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

Biozentrum of the University of Basel, Klingelbergstrasse 50, CH-4054 Basel, Switzerland.
Molecular cell (Impact Factor: 14.02). 08/2011; 43(4):550-60. DOI: 10.1016/j.molcel.2011.07.018
Source: PubMed


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.

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    • "Our results show that the abundance of NstA during the cell cycle is regulated at the post-translational level by the protease ClpXP. Interestingly, ClpXP does not act on NstA at the same time point in the cell cycle as that seen for CtrA (Fig. 2A), KidO, or PdeA, which are known to be degraded by ClpXP during the G1 → S transition (Domian et al. 1997; Radhakrishnan et al. 2010; Abel et al. 2011). Rather, NstA is proteolized during the S → G2 time interval in a fashion similar to that recently reported for the divisome component FtsZ (Williams et al. 2014). "
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    ABSTRACT: Topoisomerase IV (topo IV), an essential factor during chromosome segregation, resolves the catenated chromosomes at the end of each replication cycle. How the decatenating activity of the topo IV is regulated during the early stages of the chromosome cycle despite being in continuous association with the chromosome remains poorly understood. Here we report a novel cell cycle-regulated protein in Caulobacter crescentus, NstA (negative switch for topo IV decatenation activity), that inhibits the decatenation activity of the topo IV during early stages of the cell cycle. We demonstrate that in C. crescentus, NstA acts by binding to the ParC DNA-binding subunit of topo IV. Most importantly, we uncover a dynamic oscillation of the intracellular redox state during the cell cycle, which correlates with and controls NstA activity. Thus, we propose that predetermined dynamic intracellular redox fluctuations may act as a global regulatory switch to control cellular development and cell cycle progression and may help retain pathogens in a suitable cell cycle state when encountering redox stress from the host immune response. © 2015 Narayanan et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 06/2015; 29(11):1175-87. DOI:10.1101/gad.257030.114 · 10.80 Impact Factor
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    • "The PA4843 gene up-regulated 3-4-fold in both par mutant strains encodes a protein classified into TCRS containing response regulator with a CheY-like receiver domain important in sensing signals from the environment and a GGDEF domain. It shows 50% similarity to pleD gene product responding to c-di-GMP level required for the swarmer-to-stalked-cell transition in C. crescentus [59]. "
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    ABSTRACT: Accurate chromosome segregation to progeny cells is a fundamental process ensuring proper inheritance of genetic material. In bacteria with simple cell cycle, chromosome segregation follows replication initiation since duplicated oriC domains start segregating to opposite halves of the cell soon after they are made. ParA and ParB proteins together with specific DNA sequences are parts of the segregation machinery. ParA and ParB proteins in Pseudomonas aeruginosa are important for optimal growth, nucleoid segregation, cell division and motility. Comparative transcriptome analysis of parA null and parB null mutants versus parental P. aeruginosa PAO1161 strain demonstrated global changes in gene expression pattern in logarithmically growing planktonic cultures. The set of genes similarly affected in both mutant strains is designated Par regulon and comprises 536 genes. The Par regulon includes genes controlled by two sigma factors (RpoN and PvdS) as well as known and putative transcriptional regulators. In the absence of Par proteins, a large number of genes from RpoS regulon is induced, reflecting the need for slowing down the cell growth rate and decelerating the metabolic processes. Changes in the expression profiles of genes involved in c-di-GMP turnover point out the role of this effector in such signal transmission. Microarray data for chosen genes were confirmed by RT-qPCR analysis. The promoter regions of selected genes were cloned upstream of the promoter-less lacZ gene and analyzed in the heterologous host E. coliΔlac. Regulation by ParA and ParB of P. aeruginosa was confirmed for some of the tested promoters. Our data demonstrate that ParA and ParB besides their role in accurate chromosome segregation may act as modulators of genes expression. Directly or indirectly, Par proteins are part of the wider regulatory network in P. aeruginosa linking the process of chromosome segregation with the cell growth, division and motility.
    PLoS ONE 01/2014; 9(1):e87276. DOI:10.1371/journal.pone.0087276 · 3.23 Impact Factor
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    • "In C. crescentus, DivK inhibits CtrA via DivL/CckA (Biondi et al., 2006b; Tsokos et al., 2011) and triggers c-di-GMP production via PleD (Paul et al., 2008; Abel et al., 2011). If DivJ/DivK function to inhibit CtrA phosphorylation in S. meliloti, deletion of divJ should lead to a more severe/ lethal phenotype when CtrA levels are increased. "
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    ABSTRACT: Sinorhizobium meliloti is a soil bacterium that invades the root nodules it induces on Medicago sativa, whereupon it undergoes an alteration of its cell cycle and differentiates into nitrogen-fixing, elongated and polyploid bacteroid with higher membrane permeability. In Caulobacter crescentus, a related alphaproteobacterium, the principal cell cycle regulator, CtrA, is inhibited by the phosphorylated response regulator DivK. The phosphorylation of DivK depends on the histidine kinase DivJ, while PleC is the principal phosphatase for DivK. Despite the importance of the DivJ in C. crescentus, the mechanistic role of this kinase has never been elucidated in other Alphaproteobacteria. We show here that the histidine kinases DivJ together with CbrA and PleC participate in a complex phosphorylation system of the essential response regulator DivK in S. meliloti. In particular, DivJ and CbrA are involved in DivK phosphorylation and in turn CtrA inactivation, thereby controlling correct cell cycle progression and the integrity of the cell envelope. In contrast, the essential PleC presumably acts as a phosphatase of DivK. Interestingly, we found that a DivJ mutant is able to elicit nodules and enter plant cells, but fails to establish an effective symbiosis suggesting that proper envelope and/or low CtrA levels are required for symbiosis.
    Molecular Microbiology 07/2013; 90(1). DOI:10.1111/mmi.12347 · 4.42 Impact Factor
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