A phospho-signaling pathway controls the localization and activity of a protease complex critical for bacterial cell cycle progression

Iniesta, Antonio A.; McGrath, Patrick T.; Reisenauer, Ann; McAdams, Harley H.; Shapiro, Lucy

doi:10.1073/pnas.0604554103

Cited by 190 publications

(292 citation statements)

References 38 publications

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“…To control the timing of CtrA function, the cell regulates both CtrA activity, by controlling its phosphorylation state, and CtrA accumulation, by inhibiting ctrA transcription upon DNA remethylation of newly replicated chromosomes (11), and by the temporal regulation of CtrA proteolysis (12,13). We report here that SciP (CC0903), also identified by Gora et al (14), provides another layer of control.…”

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confidence: 84%

An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation

Tan

Kozdon

Shen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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118

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A cyclical control circuit composed of four master regulators drives the Caulobacter cell cycle. We report that SciP, a helix-turn-helix transcription factor, is an essential component of this circuit. SciP is cell cycle-controlled and co-conserved with the global cell cycle regulator CtrA in the α-proteobacteria. SciP is expressed late in the cell cycle and accumulates preferentially in the daughter swarmer cell. At least 58 genes, including many flagellar and chemotaxis genes, are regulated by a type 1 incoherent feedforward motif in which CtrA activates sciP, followed by SciP repression of ctrA and CtrA target genes. We demonstrate that SciP binds to DNA at a motif distinct from the CtrA binding motif that is present in the promoters of genes co-regulated by SciP and CtrA. SciP overexpression disrupts the balance between activation and repression of the CtrASciP coregulated genes yielding filamentous cells and loss of viability. The type 1 incoherent feedforward circuit motif enhances the pulse-like expression of the downstream genes, and the negative feedback to ctrA expression reduces peak CtrA accumulation. The presence of SciP in the control network enhances the robustness of the cell cycle to varying growth rates.CtrA | feedback | genetic circuit

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confidence: 84%

An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation

Tan

Kozdon

Shen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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118

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“…The tacA translation product along with 54 -containing RNA polymerase (E 54 ) catalyzes transcription of spmX and staR, the gene for a transcriptional regulator of stalk biogenesis (Biondi et al 2006b). At the swarmer-to-stalked cell transition, SpmX accumulates to localize and activate DivJ (event 2), thereby producing a surge in DivK∼P that signals the removal of CtrA∼P by a complex phosphosignaling cascade (Biondi et al 2006a;Iniesta et al 2006). This event, coupled with the disappearance of TacA at the swarmer-to-stalked cell transition (see Fig.…”

Section: Figure 1 Graphical Representation Of the Cell Fate Regulatomentioning

confidence: 99%

“…1A; Domian et al 1997), and DivK controls both these events. In the stalked cell, DivK∼P triggers the removal of phosphorylated CtrA (CtrA∼P) (Hung and Shapiro 2002;Biondi et al 2006a;Iniesta et al 2006). In the swarmer cell, CtrA∼P represses DNA replication by binding to five target sites within the chromosomal origin of replication (Cori) (Quon et al 1998).…”

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confidence: 99%

The dynamic interplay between a cell fate determinant and a lysozyme homolog drives the asymmetric division cycle of Caulobacter crescentus

Radhakrishnan¹,

Thanbichler

Viollier³

2008

Genes Dev.

138

233

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Caulobacter crescentus divides asymmetrically into a swarmer cell and a stalked cell, a process that is governed by the imbalance in phosphorylated levels of the DivK cell fate determinant in the two cellular compartments. The asymmetric polar localization of the DivJ kinase results in its specific inheritance in the stalked daughter cell where it phosphorylates DivK. The mechanism for the polar positioning of DivJ is poorly understood. SpmX, an uncharacterized lysozyme homolog, is shown here to control DivJ localization and activation. In the absence of SpmX, DivJ is delocalized and dysfunctional, resulting in developmental defects caused by an insufficiency in phospho-DivK. While SpmX stimulates DivK phosphorylation in the stalked cell, unphosphorylated DivK in the swarmer cell activates an intricate transcriptional cascade that leads to the production of the spmX message. This event primes the swarmer cell for the impending transition into a stalked cell, a transition that is sparked by the abrupt accumulation and localization of SpmX to the future stalked cell pole. Localized SpmX then recruits and stimulates DivJ, and the resulting phospho-DivK implements the stalked cell fate. The dynamic interplay between SpmX and DivK is at the heart of the molecular circuitry that sustains the Caulobacter developmental cycle.[Keywords: Asymmetric cell division; cell fate determinant; polar protein localization; muramidase; kinase] Supplemental material is available at http://www.genesdev.org.

