Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis

Nazarova, Evgeniya V.; Montague, Christine R; La, Thuy; Wilburn, Kaley M; Sukumar, Neelima; Lee, Wonsik; Caldwell, Shannon; Russell, David G.; VanderVen, Brian C.

doi:10.7554/elife.26969

Cited by 155 publications

(202 citation statements)

References 70 publications

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“…These data are supportive of the conclusion that the mce6 genes are repressed in a whiB6-dependent manner, although further characterization studies will be required to support this hypothesis. mce genes have been associated with carbon nutrient uptake, including mce1, promoting uptake of fatty acids (88), and mce4, promoting uptake of cholesterol (89). mce6 is absent in the M. tuberculosis genome but is present in the genomes of many nontuberculous mycobacterial species (90) and could play a role in controlling metabolite import to promote survival in the phagosome or cytosol.…”

Section: Figmentioning

confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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Pathogenic mycobacteria encounter multiple environments during macrophage infection. Temporally, the bacteria are engulfed into the phagosome, lyse the phagosomal membrane, and interact with the cytosol before spreading to another cell. Virulence factors secreted by the mycobacterial ESX-1 (ESAT-6-system-1) secretion system mediate the essential transition from the phagosome to the cytosol. It was recently discovered that the ESX-1 system also regulates mycobacterial gene expression in Mycobacterium marinum (R. E. Bosserman, T. T. Nguyen, K. G. Sanchez, A. E. Chirakos, et al., Proc Natl Acad Sci U S A 114:E10772–E10781, 2017, https://doi.org/10.1073/pnas.1710167114), a nontuberculous mycobacterial pathogen, and in the human-pathogenic species M. tuberculosis (A. M. Abdallah, E. M. Weerdenburg, Q. Guan, R. Ummels, et al., PLoS One 14:e0211003, 2019, https://doi.org/10.1371/journal.pone.0211003). It is not known how the ESX-1 system regulates gene expression. Here, we identify the first transcription factor required for the ESX-1-dependent transcriptional response in pathogenic mycobacteria. We demonstrate that the gene divergently transcribed from the whiB6 gene and adjacent to the ESX-1 locus in mycobacterial pathogens encodes a conserved transcription factor (MMAR_5438, Rv3863, now espM). We prove that EspM from both M. marinum and M. tuberculosis directly and specifically binds the whiB6-espM intergenic region. We show that EspM is required for ESX-1-dependent repression of whiB6 expression and for the regulation of ESX-1-associated gene expression. Finally, we demonstrate that EspM functions to fine-tune ESX-1 activity in M. marinum. Taking the data together, this report extends the esx-1 locus, defines a conserved regulator of the ESX-1 virulence pathway, and begins to elucidate how the ESX-1 system regulates gene expression. IMPORTANCE Mycobacterial pathogens use the ESX-1 system to transport protein substrates that mediate essential interactions with the host during infection. We previously demonstrated that in addition to transporting proteins, the ESX-1 secretion system regulates gene expression. Here, we identify a conserved transcription factor that regulates gene expression in response to the ESX-1 system. We demonstrate that this transcription factor is functionally conserved in M. marinum, a pathogen of ectothermic animals; M. tuberculosis, the human-pathogenic species that causes tuberculosis; and M. smegmatis, a nonpathogenic mycobacterial species. These findings provide the first mechanistic insight into how the ESX-1 system elicits a transcriptional response, a function of this protein transport system that was previously unknown.

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Section: Figmentioning

confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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“…M. tuberculosis imports fatty acids from host triglycerides for synthesis of its own lipid inclusions and acquisition of dormancy traits in macrophages ( 46 , 47 ). The mycobacterial protein, LucA, was found to form a complex with Mce1 and Mce4 fatty acid transporters to facilitate cholesterol and fatty acid uptake in infected macrophages ( 48 ). In dormant M. tuberculosis , the accumulation of triglycerides is modulated by fatty acid CoA ligase 6 ( 49 ), and during nutrient starvation, the bacterium is capable of hydrolyzing these stored triglycerides, owing to its lipase activity ( 50 ).…”

Section: Host Lipids—the Protagonist and The Antagonist In The Macropmentioning

confidence: 99%

Macrophage–Bacteria Interactions—A Lipid-Centric Relationship

2017

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Macrophages are professional phagocytes at the front line of immune defenses against foreign bodies and microbial pathogens. Various bacteria, which are responsible for deadly diseases including tuberculosis and salmonellosis, are capable of hijacking this important immune cell type and thrive intracellularly, either in the cytoplasm or in specialized vacuoles. Tight regulation of cellular metabolism is critical in shaping the macrophage polarization states and immune functions. Lipids, besides being the bulk component of biological membranes, serve as energy sources as well as signaling molecules during infection and inflammation. With the advent of systems-scale analyses of genes, transcripts, proteins, and metabolites, in combination with classical biology, it is increasingly evident that macrophages undergo extensive lipid remodeling during activation and infection. Each bacterium species has evolved its own tactics to manipulate host metabolism toward its own advantage. Furthermore, modulation of host lipid metabolism affects disease susceptibility and outcome of infections, highlighting the critical roles of lipids in infectious diseases. Here, we will review the emerging roles of lipids in the complex host–pathogen relationship and discuss recent methodologies employed to probe these versatile metabolites during the infection process. An improved understanding of the lipid-centric nature of infections can lead to the identification of the Achilles’ heel of the pathogens and host-directed targets for therapeutic interventions. Currently, lipid-moderating drugs are clinically available for a range of non-communicable diseases, which we anticipate can potentially be tapped into for various infections.

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“…Recent work has shown that Dicl1 'bypass' mutants, which either alleviate methylcitrate toxicity or reduce the catabolic flux of propionyl-CoA, are able to rescue the growth defect by alleviating the accumulation of toxic metabolites. This led to the identification of a previously uncharacterized protein, Rv3723/LucA, which functions to integrate cholesterol and fatty acid uptake in M. tuberculosis [55]. Similar experiments in other key pathogens will likely uncover more uncharacterized proteins dedicated to propionate metabolism and/or alleviating toxicity.…”

Section: Mycobacteriamentioning

confidence: 99%

Loving the poison: the methylcitrate cycle and bacterial pathogenesis

et al. 2018

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Propionate is an abundant catabolite in nature and represents a rich potential source of carbon for the organisms that can utilize it. However, propionate and propionate-derived catabolites are also toxic to cells, so propionate catabolism can alternatively be viewed as a detoxification mechanism. In this review, we summarize recent progress made in understanding how prokaryotes catabolize propionic acid, how these pathways are regulated and how they might be exploited to develop novel antibacterial interventions.

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Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis

Cited by 155 publications

References 70 publications

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Macrophage–Bacteria Interactions—A Lipid-Centric Relationship

Loving the poison: the methylcitrate cycle and bacterial pathogenesis

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