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.
Keywords: ESX secretion; Pst system; RegX3; Type VII secretion.