The CpxAR Two-component System Regulates a Complex Envelope Stress Response in Gram-negative Bacteria

e CpxA membrane bound sensor kinase utilizes a periplasmic sensing domain to detect a wide variety of stresses to the bacterial envelope. !is information is communicated via typical two-component phosphotransfer mediated reactions to the response regulator CpxR. Phosphorylated CpxR binds upstream of numerous promoters to mediate adaptation. Initial studies of CpxA inducing signals and CpxR regulated genes demonstrated a role for this two-component system in responding to protein misfolding in the envelope. In this chapter, we discuss recent progress regarding the mechanisms of signal detection, transduction, and gene regulation employed by CpxA and CpxR. !e data indicate that the majority of inducing cues are sensed through the periplasmic domain of CpxA and lead to the relief of one or more inhibitory controls that function to maintain Cpx pathway activity at low basal levels in the absence of envelope stress. Some activating signals also enter the pathway downstream of CpxA, in the cytoplasm. Analysis of the Cpx regulon in multiple organisms indicates that, in addition to regulating the production of well studied envelope protein folding and degrading factors, CpxA and CpxR also control the expression of cellular functions linked to cell wall modi"cation, transport, translation, and regulation, indicating that adaptation to envelope stress involves broad changes in cellular physiology. !e Cpx two-component system has been shown to impact virulence in a number of pathogens, and our current knowledge of this "eld is discussed. Introduction !e CpxA sensor kinase and the CpxR response regulator have been recognized as a typical bacterial two-component regulatory system that impacts the envelope since the 1980s. In this decade, Phillip Silverman’s group "rst demonstrated that mutations a#ecting the cpxA gene impacted many diverse physiological functions, o$en associated with the envelope, and the genetically linked cpxR gene, encoding the cognate response regulator of CpxA, was identi"ed. In the 1990s, Tom Silhavy’s group discovered that activation of the CpxA-CpxR signalling pathway could rescue Escherichia coli mutants from the toxic e#ects of grossly misfolded and mislocalized envelope proteins, partly by activating expression of the periplasmic protease-chaperone DegP. !ese studies led to the proposal that CpxA and CpxR worked together to sense and mediate adaptation to envelope stresses, particularly those a#ecting protein folding in this compartment. !e subsequent identi"cation of the disul"de oxidase DsbA as a Cpx-regulated gene, and the demonstration that CpxA and CpxR participated in the standard phosphotransfer reactions characteristic of all two-component systems, solidi"ed this concept. In the last 15 years, our major knowledge gains have been an increased understanding about the mechanisms employed by CpxA to sense envelope stress and an appreciation that the Cpx response facilitates adaptation to envelope stress in multiple manners that a#ect many di#erent cellular processes. Additionally, our view of the Cpx response has broadened to include other