Transcriptional regulation of lipid homeostasis in mycobacteria

Salzman, Valentina; Mondino, Sonia; Sala, Claudia; Cole, Stewart T.; Gago, Gabriela; Gramajo, Hugo

doi:10.1111/j.1365-2958.2010.07313.x

Cited by 46 publications

(64 citation statements)

References 55 publications

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“…Our studies on the ⌬accD6 Mtb -P acc -accD6 Mtb mutant treated with INH suggest that P acc is regulated independently from P fasII , since P acc is insensitive to INH treatment. The findings of Salzman et al (61) support this hypothesis, showing that a palindromic motif recognized by MabR is localized uniquely in P fasII , thus suggesting that this transcriptional repressor is very unlikely to influence accD6 Mtb expression driven from the P acc promoter. However, this does not exclude the possibility that AccD6 activity is regulated following posttranslational modifications.…”

Section: Discussionmentioning

confidence: 83%

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AccD6, a Key Carboxyltransferase Essential for Mycolic Acid Synthesis in Mycobacterium tuberculosis, Is Dispensable in a Nonpathogenic Strain

et al. 2011

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Acetyl coenzyme A carboxylase (ACC) is a key enzyme providing a substrate for mycolic acid biosynthesis. Although in vitro studies have demonstrated that the protein encoded by accD6 (Rv2247) may be a functional carboxyltransferase subunit of ACC in Mycobacterium tuberculosis, the in vivo function and regulation of accD6 in slow-and fast-growing mycobacteria remain elusive. Here, directed mutagenesis demonstrated that although accD6 is essential for M. tuberculosis, it can be deleted in Mycobacterium smegmatis without affecting its cell envelope integrity. Moreover, we showed that although it is part of the type II fatty acid synthase operon, the accD6 gene of M. tuberculosis, but not that of M. smegmatis, possesses its own additional promoter (P acc ). The expression level of accD6 Mtb placed only under the control of P acc is 10-fold lower than that in wild-type M. tuberculosis but is sufficient to sustain cell viability. Importantly, this limited expression level affects growth, mycolic acid content, and cell morphology. These results provide the first in vivo evidence for AccD6 as a key player in the mycolate biosynthesis of M. tuberculosis, implicating AccD6 as the essential ACC subunit in pathogenic mycobacteria and an excellent target for new antitubercular compounds. Our findings also highlight important differences in the mechanism of acetyl carboxylation between pathogenic and nonpathogenic mycobacterial species.

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Section: Discussionmentioning

confidence: 83%

“…Recently, Salzman et al (61) identified a transcriptional factor (MabR) regulating FAS-II operon expression through its action on the P fasII promoter. Also, typical inhibitors of mycolic acid biosynthesis, such as isoniazid (INH), are able to induce a transcriptional response by genes placed under the control of P fasII (5,26,71,81).…”

Section: Discussionmentioning

confidence: 99%

AccD6, a Key Carboxyltransferase Essential for Mycolic Acid Synthesis in Mycobacterium tuberculosis, Is Dispensable in a Nonpathogenic Strain

et al. 2011

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“…The lipid transcriptional regulator FadR, a GntR family regulator, was first identified in E. coli (18,29). Other lipid transcriptional regulators recently reported include FasR of Streptomyces coelicolor (an activator of fatty acid biosynthesis) and MabR of M. tuberculosis (a repressor of genes in the cell wall mycolic acid biosynthesis pathway) (2,48). In both these bacteria, fatty acids produced in excess of the membrane phospholipid requirement may be diverted to storage granules (3,46,60).…”

Section: Discussionmentioning

confidence: 99%

Burkholderia cenocepacia ShvR-Regulated Genes That Influence Colony Morphology, Biofilm Formation, and Virulence

