Unraveling the function of a stress sentinel in the bacterial envelope

Gram-negative bacteria are surrounded by a complex multi-layered envelope that is essential for their viability. Intricate mechanisms called envelope stress response systems have been selected to detect perturbations that affect envelope integrity and to respond accordingly in order to contain or repair the damage. One major stress response system in the model bacterium Escherichia coli is the Cpx two-component system, in which various types of stress trigger a phosphotransfer from an inner membrane sensor to a cytoplasmic response regulator. Cpx is mostly known to monitor defects associated with misfolded protein accumulation and inner membrane stress. We have also shown that the Cpx sytem can also sense cell wall defects and regulate cell wall biogenesis. Interestingly, overproduction of NlpE, an outer membrane lipoprotein of unclear function, is known to activate the Cpx system. However, NlpE is not directly involved in sensing the known Cpx-inducing cues. We set out to elucidate the role of NlpE in the Cpx system and the molecular nature of the signal that is transmitted by NlpE to trigger the Cpx system. Our results led us to propose that NlpE serves as a specific Cpx sentinel that reports on key envelope biogenesis processes.