The Cpx envelope stress response is mediated by a typical two-component regulatory system consisting of the membrane-localized sensor histidine kinase (HK) CpxA and the cytoplasmic response regulator CpxR (RR). CpxA responds to envelope stresses through autophosphorylation, likely at a conserved histidine residue, and subsequent phosphotransfer to CpxR (24). As with other RRs, this phosphorylation probably occurs at a conserved aspartate residue. Phosphorylation allows CpxR to function as a transcriptional activator of genes whose products are involved in protein folding and degradation in the bacterial envelope (4) (6) (23). Footprint analysis in E.coli suggests that this occurs through binding of phosphorylated CpxR dimers to a conserved direct repeat motif upstream of Cpx-regulated promoters (23). These include the disulfide oxidase DsbA (1, 12); the peptidyl-prolyl-isomerases PpiA (17) and PpiD (5); the protease DegP (13, 14) (16) (27) (28); a small periplasmic protein of unknown function, CpxP (3); and other, as-yet-unidentified regulon members (23).

Based on the studying the Cpx pathway in E.coli, it is clear that the Cpx pathway helps protect the cell from potentially toxic, transitory stresses. For example, the Cpx envelope stress response is induced by elevated pH, and cpx mutants exhibit reduced survival in alkaline environments (3, 21). Similarly, activation of the Cpx pathway can rescue the cell from the expression of potentially toxic mutant envelope proteins (2, 26). It is likely that elevated expression of Cpx-regulated factors is necessary under such conditions to maintain proper protein folding in the bacterial envelope and thus the integrity of the cell.

In addition to its role in protection from envelope stress, several observations suggest that the Cpx envelope stress response plays an important role in the virulence of pathogenic organisms. For example, DsbA is required for the correct folding of a number of pathogenic determinants (9, 22) (29) and degP null mutants are avirulent (10). Further, VirF, a transcriptional activator of genes whose products are necessary for host cell invasion by Shigella species, is a member of the Cpx regulon (21). Finally, the Cpx envelope stress response is centrally involved in monitoring and assisting in the assembly of P pili. A number of Cpx-regulated factors, including DsbA and DegP, are required for the assembly of these extracellular appendages on the surface of uropathogenic Escherichia coli and misfolded pilin subunits lead to activation of the Cpx response (9, 11). Thus, one major role of the Cpx envelope stress response appears to be to monitor and assist in the assembly of pili, and possibly other virulence factors.

Evidence from Wulf's study suggests that the Cpx signal transduction system, in conjunction with sigmaE (rpoE) and sigma32 (rpoH), responds to a broad spectrum of adverse environmental conditions. These include heat shock, high pH, oxidative stress, and nutritional deprivation. The sigmaE stress response appears to play an essential role in outer membrane protein (OMP) folding. Activation of the pathway is triggered by misfolded OMPs (18) and leads to elevated production of at least two factors involved in the folding and degradation of such substrates (4, 7, 15), the peptidyl-prolyl-isomerase FkpA (8) (19) and the periplasmic protease DegP (2, 13, 14, 16) (26) (27)[Strauch, 1989 #24. Activating signals are transduced mainly by relief of an inhibitory interaction between a membrane-localized anti-sigma factor, RseA, and the transcription factor, E, allowing for activation of expression of downstream targets (20) (20).

Model for activation and repression of the Cpx envelope stress response in Haemophilus ducreyi

Model for activation and repression of the sigma E envelope stress response in Haemophilus ducreyi

Summary of the sigmaE and Cpx envelope stress responses

 
Referenc

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This analysis was prepared by Gary Xie, and Staff. Please direct questions concerning this analysis to Gary Xie.