A Bacterial Virulence Protein Promotes Pathogenicity by Inhibiting the Bacterium’s own F₁F_o ATP Synthase

Eun-Jin Lee, Mauricio H. Pontes, and Eduardo A. Groisman

Cell 2013; 154:146-156

Speaker: Feng-Ru, Hung (洪鳳嬬)                     Time: 15:00-16:00, Oct. 23, 2013

Commontator: Dr. I-Hsiu Huang (黃一修 博士)          Place: Room 601

Abstract:

    Several intracellular pathogens, including Salmonella and Mycobacterium, can adapt to an intracellular lifestyle and escape recognition by humoral immune responses.¹ Their ability to survive within acidic macrophage phagosome is attributed to the MgtC protein. This protein is a virulence factor of intracellular pathogens, and is involved in bacterial adaptation to low Mg²⁺environment.² Regulation of mgtC expression in response to changes in cytosolic ATP levels is required for Salmonella virulence.³ The F₁F_o ATP synthase is responsible for most of ATP synthesis in living cells, and inactivation of atpB, which encodes the F_o a subunit, could attenuate Salmonella virulence. Towards understanding the mechanism of MgtC's activity, the authors first demonstrated that MgtC interacts with the F_o a subunit of F₁F_o synthase by immunoprecipitation. By using ATP-driven proton translocation and ATP hydrolysis assay in vitro, they found that the F₁F_o ATP synthase activity was enhanced in the mgtC deletion mutant. They further determined that the mgtC mutant leads to increased intracellular ATP level and reduction of cytosolic pH by measuring the intracellular ATP and pH in vivo. The defect in macrophage survival and virulence in mice of mgtC single mutant strain was atpB-dependent. However, the intracellular ATP level of the atpB mutant expressing MgtC from a plasmid was slightly lower than that of the strain containing only the plasmid vector. These suggest that MgtC might mainly, but not exclusively, affect the F₁F_o ATP synthase activity. Based on these data, they proposed that as phagosome acidification increases the proton gradient across the Salmonella inner membrane, MgtC targets Salmonella’s own F₁F_o ATP synthase and reduces the ability of this organism to translocate protons and, consequently, ATP synthesis. In this way, the Salmonella in phagosome can avoid the accumulation of cytosolic ATP and cytoplasm acidification. MgtC is a singular example of a virulence protein that inhibits another virulence protein to enhance pathogenicity.

References:

1. Kumar, Y., and Valdivia, R.H. (2009). Leading a sheltered life: intracellular pathogens and maintenance of vacuolar compartments. Cell Host & Microbe 5, 593–601.

2. Rang, C., Alix, E., Felix, C., Heitz, A., Tasse, L., and Blanc-Potard, A.B. (2007). Dual role of the MgtC virulence factor in host and non-host environments. Mol. Microbiol. 63, 605–622.

3. Lee, E.J., and Groisman, E.A. (2012). Control of a Salmonella virulence locus by an ATP-sensing leader messenger RNA. Nature 486, 271–275.