A bacterial virulence protein promotes pathogenicity by inhibiting the bacterium's own F1Fo ATP synthase

Cell. 2013 Jul 3;154(1):146-56. doi: 10.1016/j.cell.2013.06.004.


Several intracellular pathogens, including Salmonella enterica and Mycobacterium tuberculosis, require the virulence protein MgtC to survive within macrophages and to cause a lethal infection in mice. We now report that, unlike secreted virulence factors that target the host vacuolar ATPase to withstand phagosomal acidity, the MgtC protein acts on Salmonella's own F1Fo ATP synthase. This complex couples proton translocation to ATP synthesis/hydrolysis and is required for virulence. We establish that MgtC interacts with the a subunit of the F1Fo ATP synthase, hindering ATP-driven proton translocation and NADH-driven ATP synthesis in inverted vesicles. An mgtC null mutant displays heightened ATP levels and an acidic cytoplasm, whereas mgtC overexpression decreases ATP levels. A single amino acid substitution in MgtC that prevents binding to the F1Fo ATP synthase abolishes control of ATP levels and attenuates pathogenicity. MgtC provides a singular example of a virulence protein that promotes pathogenicity by interfering with another virulence protein.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Bacterial Proteins / metabolism*
  • Cation Transport Proteins / metabolism*
  • Female
  • Hydrogen-Ion Concentration
  • Macrophages / microbiology
  • Membrane Potentials
  • Mice
  • Mice, Inbred C3H
  • Protein Subunits / antagonists & inhibitors
  • Proton-Translocating ATPases / antagonists & inhibitors*
  • Salmonella Infections / microbiology*
  • Salmonella typhimurium / cytology*
  • Salmonella typhimurium / enzymology
  • Salmonella typhimurium / pathogenicity*
  • Virulence
  • Virulence Factors / metabolism*


  • Bacterial Proteins
  • Cation Transport Proteins
  • Protein Subunits
  • Virulence Factors
  • Adenosine Triphosphate
  • MgtC protein, Salmonella typhimurium
  • Proton-Translocating ATPases