The Cpx Inner Membrane Stress Response

Abstract

In Gram-negative bacteria, envelope stress responses were originally defined in Escherichia coli based on the discovery of signaling pathways that mediated adaptation to misfolded proteins localized to the outer compartments of the cell. One of these, the Cpx response, was found to be involved in sensing and mediating adaptation to periplasmic misfolded proteins. Genetic, biochemical, and structural approaches have defined a set of signaling proteins consisting of the two-component regulatory system made up of the sensor histidine kinase CpxA and its cognate response regulator CpxR, the periplasmic chaperone-inhibitor CpxP, and the outer membrane lipoprotein NlpE. These proteins regulate the Cpx envelope stress response upon exposure to a large array of envelope perturbations, adhesion, and growth. Adaptation to Cpx-inducing signals is accomplished through multiple means, including the elevated production of chaperones and proteases and the elimination of envelope-spanning and inner membrane protein complexes. Contemporary transcriptomic studies in other Gram-negative microbes suggest that the Cpx response acts predominantly at the inner membrane. In this chapter, we review current research that insinuates a connection between the Cpx inner membrane stress response, efflux, and metal trafficking.