Salmonella expresses foreign genes during infection by degrading their silencer

Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):8074-8082. doi: 10.1073/pnas.1912808117. Epub 2020 Mar 24.

Abstract

The heat-stable nucleoid structuring (H-NS, also referred to as histone-like nucleoid structuring) protein silences transcription of foreign genes in a variety of Gram-negative bacterial species. To take advantage of the products encoded in foreign genes, bacteria must overcome the silencing effects of H-NS. Because H-NS amounts are believed to remain constant, overcoming gene silencing has largely been ascribed to proteins that outcompete H-NS for binding to AT-rich foreign DNA. However, we report here that the facultative intracellular pathogen Salmonella enterica serovar Typhimurium decreases H-NS amounts 16-fold when inside macrophages. This decrease requires both the protease Lon and the DNA-binding virulence regulator PhoP. The decrease in H-NS abundance reduces H-NS binding to foreign DNA, allowing transcription of foreign genes, including those required for intramacrophage survival. The purified Lon protease degraded free H-NS but not DNA-bound H-NS. By displacing H-NS from DNA, the PhoP protein promoted H-NS proteolysis, thereby de-repressing foreign genes-even those whose regulatory sequences are not bound by PhoP. The uncovered mechanism enables a pathogen to express foreign virulence genes during infection without the need to evolve binding sites for antisilencing proteins at each foreign gene.

Keywords: Lon; PhoP; heat-stable nucleoid structuring protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Proteins / metabolism*
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Bacterial*
  • Gene Silencing
  • Gene Transfer, Horizontal
  • Macrophages / microbiology*
  • Mice
  • Protease La / metabolism*
  • Proteolysis
  • Salmonella Infections / microbiology*
  • Salmonella typhimurium / genetics
  • Salmonella typhimurium / metabolism
  • Salmonella typhimurium / pathogenicity*
  • Transcription, Genetic
  • Virulence / genetics
  • Virulence Factors / genetics
  • Virulence Factors / metabolism

Substances

  • Bacterial Proteins
  • DNA-Binding Proteins
  • H-NS protein, bacteria
  • Virulence Factors
  • PhoP protein, Bacteria
  • Protease La