WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Pathogen Genomics Laboratory
Bioscience Core Lab
KAUST Grant NumberBAS/1/1020-01-01
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AbstractThe 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.
CitationAbdallah AM, Weerdenburg E, Guan Q, Ummels R, Borggreve S, et al. (2018) WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria. Available: http://dx.doi.org/10.1101/297440.
SponsorsWe thank Astrid van der Sar and Esther Stoop for providing the M. marinum E11 ESX-1 mutants. Work in AP’s laboratory is supported by the KAUST faculty baseline fund (BAS/1/1020-01-01). The authors thank members of the Bioscience Core Lab (BCL) at KAUST for sequencing the RNA-seq libraries on the Illumina Hiseq platform and for running protein samples through the quantitative proteomics workflow with the LTQ Orbitrap Velos instrument (Thermo Scientific).
PublisherCold Spring Harbor Laboratory