2011

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Burkholderia cenocepacia is an opportunistic pathogen that primarily infects cystic fibrosis (CF) patients. Previously, we reported that ShvR, a LysR regulator, influences colony morphology, virulence, and biofilm formation and regulates the expression of an adjacent 24-kb genomic region encoding 24 genes. In this study, we report the functional characterization of selected genes in this region. A Tn5 mutant with shiny colony morphology was identified with a polar mutation in BCAS0208, predicted to encode an acyl-coenzyme A dehydrogenase. Mutagenesis of BCAS0208 and complementation analyses revealed that BCAS0208 is required for rough colony morphology, biofilm formation, and virulence on alfalfa seedlings. It was not possible to complement with BCAS0208 containing a mutation in the catalytic site. BCAS0201, encoding a putative flavin adenine dinucleotide (FAD)-dependent oxidoreductase, and BCAS0207, encoding a putative citrate synthase, do not influence colony morphology but are required for optimum levels of biofilm formation and virulence. Both BCAS0208 and BCAS0201 contribute to pellicle formation, although individual mutations in each of these genes had no appreciable effect on pellicle formation. A mutant with a polar insertion in BCAS0208 was significantly less virulent in a rat model of chronic lung infection as well as in the alfalfa model. Genes in this region were shown to influence utilization of branched-chain fatty acids, tricarboxylic acid cycle substrates, L-arabinose, and branched-chain amino acids. Together, our data show that the ShvR-regulated genes BCAS0208 to BCAS0201 are required for the rough colony morphotype, biofilm and pellicle formation, and virulence in B. cenocepacia.

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“…A few transcription regulators that directly regulate the biosynthesis genes have been identified. FasR regulates the expression of the fas gene (15), while MabR (16) and FadR (17) regulate the expression of the fabD-accD6 cluster, the fasII operon (Fig. 1B).…”

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confidence: 99%

Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis

et al. 2015

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Mycobacterium tuberculosis, the etiological agent of tuberculosis, is a Gram-positive bacterium with a unique cell envelope composed of an essential outer membrane. Mycolic acids, which are very-long-chain (up to C 100 ) fatty acids, are the major components of this mycomembrane. The enzymatic pathways involved in the biosynthesis and transport of mycolates are fairly well documented and are the targets of the major antituberculous drugs. In contrast, only fragmented information is available on the expression and regulation of the biosynthesis genes. In this study, we report that the hadA, hadB, and hadC genes, which code for the mycolate biosynthesis dehydratase enzymes, are coexpressed with three genes that encode proteins of the translational apparatus. Consistent with the well-established control of the translation potential by nutrient availability, starvation leads to downregulation of the hadABC genes along with most of the genes required for the synthesis, modification, and transport of mycolates. The downregulation of a subset of the biosynthesis genes is partially dependent on Rel Mtb , the key enzyme of the stringent response. We also report the phylogenetic evolution scenario that has shaped the current genetic organization, characterized by the coregulation of the hadABC operon with genes of the translational apparatus and with genes required for the modification of the mycolates. IMPORTANCEMycobacterium tuberculosis infects one-third of the human population worldwide, and despite the available therapeutic arsenal, it continues to kill millions of people each year. There is therefore an urgent need to identify new targets and develop a better understanding of how the bacterium is adapting itself to host defenses during infection. A prerequisite of this understanding is knowledge of how this adaptive skill has been implanted by evolution. Nutrient scarcity is an environmental condition the bacterium has to cope with during infection. In many bacteria, adaptation to starvation relies partly on the stringent response. M. tuberculosis's unique outer membrane layer, the mycomembrane, is crucial for its viability and virulence. Despite its being the target of the major antituberculosis drugs, only scattered information exists on how the genes required for biosynthesis of the mycomembrane are expressed and regulated during starvation. This work has addressed this issue as a step toward the identification of new targets in the fight against M. tuberculosis. Mycobacterium tuberculosis, the etiological agent of tuberculosis, infects one-third of humans worldwide, with 9 million new cases and 1.5 million people dying each year from this disease (77). A long-standing challenge to the fight against tuberculosis is the ability of the pathogen to develop a nonreplicating, persistent, drug-tolerant form (1-3). In addition, the emergence of multidrug-resistant (MDR), extremely drug-resistant (XDR) (4, 5), and total-drug-resistant (TDR) strains (6) underscores the urgent need to identify new therapeutic targe...

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Transcriptional regulation of lipid homeostasis in mycobacteria

Cited by 46 publications

References 55 publications

AccD6, a Key Carboxyltransferase Essential for Mycolic Acid Synthesis in Mycobacterium tuberculosis, Is Dispensable in a Nonpathogenic Strain

AccD6, a Key Carboxyltransferase Essential for Mycolic Acid Synthesis in Mycobacterium tuberculosis, Is Dispensable in a Nonpathogenic Strain

Burkholderia cenocepacia ShvR-Regulated Genes That Influence Colony Morphology, Biofilm Formation, and Virulence

Evolution of Mycolic Acid Biosynthesis Genes and Their Regulation during Starvation in Mycobacterium tuberculosis

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