HokB Monomerization and Membrane Repolarization Control Persister Awakening

Mol Cell. 2019 Sep 5;75(5):1031-1042.e4. doi: 10.1016/j.molcel.2019.06.015. Epub 2019 Jul 18.

Abstract

Every bacterial population harbors a small subpopulation of so-called persisters that are transiently antibiotic tolerant. These persisters are associated with the recalcitrance of chronic infections because they can recolonize the host after antibiotic removal. Although several effectors have been described to induce persistence, persister cell awakening is poorly understood. We previously reported that the toxin HokB induces persistence via pore formation, resulting in membrane depolarization and ATP leakage. We now delineate mechanisms responsible for the awakening of HokB-induced persisters. We show that HokB dimerization by the oxidoreductase DsbA is essential for pore formation and peptide stability. Pores are disassembled via DsbC-mediated monomerization, which targets HokB for DegQ-mediated degradation. Finally, pore disassembly allows membrane repolarization by the electron transport chain, supporting cells to resume growth. These results provide a detailed view of both the formation and awakening of HokB-induced persister cells.

Keywords: TA module; antibiotic persistence; antibiotic tolerance; chronic infection; membrane toxin; persister awakening; population heterogeneity; single-cell monitoring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism*
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Membrane Potentials / physiology*
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism
  • Proteolysis*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*

Substances

  • Bacterial Toxins
  • Escherichia coli Proteins
  • HokB protein, E coli
  • DegQ protein, E coli
  • Serine Endopeptidases
  • Protein Disulfide-Isomerases
  • dsbA protein, E coli
  • dsbC protein, E coli