The Cpx envelope stress response is controlled by amplification and feedback inhibition

In Escherichia coli, the Cpx two-component regulatory system activates expr ession of protein folding and degrading factors in response to misfolded pr oteins in the bacterial envelope (inner membrane, periplasm, and outer memb rane). It is comprised of the histidine kinase CpxA and the response regula tor CpxR. This response plays a role in protection from stresses, such as e levated pH, as well as in the biogenesis of virulence factors. Here, we sho w that the Cpx periplasmic stress response is subject to amplification and repression through positive and negative autofeedback mechanisms. Western b lot and operon fusion analyses demonstrated that the cpxRA operon is autoac tivated. Conditions that lead to elevated levels of phosphorylated CpxR cau se a concomitant increase in transcription of cpxRA. Conversely, overproduc tion of CpxP, a small, Cpx-regulated protein of previously unknown function , represses the regulon and can block activation of the pathway. This repre ssion is dependent on an intact CpxA sensing domain. The ability to autoact ivate and then subsequently repress allows for a temporary amplification of the Cpx response that may be important in rescuing cells from transitory s tresses and cueing the appropriately timed elaboration of virulence factors .