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“…1 C and D and Fig. S1), mechanisms of the pathway are not completely identified, but the function of the pathway and the timing of its operation within the cell cycle are well characterized (14). Similarly, the time from onset to completion of DNA replication and the time from initial cell constriction to compartmentalization are known (19).…”

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confidence: 99%

“…S1 show feedback signal pathways from these two controlled subsystems to the core circuit to tie the rate of progression of the core circuit to the progression of the cell cycle. The cell-cycle control system is synchronized tightly with the progression of chromosome replication and cytokinesis by both genetic and nongenetic mechanisms (8,14). The rates of progress of the parallel independent reaction cascades are inherently unpredictable, but some pathways must be completed in a particular order.…”

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confidence: 99%

Architecture and inherent robustness of a bacterial cell-cycle control system

Shen

Collier

Dill

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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A closed-loop control system drives progression of the coupled stalked and swarmer cell cycles of the bacterium Caulobacter crescentus in a near-mechanical step-like fashion. The cell-cycle control has a cyclical genetic circuit composed of four regulatory proteins with tight coupling to processive chromosome replication and cell division subsystems. We report a hybrid simulation of the coupled cell-cycle control system, including asymmetric cell division and responses to external starvation signals, that replicates mRNA and protein concentration patterns and is consistent with observed mutant phenotypes. An asynchronous sequential digital circuit model equivalent to the validated simulation model was created. Formal model-checking analysis of the digital circuit showed that the cell-cycle control is robust to intrinsic stochastic variations in reaction rates and nutrient supply, and that it reliably stops and restarts to accommodate nutrient starvation. Model checking also showed that mechanisms involving methylationstate changes in regulatory promoter regions during DNA replication increase the robustness of the cell-cycle control. The hybrid cell-cycle simulation implementation is inherently extensible and provides a promising approach for development of whole-cell behavioral models that can replicate the observed functionality of the cell and its responses to changing environmental conditions. Caulobacter ͉ model ͉ regulatory circuit ͉ hybrid system ͉ symbolic model checking T he identification of regulatory pathways controlling the cell cycle of the bacterium Caulobacter crescentus has progressed to the point that an experimentally based system-level characterization of the cell-cycle control circuit is available. Aspects of the cyclical circuit that drives progression of the C. crescentus cell cycle are described in recent papers (1-5). Recent findings have identified novel mechanisms providing signals that tightly integrate the biochemical and genetic components of the core cell-cycle circuit with the 3D topology of the cell (4, 6, 7) and DNA replication (8).Many of the regulatory mechanisms and pathways in the C. crescentus cell-cycle circuit operate very rapidly so that they approximate discrete switching elements, whereas others, e.g., the transcriptional regulatory networks, operate relatively slowly. This suggested use of hybrid control analysis methods (9-13) to simulate this cell-cycle control system and formal analysis methods to analyze its properties. Hybrid control systems, by definition, include both continuous and discrete regulatory mechanisms (9). We constructed a hybrid control system simulation model and derived an equivalent asynchronous discrete circuit model from the simulation model. The analysis showed that the cell-cycle control is robust and that DNA methylation-based cell-cycle regulatory mechanisms (8) enhance robustness of the cell cycle.C. crescentus always divides asymmetrically, producing morphologically distinct daughters (Fig. 1A), so it is a model system not only for bacte...

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A phospho-signaling pathway controls the localization and activity of a protease complex critical for bacterial cell cycle progression

Cited by 190 publications

References 38 publications

An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation

An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation

The dynamic interplay between a cell fate determinant and a lysozyme homolog drives the asymmetric division cycle of Caulobacter crescentus

Architecture and inherent robustness of a bacterial cell-cycle control system

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