Inhibitor of intramembrane protease RseP blocks the σE response causing lethal accumulation of unfolded outer membrane proteins

Anna Konovalova, Marcin Grabowicz, Carl J. Balibar, Juliana C. Malinverni, Ronald E. Painter, Daniel Riley, Paul A. Mann, Hao Wang, Charles G. Garlisi, Brad Sherborne, Nathan W. Rigel, Dante P. Ricci, Todd A. Black, Terry Roemer, Thomas J. Silhavy, Scott S. Walker

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14 Scopus citations

Abstract

The outer membrane (OM) of Gram-negative bacteria forms a robust permeability barrier that blocks entry of toxins and antibiotics. Most OM proteins (OMPs) assume a β-barrel fold, and some form aqueous channels for nutrient uptake and efflux of intracellular toxins. The Bam machine catalyzes rapid folding and assembly of OMPs. Fidelity of OMP biogenesis is monitored by the σE stress response. When OMP folding defects arise, the proteases DegS and RseP act sequentially to liberate σE into the cytosol, enabling it to activate transcription of the stress regulon. Here, we identify batimastat as a selective inhibitor of RseP that causes a lethal decrease in σE activity in Escherichia coli, and we further identify RseP mutants that are insensitive to inhibition and confer resistance. Remarkably, batimastat treatment allows the capture of elusive intermediates in the OMP biogenesis pathway and offers opportunities to better understand the underlying basis for σE essentiality.

Original languageEnglish (US)
Pages (from-to)E6614-E6621
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number28
DOIs
StatePublished - Jul 10 2018

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Bam complex
  • Envelope stress response
  • Protein folding
  • Regulated proteolysis
  • Signal transduction

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    Konovalova, A., Grabowicz, M., Balibar, C. J., Malinverni, J. C., Painter, R. E., Riley, D., Mann, P. A., Wang, H., Garlisi, C. G., Sherborne, B., Rigel, N. W., Ricci, D. P., Black, T. A., Roemer, T., Silhavy, T. J., & Walker, S. S. (2018). Inhibitor of intramembrane protease RseP blocks the σE response causing lethal accumulation of unfolded outer membrane proteins. Proceedings of the National Academy of Sciences of the United States of America, 115(28), E6614-E6621. https://doi.org/10.1073/pnas.1806107115