Post-transcriptional regulation of type III secretion in plant and animal pathogens

Schulmeyer, Kayley H.; Yahr, Timothy L.

doi:10.1016/j.mib.2017.01.009

Cited by 20 publications

(17 citation statements)

References 51 publications

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“…2,4,5). We found that, like injectisome systems, posttranscriptional mechanisms are also involved (82). Our model is also similar to feedback regulation of the flagellar T3SS system in Campylobacter jejuni.…”

Section: Discussionsupporting

confidence: 72%

WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

Bosserman

Nguyen

Sanchez

et al. 2017

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

129

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ESX (ESAT-6 system) export systems play diverse roles across mycobacterial species. Interestingly, genetic disruption of ESX systems in different species does not result in an accumulation of protein substrates in the mycobacterial cell. However, the mechanisms underlying this observation are elusive. We hypothesized that the levels of ESX substrates were regulated by a feedback-control mechanism, linking the levels of substrates to the secretory status of ESX systems. To test this hypothesis, we used a combination of genetic, transcriptomic, and proteomic approaches to define export-dependent mechanisms regulating the levels of ESX-1 substrates in WhiB6 is a transcription factor that regulates expression of genes encoding ESX-1 substrates. We found that, in the absence of the genes encoding conserved membrane components of the ESX-1 system, the expression of the gene and genes encoding ESX-1 substrates were reduced. Accordingly, the levels of ESX-1 substrates were decreased, and WhiB6 was not detected in strains lacking genes encoding ESX-1 components. We demonstrated that, in the absence of EccCb, a conserved ESX-1 component, substrate gene expression was restored by constitutive, but not native, expression of the gene. Finally, we found that the loss of WhiB6 resulted in a virulent strain with reduced ESX-1 secretion. Together, our findings demonstrate that the levels of ESX-1 substrates in are fine-tuned by negative feedback control, linking the expression of the gene to the presence, not the functionality, of the ESX-1 membrane complex.

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Section: Discussionsupporting

confidence: 72%

WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

Bosserman

Nguyen

Sanchez

et al. 2017

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

129

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“…Regulation of the EspM transcription factor may be similar to the control of gene expression by type III secretion systems (T3SS) in Gram-negative bacteria (60)(61)(62)(63). The injectisome T3SS uses cytoplasmic substrates and/or chaperones to posttranscriptionally modulate the levels or activity of transcription factors that regulate secretion-associated genes (62,(64)(65)(66)(67)(68)(69). ESX-1 substrates or chaperones may posttranscriptionally regulate the activity of EspM in response to the presence or absence of the ESX-1 membrane complex.…”

Section: Discussionmentioning

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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“…Bacterial type III secretion system (T3SS) is known to play an important role during bacterial interaction with plants and animals [16,51]. However, knowledge about its involvement in bacterial-fungal interactions is limited.…”

Section: Discussionmentioning

confidence: 99%

Calcium regulates the mycophagous ability of Burkholderia gladioli strain NGJ1 in a type III secretion system-dependent manner

et al. 2020

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Background: A rice associated bacterium Burkholderia gladioli strain NGJ1 demonstrates mycophagy, a phenomenon wherein bacteria feed on fungi. Previously, we have reported that NGJ1 utilizes type III secretion system (T3SS) to deliver a prophage tail-like protein (Bg_9562) into fungal cells to establish mycophagy. Results: In this study, we report that calcium ion concentration influences the mycophagous ability of NGJ1 on Rhizoctonia solani, an important fungal pathogen. The calcium limiting condition promotes mycophagy while high calcium environment prevents it. The expression of various T3SS apparatus encoding genes of NGJ1 was induced and secretion of several potential T3SS effector proteins (including Bg_9562) into extracellular milieu was triggered under calcium limiting condition. Using LC-MS/MS proteome analysis, we identified several calcium regulated T3SS effector proteins of NGJ1. The expression of genes encoding some of these effector proteins was upregulated during mycophagous interaction of NGJ1 with R. solani. Further, mutation of one of these genes (endo-β-1, 3-glucanase) rendered the mutant NGJ1 bacterium defective in mycophagy while complementation with full length copy of the gene restored its mycophagous activity. Conclusion: Our study provides evidence that low calcium environment triggers secretion of various T3SS effectors proteins into the extracellular milieu and suggests the importance of cocktail of these proteins in promoting mycophagy.

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Post-transcriptional regulation of type III secretion in plant and animal pathogens

Cited by 20 publications

References 51 publications

WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop inMycobacterium marinum

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

Calcium regulates the mycophagous ability of Burkholderia gladioli strain NGJ1 in a type III secretion system-dependent manner

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