Everything old is new again: An update on current research on the Cpx envelope stress response

Abstract

The Cpx envelope stress response (ESR) has been linked to proteins that are integrated into and secreted across the inner membrane for several decades. Initial studies of the cpx locus linked it to alterations in the protein content of both the inner and outer membrane, together with changes in proton motive driven transport and conjugation. Since the mid 1990s, the predominant view of the Cpx envelope stress response has been that it serves to detect and respond to secreted, misfolded proteins in the periplasm. Recent studies in Escherichia coli and other Gram negative organisms highlight a role for the Cpx ESR in specifically responding to perturbations that occur at the inner membrane (IM). It is clear that Cpx adaptation involves a broad suite of changes that encompass many functions in addition to protein folding. Interestingly, recent studies have refocused attention on Cpx-regulated phenotypes that were initially published over 30years ago, including antibiotic resistance and transport across the IM. In this review I will focus on the insights and models that have arisen from recent studies and that may help explain some of the originally published Cpx phenotypes. Although the molecular nature of the inducing signal for the Cpx ESR remains enigmatic, recently solved structures of signaling proteins are yielding testable models concerning the molecular mechanisms behind signaling. The identification of connections between the Cpx ESR and other stress responses in the cell reveals a complex web of interactions that involves Cpx-regulated expression of other regulators as well as small proteins and sRNAs. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.

Compartment and signal-specific codependence in the transcriptional control of Salmonella periplasmic copper homeostasis

“…We and others have shown that copper can induce genes of the CpxR/CpxA regulon (21)(22)(23). This, along with the pH-dependence in cueP expression, another CpxR/CpxA-activating condition (24), prompted us to investigate the contribution of this regulatory system to cueP expression. Deletion of the response regulator gene cpxR and/or the sensor kinase coding gene cpxA abrogated the metal induction of cueP at pH 7.0 (Fig.…”

Regulation of bacterial virulence gene expression by cell envelope stress responses

“…4,8,12 The small periplasmic protein CpxP, encoded immediately upstream of the cpxRA operon, inhibits the system, perhaps by forming an inhibitory complex with CpxA, although this remains in question. 11 This negative regulation might be relieved when CpxP is degraded, perhaps in association with misfolded proteins. However, CpxP is not required for activation of the Cpx response by any known inducing signals, including misfolded proteins.…”

“…11,12 Its core components are the IM histidine kinase CpxA and the cytoplasmic response regulator CpxR. Cpx inducing conditions include exposure to alkaline pH, overproduction and accumulation of pilus subunits in the periplasm, mutations that impact periplasmic protein folding, and exposure to environmental conditions that alter the composition of the bacterial cell envelope.…”

A cell wall damage response mediated by a sensor kinase/response regulator pair enables beta-lactam tolerance

“…Although several stress response systems are known to sense and respond to damaged/misfolded membrane proteins (13)(14)(15), there is a paucity of knowledge regarding systems that sense and ameliorate damage to the cell wall. Exceptions are TCS [e.g., WalRK and VraSR (16,17)] found in several Gram-positive genera that respond to exposure to various cell-wall-acting antibiotics by activating regulons that mediate specialized cell wall synthesis/turnover functions.…”