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

ABSTRACT 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...

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Autores principales:	Kevin G. Sanchez, Micah J. Ferrell, Alexandra E. Chirakos, Kathleen R. Nicholson, Robert B. Abramovitch, Matthew M. Champion, Patricia A. Champion
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	ESAT-6 ESX-1 Mycobacterium protein secretion regulation feedback control Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bf0cf4ea555448b694cb750f870159e3
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spelling	oai:doaj.org-article:bf0cf4ea555448b694cb750f870159e32021-11-15T15:56:58ZEspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System10.1128/mBio.02807-192150-7511https://doaj.org/article/bf0cf4ea555448b694cb750f870159e32020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02807-19https://doaj.org/toc/2150-7511ABSTRACT 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.Kevin G. SanchezMicah J. FerrellAlexandra E. ChirakosKathleen R. NicholsonRobert B. AbramovitchMatthew M. ChampionPatricia A. ChampionAmerican Society for MicrobiologyarticleESAT-6ESX-1Mycobacteriumprotein secretionregulationfeedback controlMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	ESAT-6 ESX-1 Mycobacterium protein secretion regulation feedback control Microbiology QR1-502
spellingShingle	ESAT-6 ESX-1 Mycobacterium protein secretion regulation feedback control Microbiology QR1-502 Kevin G. Sanchez Micah J. Ferrell Alexandra E. Chirakos Kathleen R. Nicholson Robert B. Abramovitch Matthew M. Champion Patricia A. Champion EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
description	ABSTRACT 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.
format	article
author	Kevin G. Sanchez Micah J. Ferrell Alexandra E. Chirakos Kathleen R. Nicholson Robert B. Abramovitch Matthew M. Champion Patricia A. Champion
author_facet	Kevin G. Sanchez Micah J. Ferrell Alexandra E. Chirakos Kathleen R. Nicholson Robert B. Abramovitch Matthew M. Champion Patricia A. Champion
author_sort	Kevin G. Sanchez
title	EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
title_short	EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
title_full	EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
title_fullStr	EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
title_full_unstemmed	EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System
title_sort	espm is a conserved transcription factor that regulates gene expression in response to the esx-1 system
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/bf0cf4ea555448b694cb750f870159e3
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EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

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