Mycobacterium tuberculosis Requires Regulation of ESX-5 Secretion for Virulence in Irgm1-Deficient Mice.

The type VII secretion system ESX-5, which has been implicated in virulence, is activated at the transcriptional level by the phosphate starvation-responsive Pst/SenX3-RegX3 signal transduction system. Deletion of , which encodes a Pst phosphate transporter component, causes constitutive activation of the response regulator RegX3, hypersecretion of ESX-5 substrates and attenuation in the mouse infection model. We hypothesized that constitutive activation of ESX-5 secretion causes attenuation of the Δ mutant.

Pst/SenX3-RegX3 Regulates Membrane Vesicle Production Independently of ESX-5 Activity.

releases membrane vesicles (MV) that modulate host immune responses and aid in iron acquisition, although they may have additional unappreciated functions. MV production appears to be a regulated process, but remains the only characterized genetic regulator of vesiculogenesis. Here, we present data supporting a role for the Pst/SenX3-RegX3 signal transduction system in regulating MV production.

PhoY Proteins Promote Persister Formation by Mediating Pst/SenX3-RegX3 Phosphate Sensing.

The phosphate-specific transport (Pst) system controls gene expression in response to phosphate availability by inhibiting the activation of the SenX3-RegX3 two-component system under phosphate-rich conditions, but the mechanism of communication between these systems is unknown. In , inhibition of the two-component system PhoR-PhoB under phosphate-rich conditions requires both the Pst system and PhoU, a putative adaptor protein. PhoU is also involved in the formation of persisters, a subpopulation of phenotypically antibiotic-tolerant bacteria.

Phosphate responsive regulation provides insights for ESX-5 function in Mycobacterium tuberculosis.

Pathogenic microbes commonly respond to environmental cues in the host by activating specialized protein secretion systems. Mycobacterium tuberculosis uses the specialized Type VII ESX protein secretion systems to transport a subset of effector proteins. The ESX-5 secretion system is involved in virulence, but both the mechanism of regulation and activating signal were unknown.

Phosphate starvation: a novel signal that triggers ESX-5 secretion in Mycobacterium tuberculosis.

Mycobacterium tuberculosis uses the Type VII ESX secretion systems to transport proteins across its complex cell wall. ESX-5 has been implicated in M. tuberculosis virulence, but the regulatory mechanisms controlling ESX-5 secretion were unknown.