Envelope stress responses defend against type six secretion system attacks independently of immunity proteins

Nat Microbiol. 2020 May;5(5):706-714. doi: 10.1038/s41564-020-0672-6. Epub 2020 Feb 24.


The arms race among microorganisms is a key driver in the evolution of not only the weapons but also defence mechanisms. Many Gram-negative bacteria use the type six secretion system (T6SS) to deliver toxic effectors directly into neighbouring cells. Defence against effectors requires cognate immunity proteins. However, here we show immunity-independent protection mediated by envelope stress responses in Escherichia coli and Vibrio cholerae against a V. cholerae T6SS effector, TseH. We demonstrate that TseH is a PAAR-dependent species-specific effector highly potent against Aeromonas species but not against its V. cholerae immunity mutant or E. coli. A structural analysis reveals TseH is probably a NlpC/P60-family cysteine endopeptidase. We determine that two envelope stress-response pathways, Rcs and BaeSR, protect E. coli from TseH toxicity by mechanisms including capsule synthesis. The two-component system WigKR (VxrAB) is critical for protecting V. cholerae from its own T6SS despite expressing immunity genes. WigR also regulates T6SS expression, suggesting a dual role in attack and defence. This deepens our understanding of how bacteria survive T6SS attacks and suggests that defence against the T6SS represents a major selective pressure driving the evolution of species-specific effectors and protective mechanisms mediated by envelope stress responses and capsule synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Regulation, Bacterial
  • Immunity* / genetics
  • Models, Molecular
  • Protein Conformation
  • Type VI Secretion Systems / chemistry
  • Type VI Secretion Systems / genetics
  • Type VI Secretion Systems / immunology*
  • Type VI Secretion Systems / metabolism*
  • Vibrio cholerae / genetics
  • Vibrio cholerae / metabolism
  • Virulence / genetics


  • Bacterial Proteins
  • Type VI Secretion Systems