AUTHOR=Qi Nan , She Guo-Lan , Du Wei , Ye Bang-Ce 

TITLE=Mycobacterium smegmatis GlnR Regulates the Glyoxylate Cycle and the Methylcitrate Cycle on Fatty Acid Metabolism by Repressing icl Transcription

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.603835

DOI=10.3389/fmicb.2021.603835

ISSN=1664-302X

ABSTRACT=<p><italic>Mycobacterium smegmatis</italic> (<italic>Msm</italic>), along with its pathogenic counterpart <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>), utilizes fatty acids and cholesterol as important carbon and energy sources during the persistence within host cells. As a dual-functional enzyme in the glyoxylate cycle and the methylcitrate cycle, isocitrate lyase (ICL, encoded by <italic>icl</italic> or <italic>MSMEG_0911</italic>) is indispensable for the growth of <italic>Msm</italic> and <italic>Mtb</italic> on short-chain fatty acids. However, regulation of <italic>icl</italic> in mycobacteria in response to nutrient availability remains largely unknown. Here, we report that the global nitrogen metabolism regulator GlnR represses <italic>icl</italic> expression by binding to an atypical binding motif in the <italic>icl</italic> promoter region under nitrogen-limiting conditions. We further show that GlnR competes with PrpR, a transcriptional activator of <italic>icl</italic>, and dominantly occupies the co-binding motif in the <italic>icl</italic> promoter region. In the absence of GlnR or in response to the excess nitrogen condition, <italic>Msm</italic> cells elongate and exhibit robust growth on short-chain fatty acids due to the PrpR-mediated activation of <italic>icl</italic>, thereby inducing enhanced apoptosis in infected macrophages. Taken together, our findings reveal the GlnR-mediated repression of <italic>icl</italic> on fatty acid metabolism, which might be a general strategy of nutrient sensing and environmental adaptation employed by mycobacteria.</p>