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Identification of a substrate domain that determines system specificity in mycobacterial type VII secretion systems.

ABSTRACT: Type VII secretion (T7S) systems are specialized machineries used by mycobacterial pathogens to transport important virulence factors across their highly hydrophobic cell envelope. There are up to five mycobacterial T7S systems, named ESX-1 to ESX-5, at least three of which specifically secrete a different subset of substrates. The T7S substrates or substrate complexes are defined by the general secretion motif YxxxD/E. However this motif does not determine system specificity. Here, we show that the substrate domain recognized by the EspG chaperone is the determinant factor for this specificity. We first show that the introduction of point mutations into the EspG₁-binding domain of the ESX-1 substrate pair PE35/PPE68_1 affects their secretion. Subsequently, we demonstrate that replacing this domain by the EspG₅-binding domain of the ESX-5 substrate PPE18 resulted in EspG₅ dependence and exclusive rerouting to the ESX-5 system. This rerouting of PE35/PPE68_1 to the ESX-5 system had a negative effect on the secretion of endogenous ESX-5 substrates.

SUBMITTER: Phan TH

PROVIDER: S-EPMC5311947 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Identification of a substrate domain that determines system specificity in mycobacterial type VII secretion systems.

Phan Trang H TH Ummels Roy R Bitter Wilbert W Houben Edith N G EN

Scientific reports 20170216

Type VII secretion (T7S) systems are specialized machineries used by mycobacterial pathogens to transport important virulence factors across their highly hydrophobic cell envelope. There are up to five mycobacterial T7S systems, named ESX-1 to ESX-5, at least three of which specifically secrete a different subset of substrates. The T7S substrates or substrate complexes are defined by the general secretion motif YxxxD/E. However this motif does not determine system specificity. Here, we show that ...[more]

PMID: 28205541

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Project description:BackgroundThe genome of Mycobacterium tuberculosis contains five copies of the ESX gene cluster, each encoding a dedicated protein secretion system. These ESX secretion systems have been defined as a novel Type VII secretion machinery, responsible for the secretion of proteins across the characteristic outer mycomembrane of the mycobacteria. Some of these secretion systems are involved in virulence and survival in M. tuberculosis; however they are also present in other non-pathogenic mycobacteria, and have been identified in some non-mycobacterial actinomycetes. Three components of the ESX gene cluster have also been found clustered in some gram positive monoderm organisms and are predicted to have preceded the ESX gene cluster.ResultsThis study used in silico and phylogenetic analyses to describe the evolution of the ESX gene cluster from the WXG-FtsK cluster of monoderm bacteria to the five ESX clusters present in M. tuberculosis and other slow-growing mycobacteria. The ancestral gene cluster, ESX-4, was identified in several nonmycomembrane producing actinobacteria as well as the mycomembrane-containing Corynebacteriales in which the ESX cluster began to evolve and diversify. A novel ESX gene cluster, ESX-4EVOL, was identified in some non-mycobacterial actinomycetes and M. abscessus subsp. bolletii. ESX-4EVOL contains all of the conserved components of the ESX gene cluster and appears to be a precursor of the mycobacterial ESX duplications. Between two and seven ESX gene clusters were identified in each mycobacterial species, with ESX-2 and ESX-5 specifically associated with the slow growers. The order of ESX duplication in the mycobacteria is redefined as ESX-4, ESX-3, ESX-1 and then ESX-2 and ESX-5. Plasmid-encoded precursor ESX gene clusters were identified for each of the genomic ESX-3, -1, -2 and -5 gene clusters, suggesting a novel plasmid-mediated mechanism of ESX duplication and evolution.ConclusionsThe influence of the various ESX gene clusters on vital biological and virulence-related functions has clearly influenced the diversification and success of the various mycobacterial species, and their evolution from the non-pathogenic fast-growing saprophytic to the slow-growing pathogenic organisms.

Dataset Information

Identification of a substrate domain that determines system specificity in mycobacterial type VII secretion systems.

Publications

Identification of a substrate domain that determines system specificity in mycobacterial type VII secretion systems.

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