AUTHOR=Pei Jin-Feng , Qi Nan , Li Yu-Xin , Wo Jing , Ye Bang-Ce 

TITLE=RegX3-Mediated Regulation of Methylcitrate Cycle in Mycobacterium smegmatis

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.619387

DOI=10.3389/fmicb.2021.619387

ISSN=1664-302X

ABSTRACT=<p><italic>Mycobacterium tuberculosis</italic> is a global human pathogen that infects macrophages and can establish a latent infection. Emerging evidence has established the nutrients metabolism as a key point to study the pathogenesis of <italic>M. tuberculosis</italic> and host immunity. It was reported that fatty acids and cholesterol are the major nutrient sources of <italic>M. tuberculosis</italic> in the period of infection. However, the mechanism by which <italic>M. tuberculosis</italic> utilizes lipids for maintaining life activities in nutrient-deficiency macrophages is poorly understood. <italic>Mycobacterium smegmatis</italic> is fast-growing and generally used to study its pathogenic counterpart, <italic>M. tuberculosis</italic>. In this work, we found that the phosphate sensing regulator RegX3 of <italic>M. smegmatis</italic> is required for its growing on propionate and surviving in macrophages. We further demonstrated that the expression of <italic>prpR</italic> and related genes (<italic>prpDBC</italic>) in methylcitrate cycle could be enhanced by RegX3 in response to the phosphate-starvation condition. The binding sites of the promoter region of <italic>prpR</italic> for RegX3 and PrpR were investigated. In addition, cell morphology assay showed that RegX3 is responsible for cell morphological elongation, thus promoting the proliferation and survival of <italic>M. smegmatis</italic> in macrophages. Taken together, our findings revealed a novel transcriptional regulation mechanism of RegX3 on propionate metabolism, and uncovered that the nutrients-sensing regulatory system puts bacteria at metabolic steady state by altering cell morphology. More importantly, since we observed that <italic>M. tuberculosis</italic> RegX3 also binds to the <italic>prpR</italic> operon <italic>in vitro</italic>, the RegX3-mediated regulation might be general in <italic>M. tuberculosis</italic> and other mycobacteria for nutrient sensing and environmental adaptation.</p>