyong Feng;Yunyun Wang;Deepak Chhangani;Tiffany Ou;Wenle Li;Ze Yang;Jennifer McAdow;Diego E Rincon-Limas;Xin Yin;Wanbo Tai;Gong Cheng;Aaron Johnson - bioRxiv : the preprint server for biology (2022)
8. Make and break the alarmone: regulation of (p)ppGpp synthetase/hydrolase enzymes in bacteria. - Séverin Ronneau;Régis Hallez - FEMS microbiology reviews (2019)
9. Triggering the stringent response: signals responsible for activating (p)ppGpp synthesis in bacteria. - Sophie E Irving;Rebecca M Corrigan - Microbiology (Reading, England) (2018)
10. Two compounds implicated in the function of the RC gene of Escherichia coli. - M Cashel;J Gallant - Nature (1969)

Literatures Citing This Work

1. The HrpG/HrpX Regulon of Xanthomonads-An Insight to the Complexity of Regulation of Virulence Traits in Phytopathogenic Bacteria. - Doron Teper;Sheo Shankar Pandey;Nian Wang - Microorganisms (2021)
2. Proteomic Analysis Identifies Dysregulated Proteins in Butanol-Tolerant Gram-Positive Lactobacillus mucosae BR0713-33. - Siqing Liu;Nasib Qureshi;Kenneth Bischoff;Costel C Darie - ACS omega (2021)
3. Homology Model of a Catalytically Competent Bifunctional Rel Protein. - Monica Civera;Sara Sattin - Frontiers in molecular biosciences (2021)
4. The Dynamic SecYEG Translocon. - Julia Oswald;Robert Njenga;Ana Natriashvili;Pinku Sarmah;Hans-Georg Koch - Frontiers in molecular biosciences (2021)
5. Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis. - N Y Elizabeth Chau;Shehryar Ahmad;John C Whitney;Brian K Coombes - PLoS pathogens (2021)
6. C Group-Mediated Antibiotic Stress Mimics the Cold Shock Response. - Evieann Cardoza;Harinder Singh - Current microbiology (2021)
7. NirD curtails the stringent response by inhibiting RelA activity in Escherichia coli. - Loïc Léger;Deborah Byrne;Paul Guiraud;Elsa Germain;Etienne Maisonneuve - eLife (2021)
8. Digital Insights Into Nucleotide Metabolism and Antibiotic Treatment Failure. - Allison J Lopatkin;Jason H Yang - Frontiers in digital health (2021)
9. Sphingobacterium pedocola sp. nov. a novel halotolerant bacterium isolated from agricultural soil. - Ákos Tóth;Ildikó Bata-Vidács;Judit Kosztik;Rózsa Máté;József Kutasi;Erika Tóth;Károly Bóka;András Táncsics;István Nagy;Gábor Kovács;József Kukolya - Antonie van Leeuwenhoek (2021)
10. The Alarmone (p)ppGpp Regulates Primer Extension by Bacterial Primase. - Christina N Giramma;McKenna B DeFoer;Jue D Wang - Journal of molecular biology (2021)

... (184 more literatures)

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