Sala, ClaudiaOdermatt, Nina T.Soler-Arnedo, PalomaGuelen, Muhammet F.von Schultz, SofiaBenjak, AndrejCole, Stewart T.2019-01-232019-01-232019-01-232018-12-0110.1371/journal.ppat.1007491https://infoscience.epfl.ch/handle/20.500.14299/153807WOS:000454721500033The ESX-1, type VII, secretion system represents the major virulence determinant of Mycobacterium tuberculosis, one of the most successful intracellular pathogens. Here, by combining genetic and high-throughput approaches, we show that EspL, a protein of 115 amino acids, is essential for mediating ESX-1-dependent virulence and for stabilization of EspE, EspF and EspH protein levels. Indeed, an espL knock-out mutant was unable to replicate intracellularly, secrete ESX-1 substrates or stimulate innate cytokine production. Moreover, proteomic studies detected greatly reduced amounts of EspE, EspF and EspH in the espL mutant as compared to the wild type strain, suggesting a role for EspL as a chaperone. The latter conclusion was further supported by discovering that EspL interacts with EspD, which was previously demonstrated to stabilize the ESX-1 substrates and effector proteins, EspA and EspC. Loss of EspL also leads to downregulation in M. tuberculosis of WhiB6, a redox-sensitive transcriptional activator of ESX-1 genes. Overall, our data highlight the importance of a so-far overlooked, though conserved, component of the ESX-1 secretion system and begin to delineate the role played by EspE, EspF and EspH in virulence and host-pathogen interaction.MicrobiologyParasitologyVirologyMicrobiologyParasitologyVirologyesx-1 secretioncalmette-guerinbovis bcgproteinesat-6dnaexpressionwhib6transcriptomepurificationtext::journal::journal article::research article