Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?

Bosserman, Rachel E.; Champion, Patricia A.

doi:10.1128/jb.00131-17

Cited by 33 publications

(29 citation statements)

References 187 publications

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“…3C). We generated an isogenic ΔeccCb 1 strain (no ESX-1 membrane complex [30]), as well as an isogenic WT strain overexpressing the espM MM gene. The level of ␤-galactosidase activity was significantly reduced in the ΔeccCb 1 strain compared to the WT strain ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The ESX-1 membrane complex recognizes ESX-1 substrates and provides the energy and the pore for the export of ESX-1 substrates across the CM (28,29). The protein substrates are then translocated across the periplasm and mycolate outer membrane via an unknown process (30). ESX-1 substrates can be localized to the cell surface and/or secreted from the bacterial cell into the extracellular environment (31)(32)(33)(34).…”

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confidence: 99%

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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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108

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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: Resultsmentioning

confidence: 99%

mentioning

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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108

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“…This specialized cell envelope requires specialized secretion systems. ESX secretion systems have been consistently associated with mycobacterial cell envelope synthesis, permeability, and related characteristics, such as colony morphology (30,31). The SigM regulon includes putative hydrolases, MKD8_1686 and MKD8_6925, which may be secreted by ESX-4.…”

Section: Discussionmentioning

confidence: 99%

Direct cell–cell contact activates SigM to express the ESX-4 secretion system inMycobacterium smegmatis

Clark

Judd

Lasek‐Nesselquist

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Conjugal cell-cell contact between strains of induces the transcript, which encodes the putative primary substrates of the ESAT-6 secretion system 4 (ESX-4) secretion system. This recipient response was required for conjugal transfer of chromosomal DNA from the donor strain. Here we show that the extracytoplasmic σ factor, SigM, is a cell contact-dependent activator of ESX-4 expression and is required for conjugal transfer of DNA in the recipient strain. The SigM regulon includes genes outside the seven-gene core locus that we show are also required for conjugation, and we show that some of these SigM-induced proteins likely function through ESX-4. A fluorescent reporter revealed that SigM is specifically activated in recipient cells in direct contact with donor cells. Coculture RNA-seq experiments indicated that SigM regulon induction occurred early and before transconjugants are detected. This work supports a model wherein donor contact with the recipient cell surface inactivates the transmembrane anti-SigM, thereby releasing SigM. Free SigM induces an extended ESX-4 secretion system, resulting in changes that facilitate chromosomal transfer. The contact-dependent inactivation of an extracytoplasmic σ-factor that tightly controls ESX-4 activity suggests a mechanism dedicated to detect, and appropriately respond to, external stimuli from mycobacteria.

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“…We expect that by comparing other smaller 488 rearrangements and mutational changes between the 1218R and DE4381 (1218S) strains, 489 and differences in transcriptional profiles, will gain insights into the compensational 490 mutations that presumably result in this partial suppression of virulence associated with the 491 DE4381 strain. In this context we also note that absence of ESX-1 genes have been 492 discussed to be associated with changes in colony morphologies such as exhibition of 493 smooth or rough colony morphology (Bosserman and Champion 2017). 494…”

Section: Phylogenetic Analysis 331mentioning

confidence: 84%

“…Interestingly, the type (I) plasmid carries genes 146 encoding for two secretion systems, type IV and type VII, where the type VII genes show 147 high homology to the ESX-5 category. The significance of the presence of these genes 148 remains to be studied but noteworthy, ESX-5 has been suggested to be associated with 149 slow growing pathogenic mycobacteria and to have an impact on virulence (Gröschel et al 150 2016;Bosserman and Champion 2017). 151 6 152 Average nucleotide identity revealed two distinct M. marinum strain clusters 153…”

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confidence: 99%

Extensive genomic diversity among Mycobacterium marinum strains revealed by whole genome sequencing

Das¹,

Pettersson²,

Behra³

et al. 2018

Preprint

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33Mycobacterium marinum is the causative agent for the tuberculosis-like disease 34 mycobacteriosis in fish and skin lesions in humans. Ubiquitous in its geographical 35 distribution, M. marinum is known to occupy diverse fish as hosts. However, information 36 about its genomic diversity is limited. Here, we provide the genome sequences for 15 M. 37 marinum strains isolated from infected humans and fish. Comparative genomic analysis of 38 these and four available genomes of the M. marinum strains M, E11, MB2 and Europe 39 reveal high genomic diversity among the strains, leading to the conclusion that M. 40 marinum should be divided into two different clusters, the "M"-and the "Aronson"-type. 41We suggest that these two clusters should be considered, if not two separate species, at 42 least two M. marinum subspecies. Our data also show that the M. marinum pan-genome for

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Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?

Cited by 33 publications

References 187 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

Direct cell–cell contact activates SigM to express the ESX-4 secretion system inMycobacterium smegmatis

Extensive genomic diversity among Mycobacterium marinum strains revealed by whole genome sequencing

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