6 kDa early secretory antigenic target (ESAT6) secretion systems (ESX; also known as type VII secretion systems) are sophisticated secretion systems that are present in a wide variety of mycobacterial and non-mycobacterial members of the phylum Actinobacteria.
The ESX-1 system of Mycobacterium tuberculosis is the most well-studied ESX system, owing to its important function in virulence, which is linked — at least in part — to the ability of one of its secreted effector proteins, EsxA, to induce phagosomal rupture in host phagocytes.
ESX-1 systems are also present in many non-pathogenic, rapid-growing mycobacteria, such as Mycobacterium smegmatis, in which they are involved in conjugal DNA transfer between donor and recipient strains. Interestingly, the ESX-1 effectors EspA, EspC and EspD, which are present in slow-growing, pathogenic mycobacteria, are absent from these non-pathogenic species.
Besides ESX-1, M. tuberculosis, which causes tuberculosis, has four additional ESX systems: ESX-3 is involved in iron acquisition; ESX-5 is involved in the secretion of members from two large mycobacterial protein families, named PE and PPE according to their Pro-Glu and Pro-Pro-Glu amino-terminal motifs; and ESX-2 and ESX-4 are systems for which the functions are currently unknown.
ESX systems are thought to have evolved from ESX-4 or ESX-4-like systems by gene duplication and diversification, as well as plasmid-mediated horizontal gene transfer.
ESX-like systems are secretion systems that are similar to mycobacterial ESX systems but that are found in Gram-positive bacteria in the phylum Firmicutes, rather than in Actinobacteria. Similarly to ESX systems, ESX-like systems contain Esx proteins that have a highly conserved WXG motif, contain an Ftsk–SpoIIIE-like ATPase, and, in some cases (for example, in Staphylococcus aureus), can be involved in pathogenicity.
Mycobacterium tuberculosis uses sophisticated secretion systems, named 6 kDa early secretory antigenic target (ESAT6) protein family secretion (ESX) systems (also known as type VII secretion systems), to export a set of effector proteins that helps the pathogen to resist or evade the host immune response. Since the discovery of the esx loci during the M. tuberculosis H37Rv genome project, structural biology, cell biology and evolutionary analyses have advanced our knowledge of the function of these systems. In this Review, we highlight the intriguing roles that these studies have revealed for ESX systems in bacterial survival and pathogenicity during infection with M. tuberculosis. Furthermore, we discuss the diversity of ESX systems that has been described among mycobacteria and selected non-mycobacterial species. Finally, we consider how our knowledge of ESX systems might be applied to the development of novel strategies for the treatment and prevention of disease.
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The authors gratefully acknowledge the support of grants from the European Community (grant H2020-PHC- 643381), the Agence Nationale de Recherche (grant ANR-14-JAMR-001-02), Institut Pasteur (grant PTR 441) and the Fondation pour la Recherche Médicale (grant DEQ20130326471). R.B. is a member of the LabEx Integrative Biology of Emerging Infectious Diseases (IBEID) consortium at Institut Pasteur. M.I.G. is supported by an M.D.–Ph.D. grant from the University of Groningen, The Netherlands.
The authors declare no competing financial interests.
A phylum of Gram-positive bacteria that is characterized by high GC content.
- Mycolic acids
Long-chain (C60–C90) fatty acids that are specifically found in the mycobacterial cell envelope; together with extractable lipids, mycolic acids form the mycobacterial outer membrane (also known as the mycomembrane).
- Arabinogalactan–peptidoglycan matrix
An essential constituent of the mycobacterial cell wall, consisting of peptidoglycan that is covalently attached to the heteropolysaccharide arabinogalactan, which is linked to the mycolic acid layer.
An iron-binding compound that is synthesized by most mycobacteria and is necessary for the recovery of iron, which is an essential element for growth.
Refers to the presence of two membranes (an inner membrane and an outer membrane) in the cell envelope. Diderm phyla encompass both Gram-negative bacteria and mycobacteria.
- Bootstrap replicates
Statistical confidence values in phylogenetic trees that are inferred from phylogenetic bootstrapping, which is an informatics-based method that is based on reconstructing many trees or replicates from minor variations of the input data.
- AAA+ ATPase
A member of a large, functionally diverse protein family of ATPases that are associated with various cellular activities that involve energy-dependent remodelling or the translocation of macromolecules.
- Tubercle bacilli
Mycobacteria that can cause tuberculosis; that is, the M. tuberculosis complex (MTBC; for example, M. africanum, M. bovis, M. microti and M. tuberculosis) and strains of the M. canettii clade, which represents the putative progenitor pool from which the MTBC evolved.
- Type IV secretion coupling proteins
Proteins that recruit nucleotide substrates to the mating pore formation system for subsequent DNA transfer.
- Mycosin 1
(MycP1). One of a family of subtilisin-like serine proteases that is found in mycobacteria.
- Pathogenicity-associated genomic island
A mobile segment of the genome, transferred by horizontal transfer, that contributes to rapid changes in virulence potential.
- Response regulator
A transcriptional regulator that activates transcription of a specific set of genes in response to certain stimuli.
- Two-component system
A regulator system that consists of a membrane-embedded sensor protein and a cytoplasmic response regulator. Two-component systems govern numerous cellular activities in diverse species of bacteria and archaea.
An iron-containing porphyrin, corresponding to a crystalline chloride of haem, which is obtained when haemoglobin reacts with acetic acid and sodium chloride.
The full set of genes of a defined species of bacteria or archaea, which comprises all of the genes that are collectively found in individual genomes of the species.
- Pathogen-associated molecular patterns
(PAMPs). Conserved molecular structures that are produced by microorganisms and that are recognized as foreign by the receptors of cells of the innate immune system.
A multiprotein signalling platform that controls the inflammatory response and coordinates antimicrobial host defences through the activation of caspase 1, which induces the processing of pro-interleukin-1β and pro-interleukin-18 into mature cytokines to be released from the cell.
Organized immune cell aggregates that form in response to selected stimuli of an infectious or non-infectious nature.
- Caspase-independent cell death
Programmed host cell death that is independent of caspase activation. In the context of mycobacterial infection, caspase-independent cell death suggests the involvement of non-endogenous factors, such as bacterial effectors, in mediating host cell death.
- Severe combined immunodeficiency
(SCID). A severe genetic disorder that is characterized by the absence of functioning T lymphocytes and B lymphocytes.
- PE_PGRS proteins
Products of a mycobacterial multigene family that is characterized by polymorphic GC-rich repetitive sequence (PGRS) motifs. PE_PGRS proteins have a highly conserved amino-terminal domain of ∼ 110 amino acids, which contains the Pro-Glu (PE) motif, and variable carboxy-terminal domains that contain numerous repetitive sequence motifs.
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Gröschel, M., Sayes, F., Simeone, R. et al. ESX secretion systems: mycobacterial evolution to counter host immunity. Nat Rev Microbiol 14, 677–691 (2016). https://doi.org/10.1038/nrmicro.2016.131
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