A Kinase-Phosphatase Switch Transduces Environmental Information into a Bacterial Cell Cycle Circuit

Heinrich, Kristina; Sobetzko, Patrick; Jonas, Kristina

doi:10.1371/journal.pgen.1006522

Cited by 35 publications

(34 citation statements)

References 54 publications

(112 reference statements)

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“…However, when PopZ is deleted, CckA predominantly functions as a phosphatase, resulting in dephosphoryation of CpdR and constitutively activation of adaptor dependent ClpXP proteolysis. Interestingly, recent work shows that certain stresses lead to rapid clearance of CtrA through a switch in CckA to its phosphatase state without changes in CckA localization (35), further supporting the critical role in CckA activity rather than its localization per se in controlling CtrA degradation.…”

Section: Discussionmentioning

confidence: 88%

The polar localization hub protein PopZ restrains adaptor dependent ClpXP proteolysis inCaulobacter crescentus

Joshi

2018

Preprint

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24In Caulobacter crescentus, timely degradation of several proteins by the ClpXP 25 protease is critical for proper cell cycle progression. During the cell cycle, the 26 ClpXP protease, the substrate CtrA and many other proteins are localized to the 27 stalked pole dependent on a polar interaction hub composed of PopZ protein 28 oligomers. Prior work suggests that the localization of ClpXP, protease 29 substrates, and cofactors is needed for recognition of substrates such as CtrA by 30ClpXP. Here, we formally test this hypothesis by examining the role of PopZ in 31ClpXP activity and find surprisingly that CtrA degradation is enhanced in cells 32 lacking polar localization due to loss of PopZ. The ClpXP adaptor CpdR is 33 required for this enhanced degradation of CtrA and other adaptor-dependent 34substrates, but adaptor-independent substrate degradation is not affected upon 35 loss of PopZ. We find that overexpression of PopZ also leads to faster 36 degradation of CtrA, but is likely due to nonphysiologically relevant recognition of 37CtrA by ClpXP alone as loss of CpdR does not affect this enhancement. Our 38 main conclusion is that loss of PopZ, and therefore loss of polar localization, 39 does not result in the loss of ClpXP regulated proteolysis, as would be predicted 40 from a model which requires polar localization of ClpXP for its activation. Rather, 41 our data point to a model where PopZ normally restrains ClpXP proteolysis by 42 promoting the inactivation of the CpdR adaptor, likely through the 43 phosphorylation activity of the CckA kinase. 44 45 46 IMPORTANCE 47 Regulated proteolysis is critical for the cell cycle progression of bacteria such as 48 Caulobacter crescentus. According to one model, this regulated proteolysis 49 requires localization of the ClpXP protease at the stalked pole for its subsequent 50 degradation of substrates such as CtrA. This study offers evidence that supports 51 an alternative model to explain how localization might influence protein 52 degradation. Using a delocalized in vivo system created by the deletion of a pole 53 organizing protein PopZ, we show that activation of the ClpXP protease is 54 independent of its polar localization. The data points to a role for PopZ in 55 restraining ClpXP activity, likely by controlling the activity of upstream regulators 56 of protease activity, such as CckA, though changes in its localization. 57 58

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Section: Discussionmentioning

confidence: 88%

The polar localization hub protein PopZ restrains adaptor dependent ClpXP proteolysis inCaulobacter crescentus

Joshi

2018

Preprint

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“…Thus, an elaborate cell cycle program that controls CtrA abundance in time and space is sufficiently explained by these accessory factors. However, it is possible that additional factors also play a part in modulating CtrA stability under stress conditions (Heinrich et al, 2016). Anti-adaptor model.…”

Section: Regulation Of Ctramentioning

confidence: 99%

Regulation of replication initiation: lessons from <i>Caulobacter crescentus</i>

Ozaki

2019

Genes Genet. Syst.

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Chromosome replication is a fundamental process in all domains of life. To accurately transmit genetic material to offspring, the initiation of chromosome replication is tightly regulated to ensure that it occurs only once in each cell division cycle. In the model bacterium Caulobacter crescentus, the CtrA response regulator inhibits the origin of replication at the pre-replication stage. Inactivation of CtrA permits the universal DnaA initiator to form an initiation complex at the origin, leading to replication initiation. Subsequently, the initiation complex is inactivated to prevent extra initiation. Whereas DNA replication occurs periodically in exponentially growing cells, replication initiation is blocked under various stress conditions to halt cell cycle progression until the normal condition is restored or the cells adapt to the stress. Thus, regulating the initiation complex plays an important role in not only driving cell cycle progression, but also maintaining cell integrity under stress. Multiple regulatory signaling pathways controlling CtrA and DnaA have been identified and recent studies have advanced our knowledge of the underlying mechanistic and molecular processes. This review focuses on how bacterial cells control replication initiation, highlighting the latest findings that have emerged from studies in C. crescentus.

