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. Our work, reviewed here, has established that the phosphate sensing Pst/SenX3-RegX3 system directly activates ESX-5 secretion in response to phosphate limitation, a relevant environmental signal likely encountered by M. tuberculosis in the host. This review focuses on how elucidation of the ESX-5 regulatory network provides insight into its biological roles, which may include both phosphate acquisition and pathogenesis.