Molecular Connectivity between Extracytoplasmic Sigma Factors and PhoP Accounts for Coupled Mycobacterial Stress Response

Mycobacterium tuberculosis encounters numerous stress conditions within the host, but how it is able to mount a coupled stress response remains unknown. Growing evidence suggests that under acidic pH, M. tuberculosis modulates redox homeostasis. In an attempt to dissect the mechanistic details of responses to multiple stress conditions, here we studied the significance of connectivity of extracytoplasmic sigma factors with PhoP. We show that PhoP impacts the mycothiol redox state, and the H37Rv Δ deletion mutant strain displays a significantly higher susceptibility to redox stress than the wild-type bacilli. To probe how the two regulators PhoP and redox-active sigma factor SigH contribute to redox homeostasis, we show that SigH controls expression of redox-active thioredoxin genes, a major mycobacterial antioxidant system, and under redox stress, SigH, but not PhoP, is recruited at the target promoters. Consistent with these results, interaction between PhoP and SigH fails to impact redox-dependent gene expression. This is in striking contrast to our previous results showing PhoP-dependent SigE recruitment within acid-inducible mycobacterial promoters to maintain pH homeostasis. Our subsequent results demonstrate reduced PhoP-SigH interaction in the presence of diamide and enhanced PhoP-SigE interaction under low pH. These contrasting results uncover the underlying mechanism of the mycobacterial adaptive program, coupling low pH with maintenance of redox homeostasis. M. tuberculosis encounters reductive stress under acidic pH. To investigate the mechanism of coupled stress response, we show that PhoP plays a major role in mycobacterial redox stress response. We observed a strong correlation of -dependent redox-active expression of thioredoxin genes, a major mycobacterial antioxidant system. Further probing of functioning of regulators revealed that while PhoP controls pH homeostasis via its interaction with SigE, direct recruitment of SigH, but not PhoP-SigH interaction, controls expression of thioredoxin genes. These strikingly contrasting results showing enhanced PhoP-SigE interaction under acidic pH and reduced PhoP-SigH interaction under redox conditions uncover the underlying novel mechanism of the mycobacterial adaptive program, coupling low pH with maintenance of redox homeostasis.