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“…Moreover, cells experiencing stress or suboptimal growth conditions respond by adjusting their development and cell cycle progression (3). For instance, when starved for carbon cells respond by blocking cell cycle progression and chromosome replication (4,5). In contrast, C. crescentus cells experiencing heat or ethanol stress respond by over-replicating their chromosomes (5).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, when starved for carbon cells respond by blocking cell cycle progression and chromosome replication (4,5). In contrast, C. crescentus cells experiencing heat or ethanol stress respond by over-replicating their chromosomes (5). While these responses are thought to increase bacterial survival, the underlying molecular mechanisms coordinating the stress response with developmental or reproductive processes remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

A single-domain response regulator functions as integrating hub to coordinate general stress response and development in alpha-proteobacteria

Lori

Kaczmarczyk

Jong

et al. 2018

Preprint

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The alpha-proteobacterial general stress response is governed by a conserved partner-switching mechanism that is triggered by phosphorylation of the response regulator PhyR. In the model organism Caulobacter crescentus PhyR was proposed to be phosphorylated by the histidine kinase PhyK, but biochemical evidence in support of such a role of PhyK is missing. Here, we identify a single-domain response regulator, MrrA, that is essential for general stress response activation in C. crescentus. We demonstrate that PhyK does not function as a kinase but accepts phosphoryl groups from MrrA and passes them on to PhyR, thereby adopting the role of a histidine phosphotransferase. MrrA is phosphorylated by at least six histidine kinases that likely serve as stress sensors. MrrA also transfers phosphate to LovK, a histidine kinase involved in C. crescentus holdfast production and attachment, that also negatively regulates the general stress response. We show that LovK together with the response regulator LovR acts as a phosphate sink to redirect phosphate flux away from the PhyKR branch. In agreement with the biochemical data, a mrrA mutant is unable to activate the general stress response and shows a hyper-attachment phenotype, which is linked to decreased expression of the major holdfast inhibitory protein HfiA. We propose that MrrA serves as a central phosphorylation hub that coordinates the general stress response with C. crescentus development and other adaptive behaviors. The characteristic bow-tie architecture of this phosphorylation network with MrrA as the central knot may expedite the evolvability and species-specific niche adaptation of this group of bacteria. ImportanceTwo-component systems (TCSs) consisting of a histidine kinase and a cognate response regulator are predominant signal transduction systems in bacteria. To avoid cross-talk, TCS are generally thought to be highly insulated from each other. However, this notion is based largely on studies of the HisKA subfamily of histidine kinases, while little information is available for the HWE and HisKA2 subfamilies. The latter have been implicated in the alpha-proteobacterial general stress response. Here, we show that in the model organism Caulobacter crescentus an atypical FATGUY-type single-domain response regulator (SDRR), MrrA, is highly promiscuous both in accepting and transferring phosphoryl groups from and to a number of up-and downstream kinases, challenging the current view of strictly insulated TCSs. Instead, we propose that FATGUY response regulators have evolved in alpha-proteobacteria to serve as central phosphorylation hubs to broadly sample information and distribute phosphoryl groups between the general stress response pathway and other TCSs, thereby coordinating multiple cellular behaviors. This signaling cascade includes presumable histidine kinases harboring intact catalytic and ATP-binding (CA) domains that, however, do not function as kinases, but instead have adopted a role as histidine phosphotransferases. Our work highlights a complex p...

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A Kinase-Phosphatase Switch Transduces Environmental Information into a Bacterial Cell Cycle Circuit

Cited by 35 publications

References 54 publications

The polar localization hub protein PopZ restrains adaptor dependent ClpXP proteolysis inCaulobacter crescentus

The polar localization hub protein PopZ restrains adaptor dependent ClpXP proteolysis inCaulobacter crescentus

Regulation of replication initiation: lessons from <i>Caulobacter crescentus</i>

A single-domain response regulator functions as integrating hub to coordinate general stress response and development in alpha-proteobacteria

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