Abstract
Mycobacterium smegmatis (Msm), along with its pathogenic counterpart Mycobacterium tuberculosis (Mtb), 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 icl or MSMEG_0911) is indispensable for the growth of Msm and Mtb on short-chain fatty acids. However, regulation of icl in mycobacteria in response to nutrient availability remains largely unknown. Here, we report that the global nitrogen metabolism regulator GlnR represses icl expression by binding to an atypical binding motif in the icl promoter region under nitrogen-limiting conditions. We further show that GlnR competes with PrpR, a transcriptional activator of icl, and dominantly occupies the co-binding motif in the icl promoter region. In the absence of GlnR or in response to the excess nitrogen condition, Msm cells elongate and exhibit robust growth on short-chain fatty acids due to the PrpR-mediated activation of icl, thereby inducing enhanced apoptosis in infected macrophages. Taken together, our findings reveal the GlnR-mediated repression of icl on fatty acid metabolism, which might be a general strategy of nutrient sensing and environmental adaptation employed by mycobacteria.
Highlights
Mycobacterium tuberculosis (Mtb) is the pathogenic agent of tuberculosis (TB) that causes the death of millions of people annually (Data from the WHO Global Tuberculosis Report)
We demonstrate that GlnR represses the transcription of icl and decreases the abundance of isocitrate lyase (ICL) products in the glyoxylate cycle and the methylcitrate cycle under nitrogen starvation condition, thereby impairing the growth, morphology and survival of Mycobacterium smegmatis (Msm) on short-chain fatty acids
ICL is a dual-functional enzyme in the glyoxylate cycle and the methylcitrate cycle essential for the metabolism of fatty acids in Msm (Supplementary Figure S1)
Summary
Mycobacterium tuberculosis (Mtb) is the pathogenic agent of tuberculosis (TB) that causes the death of millions of people annually (Data from the WHO Global Tuberculosis Report). It was reported that the metabolic enzymes of Mtb, such as methylisocitrate lyase (MCL) and malate synthase (MA), are important for its pathogenicity and survival Our previous studies have shown that GlnR regulates the methylcitrate cycle by inhibiting the transcription of prpDBC operon (prpD encode Methylcitrate dehydratase; prpB encode methylisocitrate lyase and prpC encode methylcitrate synthase) in Mycobacterium smegmatis (Msm), the non-pathogenic counterpart of Mtb (Liu et al, 2019). We demonstrate that GlnR represses the transcription of icl and decreases the abundance of ICL products in the glyoxylate cycle and the methylcitrate cycle under nitrogen starvation condition, thereby impairing the growth, morphology and survival of Msm on short-chain fatty acids. Our findings reveal a regulatory role of GlnR on fatty acid metabolism by repressing icl, which might be a general strategy employed by mycobacteria in response to different nutrition status
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