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Envelope-Stress Sensing Mechanism of Rcs and Cpx Signaling Pathways in Gram-Negative Bacteria

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Abstract

The global public health burden of bacterial antimicrobial resistance (AMR) is intensified by Gram-negative bacteria, which have an additional membrane, the outer membrane (OM), outside of the peptidoglycan (PG) cell wall. Bacterial two-component systems (TCSs) aid in maintaining envelope integrity through a phosphorylation cascade by controlling gene expression through sensor kinases and response regulators. In Escherichia coli, the major TCSs defending cells from envelope stress and adaptation are Rcs and Cpx, which are aided by OM lipoproteins RcsF and NlpE as sensors, respectively. In this review, we focus on these two OM sensors. β-Barrel assembly machinery (BAM) inserts transmembrane OM proteins (OMPs) into the OM. BAM co-assembles RcsF, the Rcs sensor, with OMPs, forming the RcsF-OMP complex. Researchers have presented two models for stress sensing in the Rcs pathway. The first model suggests that LPS perturbation stress disassembles the RcsF-OMP complex, freeing RcsF to activate Rcs. The second model proposes that BAM cannot assemble RcsF into OMPs when the OM or PG is under specific stresses, and thus, the unassembled RcsF activates Rcs. These two models may not be mutually exclusive. Here, we evaluate these two models critically in order to elucidate the stress sensing mechanism. NlpE, the Cpx sensor, has an N-terminal (NTD) and a C-terminal domain (CTD). A defect in lipoprotein trafficking results in NlpE retention in the inner membrane, provoking the Cpx response. Signaling requires the NlpE NTD, but not the NlpE CTD; however, OM-anchored NlpE senses adherence to a hydrophobic surface, with the NlpE CTD playing a key role in this function.

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Data availability

The statistics for NlpE NTD (PF04170) architecture from the website for the Pfam database and supplementary figures are available upon request.

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Acknowledgements

This work was funded by WELBIO (Grant no. WELBIO-CR-20190-03).

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  1. Kilian Dekoninck

    Present address: University of California, Berkeley, CA, 94720, USA

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  1. WELBIO-Walloon Excellence in Life Sciences and Biotechnology, 1200, Brussels, Belgium

    Seung-Hyun Cho, Kilian Dekoninck & Jean-Francois Collet

  2. de Duve Institute, Université Catholique de Louvain, 1200, Brussels, Belgium

    Seung-Hyun Cho, Kilian Dekoninck & Jean-Francois Collet

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Cho, SH., Dekoninck, K. & Collet, JF. Envelope-Stress Sensing Mechanism of Rcs and Cpx Signaling Pathways in Gram-Negative Bacteria. J Microbiol. 61, 317–329 (2023). https://doi.org/10.1007/s12275-023-00030-y

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