Key Points
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Alphaproteobacteria are Gram-negative bacteria that have heterogeneous lifestyles, including aquatic and soil-dwelling lineages, endosymbionts, pathogens of plants, arthropods or mammals, as well as the ancestors of eukaryotic mitochondria.
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The phosphorylated guanosines cyclic di-GMP (c-di-GMP), and guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as (p)ppGpp) act as antagonistic second messengers that control the progression of the cell cycle in Alphaproteobacteria.
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The intracellular concentration of c-di-GMP surges at the G1–S transition of the cell cycle in Caulobacter crescentus to stimulate the initiation of DNA replication, and c-di-GMP coordinates remodelling of the differentiating pole.
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c-di-GMP regulates the proteolytic degradation of key regulators of the cell cycle.
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The alarmone (p)ppGpp promotes the swarmer phase of C. crescentus cells by delaying the initiation of DNA replication and polar differentiation.
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The alarmone is crucial for several Rhizobiales to sustain symbiotic or pathogenic relationships with their respective eukaryotic host cells.
Abstract
The class Alphaproteobacteria includes Gram-negative free-living, symbiotic and obligate intracellular bacteria, as well as important plant, animal and human pathogens. Recent work has established the key antagonistic roles that phosphorylated guanosines, cyclic-di-GMP (c-di-GMP) and the alarmones guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as (p)ppGpp), have in the regulation of the cell cycle in these bacteria. In this Review, we discuss the insights that have been gained into the regulation of the initiation of DNA replication and cytokinesis by these second messengers, with a particular focus on the cell cycle of Caulobacter crescentus. We explore how the fluctuating levels of c-di-GMP and (p)ppGpp during the progression of the cell cycle and under conditions of stress control the synthesis and proteolysis of key regulators of the cell cycle. As these signals also promote bacterial interactions with host cells, the enzymes that control (p)ppGpp and c-di-GMP are attractive antibacterial targets.
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Acknowledgements
R.H. is a research associate of the Fond de la Recherche Scientifique-FNRS (F.R.S.-FNRS). P.H.V. is supported by the Swiss National Science Foundation (grants CRSII3_160703 and 31003A_162716) and the Département de l'Instruction Publique du Canton de Genève.
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Glossary
- Endosymbionts
-
Organisms that live inside other organisms with which they sustain biological interactions.
- Magic spot
-
The first visualization of (p)ppGpp, which appeared as a spot on a thin-layer chromatogram of radiolabelled nucleotides extracted from Escherichia coli cells that were starved of amino acids.
- Holdfast
-
An adhesive material that is located at the tip of the stalk and is composed of proteins and polysaccharides.
- Stalk
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An extension of the cell envelope that is constructed at the flagellated pole of Caulobacter crescentus following differentiation, when the flagellum is ejected and the polar pili are retracted.
- Exponential phase
-
A growth phase during which the nutrients are not limiting, which enables the number of microorganisms to increase exponentially and at a constant growth rate.
- Stationary phase
-
A growth phase during which a growth-limiting factor emerges that results in the number of microorganisms remaining roughly constant.
- Fluorescence resonance energy transfer
-
(FRET). A phenomenon by which the energy of a fluorophore (donor) after excitation is transferred to another fluorophore (acceptor), so that the second one will emit fluorescence without being directly excited. This technique is useful for measuring interactions between molecules in vivo.
- Phosphodiesterase
-
An enzyme that breaks phosphodiester bonds in cyclic nucleotides.
- Per–Arnt–Sim domains
-
(PAS domains). Domains that are commonly found at the amino-terminal extremity of signalling proteins and are involved in the binding of a range of small ligands, such as metabolites.
- FtsZ cytokinetic tubulin
-
FtsZ is a tubulin-like GTPase that is involved in cytokinesis in almost all bacteria. Following GTP binding, FtsZ monomers self-assemble to generate a ring-like structure at the division site, where it acts not only as a recruitment platform for cell division proteins but also as an coordinator of cell wall synthesis at the septum.
- Basal body
-
A protein complex that is found at the base of a bacterial flagellum and is composed of several ring-like structures, each of which is associated with, embedded or anchored in one layer of the cell envelope.
- Cyclic GMP phosphodiesterase–adenylyl cyclase–FhlA domain
-
(GAF domain). A domain that is commonly found in enzymes and is involved in the binding of a range of small ligands, such as metabolites.
- Symbiotic relationship
-
Biological interactions between two organisms, in which neither (amensalism), one (commensalism or parasitism) or both organisms (mutualism) benefit from the interactions.
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Hallez, R., Delaby, M., Sanselicio, S. et al. Hit the right spots: cell cycle control by phosphorylated guanosines in alphaproteobacteria. Nat Rev Microbiol 15, 137–148 (2017). https://doi.org/10.1038/nrmicro.2016.183
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DOI: https://doi.org/10.1038/nrmicro.2016.183
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