Enhanced uptake of potassium or glycine betaine or export of cyclic-di-AMP restores osmoresistance in a high cyclic-di-AMP Lactococcus lactis mutant
Open accessAbstract
The broadly conserved bacterial signalling molecule cyclic-di-adenosine monophosphate (c-di-AMP) controls osmoresistance via its regulation of potassium (K+) and compatible solute uptake. High levels of c-di-AMP resulting from inactivation of c-di-AMP phosphodiesterase activity leads to poor growth of bacteria under high osmotic conditions. To better understand how bacteria can adjust in response to excessive c-di-AMP levels and to identify signals that feed into the c-di-AMP network, we characterised genes identified in a screen for osmoresistant suppressor mutants of the high c-di-AMP Lactococcus ΔgdpP strain. Mutations were identified which increased the uptake of osmoprotectants, including gain-of-function mutations in a Kup family K+ importer (KupB) and inactivation of the glycine betaine transporter transcriptional repressor BusR. The KupB mutations increased the intracellular K+ level while BusR inactivation increased the glycine betaine level. In addition, BusR was found to directly bind c-di-AMP and repress expression of the glycine betaine transporter in response to elevated c-di-AMP. Interestingly, overactive KupB activity or loss of BusR triggered c-di-AMP accumulation, suggesting turgor pressure changes act as a signal for this second messenger. In another group of suppressors, overexpression of an operon encoding an EmrB family multidrug resistance protein allowed cells to lower their intracellular level of c-di-AMP through active export. Lastly evidence is provided that c-di-AMP levels in several bacteria are rapidly responsive to environmental osmolarity changes. Taken together, this work provides evidence for a model in which high c-di-AMP containing cells are dehydrated due to lower K+ and compatible solute levels and that this osmoregulation system is able to sense and respond to cellular water stress.
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A pgpH gdpP double mutant accumulates toxic levels of c-di-AMP, and this strain rapidly picks up suppressors.
“A pgpH gdpP double mutant accumulates toxic levels of c-di-AMP, and this strain rapidly picks up suppressors (38, 39).”
From A Central Role for Magnesium Homeostasis during Adaptation to Osmotic Stress (2022) · cites this paper as [39]
The Results section on suppressor mutations describes a high-c-di-AMP ΔgdpP strain and reports 212 osmoresistant suppressors. The cited paper studies this single mutant, not a pgpH gdpP double mutant; its Genetic manipulation of strains section says mutations can arise during prolonged subculture, but does not establish that the double mutant rapidly acquires suppressors or that its c-di-AMP levels are toxic. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe pgpH gdpP double mutant was not rescued by glycine betaine.
“Interestingly, and consistent with the established inhibition of compatible solute import by c-di-AMP (35, 39, 40), the pgpH gdpP double mutant was not rescued by GB (Fig. S4B).”
From A Central Role for Magnesium Homeostasis during Adaptation to Osmotic Stress (2022) · cites this paper as [39]
The Results section on BusR and glycine betaine uptake reports reduced glycine betaine in a Lactococcus lactis ΔgdpP mutant, but does not report a pgpH gdpP double mutant or test whether glycine betaine rescues it. A search for pgpH in our copy found no passage addressing that mutant. In the citing sentence, the source appears to support the background point about inhibited solute import; the non-rescue result is attributed to the citing paper’s Fig. S4B. (LLM, conf=0.76)
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Nucleotides as Bacterial Second Messengers
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The many roles of cyclic di-AMP to control the physiology of Bacillus subtilis
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Bacterial second messenger cyclic di‐AMP in streptococci
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Modeling control and transduction of electrochemical gradients in acid-stressed bacteria
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Onward and [K + ]Upward: a New Potassium Importer under the Spell of Cyclic di-AMP
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The substrate-binding domains of the osmoregulatory ABC importer OpuA transiently interact
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Putative nucleotide-based second messengers in archaea
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Second messenger signaling in Clostridioides difficile
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Characterization of c‐di‐AMP signaling in the periodontal pathobiont, Treponema denticola
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Self-citationMembrane-embedded CdaA is required for efficient synthesis of second messenger cyclic di-AMP
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Self-citationThe substrate-binding domains of the osmoregulatory ABC importer OpuA physically interactPreprint
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The Bacterial Second Messenger Cyclic di-AMP and Inflammation
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Proteomic Analysis of Lactococcus lactis FM03 Under Prolonged Alkaline Stress
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The substrate-binding domains of the osmoregulatory ABC importer OpuA transiently interact
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Osmoregulation via Cyclic di-AMP Signaling
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The substrate-binding domains of the osmoregulatory ABC importer OpuA transiently interactPreprint
van den Noort, M., Drougkas, P., Paulino, C., & Poolman, B. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.13.548808 · Cited by 1 · see citing works
Structural and biochemical characterization of c-di-AMP synthesizing enzymes
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A rationally designed c-di-AMP FRET biosensor to monitor nucleotide dynamicsPreprint
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Self-citationStructure-based Search for novel c-di-AMP Synthase Inhibiting Fragments
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Cyclic Di‐ AMP Affects Cell Membrane Integrity of Streptococcus pneumoniae
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Self-citationMg2+, ATP, and the Control of Bacterial Metabolism
Pokorzynski, N. D., & Groisman, E. A. (2026) · Annual Review of Microbiology · doi:10.1146/annurev-micro-041326-012651
- Authors
- Pham, H. T., Nhiep, N. T. H., Vu, T. N. M., Huynh, T. N., Zhu, Y., Huynh, A. L. D., Chakrabortti, A., Marcellin, E., Lo, R., Howard, C. B., Bansal, N., Woodward, J. J., Liang, Z.-X., & Turner, M. S.
- Affiliations
- The University of Queensland (AU)
- University of Washington (US)
- Monash University (AU)
- Nanyang Technological University (SG)
- Corresponding author
- Turner, Mark S.
- ORCID
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-08-03
- Volume
- 14
- Issue
- 8
- Pages
- e1007574
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC6108528
- OpenAlex
- W2886104063
- Cited by
- 75
- References
- 54
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 16 · 2022: 5 · 2021: 12 · 2020: 12 · 2019: 12 · 2018: 1
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Update notices
- new_version (2018-08-24)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Greater South Information System
- Funders
- Australian Research Council (LP120100282)
- Ministry of Education - Singapore (M4020112)
- National Institutes of Health (R01AI116669)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- cyclic di-AMP, osmoregulation, Lactococcus lactis, potassium uptake, betaine, osmolytes, suppressor mutants, turgor pressure, water stress, second messenger signaling
- MeSH terms
- Cyclic AMP, Adenosine Monophosphate, Bacterial Proteins, Betaine, Mutation, Operon, Osmolar Concentration, Potassium, Lactococcus lactis, Second Messenger Systems, Gene Expression Regulation, Bacterial, Osmoregulation
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