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Control of a Salmonella virulence locus by an ATP-sensing leader messenger RNA


The facultative intracellular pathogen Salmonella enterica resides within a membrane-bound compartment inside macrophages1. This compartment must be acidified for Salmonella to survive within macrophages2, possibly because acidic pH promotes expression of Salmonella virulence proteins3,4. We reasoned that Salmonella might sense its surroundings have turned acidic not only upon protonation of the extracytoplasmic domain of a protein sensor5 but also by an increase in cytosolic ATP levels, because conditions that enhance the proton gradient across the bacterial inner membrane stimulate ATP synthesis6,7. Here we report that an increase in cytosolic ATP promotes transcription of the coding region for the virulence gene mgtC, which is the most highly induced horizontally acquired gene when Salmonella is inside macrophages8. This transcript is induced both upon media acidification and by physiological conditions that increase ATP levels independently of acidification. ATP is sensed by the coupling/uncoupling of transcription of the unusually long mgtC leader messenger RNA and translation of a short open reading frame located in this region. A mutation in the mgtC leader messenger RNA that eliminates the response to ATP hinders mgtC expression inside macrophages and attenuates Salmonella virulence in mice. Our results define a singular example of an ATP-sensing leader messenger RNA. Moreover, they indicate that pathogens can interpret extracellular cues by the impact they have on cellular metabolites.

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Figure 1: Mild acidic pH promotes transcription of the mgtC and mgtB coding regions in a Salmonella strain lacking the extracytoplasmic pH sensor PhoQ.
Figure 2: ATP promotes gene transcription in a manner dependent on conserved adenine nucleotides in the mgtCBR leader region.
Figure 3: Regulation of the Salmonella mgtCBR virulence operon by the PhoP/PhoQ system and mgtCBR leader region.
Figure 4: Expression of the mgtC coding region inside macrophages is dependent on its leader region’s ability to sense ATP, a property required for Salmonella virulence.


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We thank C. Turnbough for discussions, M. Wade for help with the mouse virulence assays, and R. Breaker and A. Roth for help with in-line probing experiments. This work was supported, in part, by grant AI49561 from the National Institutes of Health to E.A.G., who is an investigator of the Howard Hughes Medical Institute.

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E.-J.L. conducted the experiments. E.-J.L. and E.A.G. designed the study and wrote the paper. Both authors read the paper and contributed to its final form.

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Correspondence to Eduardo A. Groisman.

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

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