PhoY2 of mycobacteria is required for metabolic homeostasis and stress response

The ability of pathogenic mycobacteria to adapt to diverse environments is essential for their success as pathogens. Here we describe a transposon-inactivated phoY2 mutant of Mycobacterium marinum. PhoY2 of mycobacteria is a functional homologue of PhoU in Escherichia coli and an important component of the Pho regulon. We found that PhoY2 is required for maintaining intracellular inorganic phosphate (P(i)) homeostasis and balanced energy and redox states. Disruption of phoY2 resulted in elevated levels of intracellular poly-P(i) and ATP and an elevated NAD(+)/NADH ratio, and the mutant strain exhibited increased sensitivity to environmental stress conditions, including nutrient deprivation as well as SDS and antibiotic treatments. Taken together, our results suggest that PhoY2 is required for maintaining metabolic homeostasis and adaptation to stress conditions, which may provide an explanation for the suggested role of PhoY2 in drug tolerance.