Integrated transcriptomic and proteomic analysis of pathogenic mycobacteria and their esx-1 mutants reveal secretion-dependent regulation of ESX-1 substrates and WhiB6 as a transcriptional regulator

Manganelli, R. et al. (2019) Integrated transcriptomic and proteomic analysis of pathogenic mycobacteria and their esx-1 mutants reveal secretion-dependent regulation of ESX-1 substrates and WhiB6 as a transcriptional regulator. PLoS ONE, 14(1), e0211003. (doi: 10.1371/journal.pone.0211003) (PMID:30673778) (PMCID:PMC6343904)

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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. 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.

Item Type:Articles
Additional Information:Work in AP’s laboratory is supported by the KAUST faculty baseline fund (BAS/1/1020-01- 01).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Otto, Dr Thomas
Creator Roles:
Otto, T. D.Methodology
Authors: Manganelli, R., Abdallah, A. M., Weerdenburg, E. M., Guan, Q., Ummels, R., Borggreve, S., Adroub, S. A., Malas, T. B., Naeem, R., Zhang, H., Otto, T. D., Bitter, W., and Pain, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in PLoS ONE 14(1):e0211003
Publisher Policy:Reproduced under a Creative Commons License

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