ESAT-6-Like Protein Secretion in<i>Bacillus anthracis</i>

Garufi, Gabriella; Butler, Emily K.; Missiakas, Dominique

doi:10.1128/jb.00458-08

Cited by 73 publications

(76 citation statements)

References 31 publications

(31 reference statements)

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“…Homologs of the mycobacterial T7SS that transport WXG100 proteins have also been described in firmicutes, including Bacillus anthracis (32), Bacillus subtilis (33), and Staphylococcus aureus (14). Firmicutes carry some (EsxA, EsxB, and EccC), but not all, of the mycobacterial ESX-1 components required for secretion of ESAT-6 and CFP-10 (34), and their pathways are designated type VIIb (29).…”

Section: Discussionmentioning

confidence: 99%

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

et al. 2017

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Staphylococcus aureus, an invasive pathogen of humans and animals, requires a specialized ESS pathway to secrete proteins (EsxA, EsxB, EsxC, and EsxD) during infection. Expression of ess genes is required for S. aureus establishment of persistent abscess lesions following bloodstream infection; however, the mechanisms whereby effectors of the ESS pathway implement their virulence strategies were heretofore not known. Here, we show that EssE forms a complex with other members of the ESS secretion pathway and its substrates, promoting the secretion of EsxA, EsxB, EsxC, EsxD, and EssD. During bloodstream infection of mice, the S. aureus essE mutant displays defects in host cytokine responses, specifically in the production of interleukin-12 (IL-12) (p40/p70) and the suppression of RANTES (CCL5), activators of T H 1 T cell responses and immune cell chemotaxis, respectively. Thus, essE-mediated secretion of protein effectors via the ESS pathway may enable S. aureus to manipulate host immune responses by modifying the production of cytokines.IMPORTANCE Staphylococcus aureus and other firmicutes evolved a specialized ESS (EsxA/ESAT-6-like secretion system) pathway for the secretion of small subsets of proteins lacking canonical signal peptides. The molecular mechanisms for ESSdependent secretion and their functional purpose are still unknown. We demonstrate here that S. aureus EssE functions as a membrane assembly platform for elements of the secretion machinery and their substrates. Furthermore, S. aureus EssEmediated secretion contributes to the production or the suppression of specific cytokines during host infection, thereby modifying immune responses toward this pathogen.

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Section: Discussionmentioning

confidence: 99%

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

et al. 2017

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“…"Type VII" secretion systems distantly related to mycobacterial ESX systems have been identified in numerous other Gram-positive bacteria (13)(14)(15)(16)(17). The protein components of type VII secretion systems differ considerably between bacterial species but generally include the following: (i) one or more small helical proteins of the WXG100 protein family (e.g., ESAT-6, YukE), (ii) an FtsK/SpoIII-type ATPase that is thought to drive protein secretion (e.g., EccC, YukB), and (iii) a multipass transmembrane protein that may form the pore of the translocon (e.g., EccD, YueB).…”

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confidence: 99%

Structure of a PE–PPE–EspG complex fromMycobacterium tuberculosisreveals molecular specificity of ESX protein secretion

Ekiert

Cox

2014

Proc. Natl. Acad. Sci. U.S.A.

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Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed "type VII." How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE-PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis-acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways.tuberculosis | protein secretion | antigenic variation | virulence factor | host-pathogen interactions

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“…T he ESAT-6 system-1 (ESX-1)/WXG-100 secretion system (Wss) is required for the virulence of both Gram-positive and mycobacterial pathogens (1)(2)(3)(4)(5). In mycobacterial pathogens the ESX-1 system likely promotes permeabilization of the phagosomal membrane allowing either the bacterial cell or bacterial products access to the cytosol of the macrophage (6)(7)(8)(9)(10).…”

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A Novel ESX-1 Locus Reveals that Surface-Associated ESX-1 Substrates Mediate Virulence in Mycobacterium marinum

et al. 2014

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EsxA (ESAT-6) and EsxB (CFP-10) are virulence factors exported by the ESX-1 system in mycobacterial pathogens. In Mycobacterium marinum, an established model for ESX-1 secretion in Mycobacterium tuberculosis, genes required for ESX-1 export reside at the extended region of difference 1 (RD1) locus. In this study, a novel locus required for ESX-1 export in M. marinum was identified outside the RD1 locus. An M. marinum strain bearing a transposon-insertion between the MMAR_1663 and MMAR_1664 genes exhibited smooth-colony morphology, was deficient for ESX-1 export, was nonhemolytic, and was attenuated for virulence. Genetic complementation revealed a restoration of colony morphology and a partial restoration of virulence in cell culture models. Yet hemolysis and the export of ESX-1 substrates into the bacteriological medium in vitro as measured by both immunoblotting and quantitative proteomics were not restored. We show that genetic complementation of the transposon insertion strain partially restored the translocation of EsxA and EsxB to the mycobacterial cell surface. Our findings indicate that the export of EsxA and EsxB to the cell surface, rather than secretion into the bacteriological medium, correlates with virulence in M. marinum. Together, these findings not only expand the known genetic loci required for ESX-1 secretion in M. marinum but also provide an explanation for the observed disparity between in vitro ESX-1 export and virulence.T he ESAT-6 system-1 (ESX-1)/WXG-100 secretion system (Wss) is required for the virulence of both Gram-positive and mycobacterial pathogens (1-5). In mycobacterial pathogens the ESX-1 system likely promotes permeabilization of the phagosomal membrane allowing either the bacterial cell or bacterial products access to the cytosol of the macrophage (6-10). The ESX-1/Wss system is conserved and functional in nonpathogenic bacteria, where it promotes a range of activities, including conjugation (11-16).Protein substrates are translocated across the mycobacterial cytoplasmic membrane by the ESX-1 export system (3, 5). Several genes are required for protein translocation, disruption of which results in loss of substrate secretion into the bacteriological medium (culture supernatant) in vitro (3)(4)(5)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). It is unknown how the protein substrates are secreted across the mycolate outer membrane (MOM) out of the mycobacterial cell or if the known ESX genes promote MOM translocation. Likewise, it is not clear if the ESX-1 substrates are true exoproteins (released from the cell) or extrinsically associated with the MOM and shed into the bacteriological medium (27-29). Indeed, in addition to the culture supernatant, ESX-1 substrates have been localized to the mycobacterial cell wall and associated with the surface of the mycobacterial cell (28-31). It is unclear which population of ESX-1 substrates mediates virulence. The active secretion of ESX-1 substrates into the phagosome or cytosol of the macrophage has not been routinely observed.In the human ...

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ESAT-6-Like Protein Secretion inBacillus anthracis

Cited by 73 publications

References 31 publications

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection

Structure of a PE–PPE–EspG complex fromMycobacterium tuberculosisreveals molecular specificity of ESX protein secretion

A Novel ESX-1 Locus Reveals that Surface-Associated ESX-1 Substrates Mediate Virulence in Mycobacterium marinum

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