Abstract
The 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.
Highlights
Mycobacterium tuberculosis, the etiological agent of human tuberculosis, is arguably the world’s most successful human pathogen
Mycobacterium tuberculosis is the etiological agent of human tuberculosis, a life-threatening disease which has seen a recrudescence in the last decades due to the spread of drugresistant bacterial strains and to co-morbidities such as HIV and diabetes
Host-pathogen interaction and disease progression are mediated by various virulence factors encoded by the bacterial genome, the most important of them being the ESX-1 or type VII secretion system [6]
Summary
Mycobacterium tuberculosis, the etiological agent of human tuberculosis, is arguably the world’s most successful human pathogen. Host-pathogen interaction and disease progression are mediated by various virulence factors encoded by the bacterial genome, the most important of them being the ESX-1 or type VII secretion system [6]. ESX loci are characterized by genes encoding small secreted proteins with a conserved tryptophan-x-glycine (WXG) motif and by transmembrane ATPases belonging to the FtsK-SpoIIIE-like family [7,8]. The ESX-1 cluster comprises approximately twenty genes and encodes a specialized secretion apparatus, which releases effectors into the extracellular milieu. The role played by ESX-1 in cytosolic recognition and stimulation of innate immunity [15,16,17], phagosomal rupture and bacterial escape [18,19], intercellular spread and systemic disease [20,21] has been the object of numerous studies. The ESX-1 secretion system has been considered as a potential drug target for the development of anti-virulence drugs [22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
