2025-04-14 イェール大学
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<関連情報>
- https://news.yale.edu/2025/04/14/infection-control-how-pathogen-survives-hostile-environment
- https://www.pnas.org/doi/10.1073/pnas.2424337122
細胞質Mg2+は炭素源嗜好性に優先してサルモネラの代謝を規定する Cytoplasmic Mg2+ supersedes carbon source preference to dictate Salmonella metabolism
Nick D. Pokorzynski, Katarina A. Jones, Shawn R. Campagna, and Eduardo A. Groisman
Proceedings of the National Academy of Sciences Published:March 25, 2025
DOI:https://doi.org/10.1073/pnas.2424337122
Significance
Carbon source preference is critical for bacterial metabolism and physiology. Most microorganisms utilize glucose over other carbon sources when grown in laboratory media with plentiful Mg2+. However, pathogens such as Salmonella enterica serovar Typhimurium experience cytoplasmic Mg2+ starvation during infection of mammalian cells, resulting in alternative carbon sources being preferred over glucose. This altered preference results from cytoplasmic Mg2+ starvation decreasing the amount of the master regulator of carbon utilization, the cyclic adenosine monophosphate (cAMP) receptor protein (CRP) bound to its allosteric activator cAMP, and from the differential sensitivity of carbohydrate utilization genes to a decrease in CRP-cAMP amounts. Our findings explain why behaviors displayed by bacteria in their natural environments do not correspond to those reported for laboratory media.
Abstract
Glucose is the preferred carbon source of most studied microorganisms. However, we now report that glucose loses preferred status when the intracellular pathogen Salmonella enterica serovar Typhimurium experiences cytoplasmic magnesium (Mg2+) starvation. We establish that this infection-relevant stress drastically reduces synthesis of cyclic adenosine monophosphate (cAMP), the allosteric activator of the cAMP receptor protein (CRP), master regulator of carbon utilization. The resulting reduction in cAMP concentration, which is independent of carbon source, decreases transcription of CRP-cAMP-activated carbon utilization genes, hinders carbon source uptake, and restricts metabolism, rendering wild-type bacteria phenotypically CRP–. A cAMP-independent allele of CRP overcame the transcriptional, uptake, and metabolic restrictions caused by cytoplasmic Mg2+ starvation and significantly increased transcription of the glucose uptake gene when S. Typhimurium was inside murine macrophages. The reduced preference for glucose exhibited by S. Typhimurium inside macrophages reflects that transcription of the glucose uptake gene requires higher amounts of active CRP-cAMP than transcription of uptake genes for preferred carbon sources, such as gluconate and glycerol. By reducing CRP-cAMP activity, low cytoplasmic Mg2+ alters carbon source preference, adjusting metabolism and growth.
