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Regulatory cohesion of cell cycle and cell differentiation through interlinked phosphorylation and second messenger networks.

ABSTRACT: In Caulobacter crescentus, phosphorylation of key regulators is coordinated with the second messenger cyclic di-GMP to drive cell-cycle progression and differentiation. The diguanylate cyclase PleD directs pole morphogenesis, while the c-di-GMP effector PopA initiates degradation of the replication inhibitor CtrA by the AAA+ protease ClpXP to license S phase entry. Here, we establish a direct link between PleD and PopA reliant on the phosphodiesterase PdeA and the diguanylate cyclase DgcB. PdeA antagonizes DgcB activity until the G1-S transition, when PdeA is degraded by the ClpXP protease. The unopposed DgcB activity, together with PleD activation, upshifts c-di-GMP to drive PopA-dependent CtrA degradation and S phase entry. PdeA degradation requires CpdR, a response regulator that delivers PdeA to the ClpXP protease in a phosphorylation-dependent manner. Thus, CpdR serves as a crucial link between phosphorylation pathways and c-di-GMP metabolism to mediate protein degradation events that irreversibly and coordinately drive bacterial cell-cycle progression and development.

PROVIDER: S-EPMC3298681 | BioStudies |

REPOSITORIES: biostudies

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Project description:The DivJ-DivK-PleC signaling system of Caulobacter crescentus is a signaling network that regulates polar development and the cell cycle. This system is conserved in related bacteria, including the sister genus Brevundimonas Previous studies had shown unexpected phenotypic differences between the C. crescentus divK mutant and the analogous mutant of Brevundimonas subvibrioides, but further characterization was not performed. Here, phenotypic assays analyzing motility, adhesion, and pilus production (the latter characterized by a newly discovered bacteriophage) revealed that divJ and pleC mutants have phenotypes mostly similar to their C. crescentus homologs, but divK mutants maintain largely opposite phenotypes than expected. Suppressor mutations of the B. subvibrioides divK motility defect were involved in cyclic di-GMP (c-di-GMP) signaling, including the diguanylate cyclase dgcB, and cleD which is hypothesized to affect flagellar function in a c-di-GMP dependent fashion. However, the screen did not identify the diguanylate cyclase pleD Disruption of pleD in B. subvibrioides caused no change in divK or pleC phenotypes, but did reduce adhesion and increase motility of the divJ strain. Analysis of c-di-GMP levels in these strains revealed incongruities between c-di-GMP levels and displayed phenotypes with a notable result that suppressor mutations altered phenotypes but had little impact on c-di-GMP levels in the divK background. Conversely, when c-di-GMP levels were artificially manipulated, alterations of c-di-GMP levels in the divK strain had minimal impact on phenotypes. These results suggest that DivK performs a critical function in the integration of c-di-GMP signaling into the B. subvibrioides cell cycle.IMPORTANCE Cyclic di-GMP and associated signaling proteins are widespread in bacteria, but their role in physiology is often complex and difficult to predict through genomic level analyses. In C. crescentus, c-di-GMP has been integrated into the developmental cell cycle, but there is increasing evidence that environmental factors can impact this system as well. The research presented here suggests that the integration of these signaling networks could be more complex than previously hypothesized, which could have a bearing on the larger field of c-di-GMP signaling. In addition, this work further reveals similarities and differences in a conserved regulatory network between organisms in the same taxonomic family, and the results show that gene conservation does not necessarily imply close functional conservation in genetic pathways.

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Regulatory cohesion of cell cycle and cell differentiation through interlinked phosphorylation and second messenger networks.

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