Regulatory Cohesion of Cell Cycle and Cell Differentiation through Interlinked Phosphorylation and Second Messenger Networks

SummaryIn 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.

► Coordinate action of the DGCs PleD and DgcB control Caulobacter cell cycle and development ► The PDE PdeA opposes DgcB and thereby determines the swarmer cell-specific program ► Cell cycle-dependent degradation of PdeA releases its antagonist DgcB ► CpdR plays a dual role as protease localization factor and adaptor for PdeA