Context-dependent acetylation of the virulence regulator PhoP accounts for carbon-source specific mycobacterial growth inhibition under acidic conditions

Abstract

Mycobacterium tuberculosis PhoP is essential for intracellular survival and virulence of the tubercle bacilli. Genetic evidences coupled with biochemical studies uncover that PhoP affects various aspects of M. tuberculosis pathophysiology including pH sensing during intracellular adaptation and carbon source utilization. Building on this observation, herein we report essentiality of the phoP locus in carbon-source specific mycobacterial growth. Further, our results on mycobacterial growth in the presence of different carbon sources suggest accumulation of acetyl CoA, a metabolic intermediate which acetylates major transcription factors. To explore the mechanism, we examined in vivo acetylation of PhoP, and our results suggest a link between acetylation of PhoP and mycobacterial carbon source utilization. Using a genetic screening, we identified PhoP-specific mycobacterial acetylases. Our two major findings that (a) acidic conditions of growth inhibit PhoP acetylation, which represses PhoP regulon by interfering with DNA binding activity of the regulator and (b) mycobacteria expressing acetylation-defective PhoP shows growth inhibition, together suggest a role of acetylation on mycobacterial growth via carbon-source utilization. These results have implications on intracellular survival and growth program of mycobacteria under varying environmental cues.