TY - JOUR T1 - WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria JF - bioRxiv DO - 10.1101/297440 SP - 297440 AU - Abdallah M. Abdallah AU - E.M. Weerdenburg AU - Qingtian Guan AU - R. Ummels AU - S. Borggreve AU - S.A. Adroub AU - Tareq B. Malas AU - Raeece Naeem AU - Huoming Zhang AU - T.D. Otto AU - W. Bitter AU - A. Pain Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/04/08/297440.abstract N2 - The mycobacterial type VII secretion system ESX-1 is responsible for secretion of a number of proteins that play an important role during infection of the host. Regulation of expression of secreted proteins is often essential to establish a successful infection. Using transcriptome sequencing, we found that abrogation of ESX-1 function in Mycobacterium marinum leads to a pronounced increase in gene expression levels of the espA operon during infection of macrophages, suggesting an important role in ESX-1-mediated virulence during the early phase of infection. In addition, we found that disruption of ESX-1-mediated protein secretion leads to a specific down-regulation of the substrates, but not the structural components of this system, in both M. marinum and M. tuberculosis during growth in culture medium. We established that down-regulation of ESX-1 substrates is the result of a regulatory process, which is influenced by the putative transcriptional regulator whib6, located adjacent to the esx-1 locus. In addition, overexpression of the ESX-1 associated PE35/PPE68 protein pair resulted in significantly increased secretion of the ESX-1 substrate EsxA, demonstrating a functional link between these proteins. Together, these data show that ESX-1 substrates are regulated independently from the structural components, both during infection and as a result of active secretion. ER -