Insight into a Mechanism Generating Cyclic di-GMP Heterogeneity in Pseudomonas aeruginosa
Kulasekara, Bridget R.
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Phenotypic heterogeneity is a commonly observed phenomenon in cell populations that can provide a selective advantage within diverse, unpredictable conditions. Second messenger-based signaling, having a global impact on cellular physiology, can be a mechanism by which environmental signals are rapidly translated into phenotypic heterogeneity. However, such mechanisms for generating phenotypic heterogeneity have yet to be described for many cell types, including bacteria. In biology heterogeneity within populations is often overlooked, as most biochemical characterizations utilize bulk populations of cells for analyzes. The second messenger c-di-GMP (CDG) regulates diverse bacterial processes, including cell-cycle progression, motility, and exopolysaccharide production, and in human cells, innate immunity. Previously, using a FRET-based biosensor and microscopy, we observed that individual bacterial cells demonstrated heterogeneity in CDG levels within populations; however the precise mechanism by which this diversity is generated was unknown. Here we show that CDG heterogeneity in <italic>Pseudomonas aeruginosa</italic> is promoted by a CDG specific phosphodiesterase partitioned after cell division by the chemotaxis machinery. We found that reduction of CDG levels by this phosphodiesterase is dependent on components of the chemotaxis machinery, including the histidine kinase CheA. We observed that both the chemotaxis machinery and the phosphodiesterase are partitioned predominantly into the flagellated progeny. The phosphorylation of CheA is required for phosphodiesterase activity, indicating that chemotaxis signals could affect CDG degradation, thereby altering bacterial motility. Our work demonstrates that cellular heterogeneity can be generated through a second messenger whose concentration is regulated by a combination of environmental signals and the asymmetrical inheritance of organelles. Second messenger heterogeneity is likely an important mechanism for many biological processes occurring in a variety of cell types, including malignant cells, immune cells, and single cell organisms.