Mce3R, a TetR-type transcriptional repressor, controls the expression of a regulon involved in lipid metabolism in Mycobacterium tuberculosis

Abstract

The mce operons constitute four homologous regions in the Mycobacterium tuberculosis genome, each of which has 8-13 ORFs. Although the function of the Mce protein family has not been clearly established, its members are believed to be membrane lipid transporters. Based on functional experiments, we found that the regulator of the mce3 locus, Mce3R, negatively regulates the expression of the Rv1933c-Rv1935c and Rv1936-Rv1941 transcriptional units. These operons are adjacent to one another and divergently transcribed. The predicted functions of most of these genes are related to either lipid metabolism or redox reactions. Bioinformatic analysis of the 59 UTR sequences of the differentially expressed genes allowed us to define a putative Mce3R motif. Importantly, the Mce3R motif was present six and three times in the mce3R-yrbE3A and Rv1935c-Rv1936 intergenic regions, respectively. Two occurrences of this motif mapped within the two regions of the mce3 operon that were protected by Mce3R in a footprinting analysis, thus indicating that this motif is likely to serve as an operator site for the Mce3R regulator in the promoter. In addition, alterations in the lipid content of M. tuberculosis were detected in the absence of Mce3R. Taken together, these results suggest that Mce3R controls the expression of both the putative transport system encoded in the mce3 operon and the enzymes implicated in the modification of the Mce3-transported substrates.

In-Depth Characterization and Functional Analysis of Clonal Variants in a Mycobacterium tuberculosis Strain Prone to Microevolution

“…In the case of specific SNPs for variant A, the most remarkable polymorphism is a non-synonymous substitution mapping in the essential gene mce3R , a transcriptional repressor of the mce 3R regulon, which is involved in lipid metabolism and redox reactions (de la Paz Santangelo et al, 2009). The expression of the first gene in the mce 3 operon, yrbE3A , in variant A was lower than in variant B, indicating that the SNP found in variant A leads to higher efficiency of the repressor, which would likely have a functional effect.…”

Study of the in vivo role of Mce2R, the transcriptional regulator of mce2 operon in Mycobacterium tuberculosis

“…However, the low fold change detected for this gene in both experimental strategies places in doubt the biological significance of this differential expression. The type of exclusive in vitro regulation of Mce2R over the mce2 operon contrasts to that described for Mce3R, the transcriptional repressor of the mce3 operon [12,13]. Whereas during the in vitro growth of M. tuberculosis , Mce3R negatively regulates the expression of two transcriptional units likely to be involved in lipid or isoprenoid modifications [13], Mce2R seems to regulate exclusively the transcription of mce2 .…”

Pathogen roid rage: Cholesterol utilization byMycobacterium tuberculosis

“…The Mce3 regulon is under control of the Mce3R TetR-like transcriptional repressor ( Rv1963 ), as was demonstrated using transcriptional profiling of the Δ mce3R knockout strain (De La Paz Santangelo et al, 2009). The bioinformatically-annotated functions of these genes include general oxidoreductases, β-oxidation, and lipid transport genes (De La Paz Santangelo et al, 2009). …”

“…The expression of echA9 is under the control of the transcriptional regulator SigE (Rohde et al, 2012). The echA13 gene is in the same operon as fadE17 and fadE18 ; an operon that is up-regulated by cholesterol and under the control of the transcriptional repressor Mce3R (De La Paz Santangelo et al, 2009). Their role in cholesterol metabolism has yet to be determined.…”

“… i Under control of the transcriptional repressors, KstR1: (Kendall et al, 2007); KstR2: (Kendall et al, 2010); Mce3R: (De La Paz Santangelo et al, 2009). …”