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WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria

Abdallah M. Abdallah, E.M. Weerdenburg, Qingtian Guan, R. Ummels, S. Borggreve, S.A. Adroub, Tareq B. Malas, Raeece Naeem, Huoming Zhang, T.D. Otto, W. Bitter, A. Pain
doi: https://doi.org/10.1101/297440
Abdallah M. Abdallah
Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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  • For correspondence: abdallah.abdallah@kaust.edu.sa w.bitter@vumc.nl arnab.pain@kaust.edu.sa
E.M. Weerdenburg
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands
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Qingtian Guan
Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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R. Ummels
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands
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S. Borggreve
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands
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S.A. Adroub
Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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Tareq B. Malas
Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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Raeece Naeem
Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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Huoming Zhang
Bioscience Core Laboratory, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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T.D. Otto
Pathogen Genomics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
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W. Bitter
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands
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  • For correspondence: abdallah.abdallah@kaust.edu.sa w.bitter@vumc.nl arnab.pain@kaust.edu.sa
A. Pain
Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal-Jeddah, Kingdom of Saudi Arabia
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  • For correspondence: abdallah.abdallah@kaust.edu.sa w.bitter@vumc.nl arnab.pain@kaust.edu.sa
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Abstract

The mycobacterial type VII secretion system ESX-1 is responsible for the secretion of a number of proteins that play important roles during host infection. The regulation of the expression of secreted proteins is often essential to establish successful infection. Using transcriptome sequencing, we found that the abrogation of ESX-1 function in Mycobacterium marinum leads to a pronounced increase in gene expression levels of the espA operon during the infection of macrophages, suggesting an important role in ESX-1-mediated virulence during the early phase of infection. In addition, the disruption of ESX-1-mediated protein secretion also leads to a specific down-regulation of the ESX-1 substrates, but not of the structural components of this system, during growth in culture medium. This effect is observed in both M. marinum and M. tuberculosis. We established that down-regulation of ESX-1 substrates is the result of a regulatory process that is influenced by the putative transcriptional regulator whib6, which is located adjacent to the esx-1 locus. In addition, the overexpression of the ESX-1-associated PE35/PPE68 protein pair resulted in a significantly increased secretion of the ESX-1 substrate EsxA, demonstrating a functional link between these proteins. Taken together, these data show that WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates and that ESX-1 substrates are regulated independently from the structural components, both during infection and as a result of active secretion.

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Posted May 02, 2018.
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WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria
Abdallah M. Abdallah, E.M. Weerdenburg, Qingtian Guan, R. Ummels, S. Borggreve, S.A. Adroub, Tareq B. Malas, Raeece Naeem, Huoming Zhang, T.D. Otto, W. Bitter, A. Pain
bioRxiv 297440; doi: https://doi.org/10.1101/297440
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WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria
Abdallah M. Abdallah, E.M. Weerdenburg, Qingtian Guan, R. Ummels, S. Borggreve, S.A. Adroub, Tareq B. Malas, Raeece Naeem, Huoming Zhang, T.D. Otto, W. Bitter, A. Pain
bioRxiv 297440; doi: https://doi.org/10.1101/297440

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