Dynamic Interaction between the CpxA Sensor Kinase and the Periplasmic Accessory Protein CpxP Mediates Signal Recognition in E. coli

Tschauner, Karolin; Hörnschemeyer, Patrick; Müller, Volker; Hunke, Sabine

doi:10.1371/journal.pone.0107383

Cited by 54 publications

(57 citation statements)

References 56 publications

(106 reference statements)

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“…In some instances (42,43), the accessory proteins increase the number of stimuli capable of influencing the regulatory output of their associated two-component system, enabling a larger range of environments to be distinguished and a greater ability to tailor gene expression to each environment. Here, we discovered that RocA is a major regulator of virulence factor expression in serotype M1 GAS and that this regulatory activity reduces the ability of M1 GAS to survive and proliferate in human blood.…”

Section: Discussionmentioning

confidence: 99%

RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus

et al. 2017

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Regulating gene expression during infection is critical to the ability of pathogens to circumvent the immune response and cause disease. This is true for the group A Streptococcus (GAS), a pathogen that causes both invasive (e.g., necrotizing fasciitis) and noninvasive (e.g., pharyngitis) diseases. The control of virulence (CovRS) two-component system has a major role in regulating GAS virulence factor expression. The regulator of cov (RocA) protein, which is a predicted kinase, functions in an undetermined manner through CovRS to alter gene expression and reduce invasive disease virulence. Here, we show that the ectopic expression of a truncated RocA derivative, harboring the membrane-spanning domains but not the dimerization or HATPase domain, is sufficient to complement a rocA mutant strain. Coupled with a previous bioinformatic study, the data are consistent with RocA being a pseudokinase. RocA reduces the ability of serotype M1 GAS isolates to express capsule and to evade killing in human blood, phenotypes that are not observed for M3 or M18 GAS due to isolates of these serotypes naturally harboring mutant rocA alleles. In addition, we found that varying the RocA concentration attenuates the regulatory activity of Mg 2ϩ and the antimicrobial peptide LL-37, which positively and negatively regulate CovS function, respectively. Thus, we propose that RocA is an accessory protein to the CovRS system that influences the ability of GAS to modulate gene expression in response to host factors. A model of how RocA interacts with CovRS, and of the regulatory consequences of such activity, is presented.

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Section: Discussionmentioning

confidence: 99%

RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus

et al. 2017

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“…Mutations that alter the CpxP surface impair CpxA inhibition and—for at least the D61 residue—even conservative substitutions are not tolerated, hinting at specific biochemical interactions [45-47]. Recently, CpxP-CpxA cross-linking and affinity purifications in vivo have provided evidence supporting direct interaction [48]. But, as CpxP levels in wildtype cells are extremely low, these interaction studies rely on overexpression of both proteins above their physiological levels [48].…”

Section: Stress Sensing By the Cpx Responsementioning

confidence: 99%

“…Recently, CpxP-CpxA cross-linking and affinity purifications in vivo have provided evidence supporting direct interaction [48]. But, as CpxP levels in wildtype cells are extremely low, these interaction studies rely on overexpression of both proteins above their physiological levels [48]. Detecting a dynamic interaction between CpxA and CpxP at native levels remains an ongoing challenge.…”

Section: Stress Sensing By the Cpx Responsementioning

confidence: 99%

Envelope Stress Responses: An Interconnected Safety Net

Grabowicz

Silhavy

2017

Trends in Biochemical Sciences

115

128

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The Escherichia coli cell envelope is a protective barrier at the frontline of interaction with the environment. Fidelity of envelope biogenesis must be monitored to establish and maintain a contiguous barrier. Indeed, the envelope must also be repaired and modified in response to environmental assaults. Envelope stress responses (ESRs) sense envelope damage or defects and alter the transcriptome to mitigate stress. We will review recent insights into stress sensing mechanisms of the σE and Cpx systems and the interaction of these ESRs. Small RNAs (sRNAs) are increasingly prominent regulators of the transcriptional response to stress. These fast-acting regulators also provide avenues for inter-ESR regulation that could be important when cells face multiple contemporaneous stresses, as is the case during infection.

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“…In the absence of an inducing cue, CpxA phosphatase activity maintains CpxR in a dephosphorylated and inactive state (3). The auxiliary regulator CpxP inhibits the Cpx response through direct interaction with the sensing domain of CpxA (9,10).…”

mentioning

confidence: 99%

A Bacterial Stress Response Regulates Respiratory Protein Complexes To Control Envelope Stress Adaptation

et al. 2017

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The Cpx envelope stress response mediates adaptation to stresses that affect protein folding within the envelope of Gram-negative bacteria. Recent transcriptome analyses revealed that the Cpx response impacts genes that affect multiple cellular functions predominantly associated with the cytoplasmic membrane. In this study, we examined the connection between the Cpx response and the respiratory complexes NADH dehydrogenase I and cytochrome bo 3 in enteropathogenic Escherichia coli. We found that the Cpx response directly represses the transcription of the nuo and cyo operons and that Cpx-mediated repression of these complexes confers adaptation to stresses that compromise envelope integrity. Furthermore, we found that the activity of the aerobic electron transport chain is reduced in E. coli lacking a functional Cpx response despite no change in the transcription of either the nuo or the cyo operon. Finally, we show that expression of NADH dehydrogenase I and cytochrome bo 3 contributes to basal Cpx pathway activity and that overproduction of individual subunits can influence pathway activation. Our results demonstrate that the Cpx response gauges and adjusts the expression, and possibly the function, of inner membrane protein complexes to enable adaptation to envelope stress.IMPORTANCE Bacterial stress responses allow microbes to survive environmental transitions and conditions, such as those encountered during infection and colonization, that would otherwise kill them. Enteric microbes that inhabit or infect the gut are exposed to a plethora of stresses, including changes in pH, nutrient composition, and the presence of other bacteria and toxic compounds. Bacteria detect and adapt to many of these conditions by using envelope stress responses that measure the presence of stressors in the outermost compartment of the bacterium by monitoring its physiology. The Cpx envelope stress response plays a role in antibiotic resistance and host colonization, and we have shown that it regulates many functions at the bacterial inner membrane. In this report, we describe a novel role for the Cpx response in sensing and controlling the expression of large, multiprotein respiratory complexes at the cytoplasmic membrane of Escherichia coli. The significance of our research is that it will increase our understanding of how these stress responses are involved in antibiotic resistance and the mechanisms used by bacteria to colonize the gut.KEYWORDS envelope stress response, NADH dehydrogenase I, cytochrome bo 3 , membrane protein biogenesis, Cpx envelope stress response, NADH dehydrogenase, cytochrome oxidase, inner membrane, protein complex, protein folding, protein localization, respiration, two-component regulatory systems G ram-negative bacteria are characterized by the structure of their cell envelope, which consists of the inner membrane (IM), the outer membrane, and the peptidoglycan layer within the periplasmic space. Of these, the IM contains the greatest protein diversity (1). Proteins that reside within the IM...

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Dynamic Interaction between the CpxA Sensor Kinase and the Periplasmic Accessory Protein CpxP Mediates Signal Recognition in E. coli

Cited by 54 publications

References 56 publications

RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus

RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus

Envelope Stress Responses: An Interconnected Safety Net

A Bacterial Stress Response Regulates Respiratory Protein Complexes To Control Envelope Stress Adaptation

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