A unique <i>Mycobacterium</i> ESX‐1 protein co‐secretes with CFP‐10/ESAT‐6 and is necessary for inhibiting phagosome maturation

Xu, Junjie; Laine, Outi; Masciocchi, Mark; Manoranjan, Joanna; Smith, Jennifer; Du, Shao Jun; Edwards, Nathan; Zhu, Xiaoping; Fenselau, Catherine; Gao, Lian-Yong

doi:10.1111/j.1365-2958.2007.05959.x

Cited by 119 publications

(119 citation statements)

References 35 publications

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“…M. marinum culture filtrate (CF) and cell lysate (CL) preparation was done as previously described (15). M. tuberculosis cultures were grown in 7H9 medium to log phase, washed, and then transferred to Sauton's medium (with 0.05% Tween 80) at a starting OD of 0.05.…”

Section: Methodsmentioning

confidence: 99%

“…The CF was filtered and then concentrated using Amicon Ultra centrifugal filter units (Millipore). The CL was generated by resuspending the bacterial pellet in 20 mM Tris-HCl (pH 7.6) and breaking up the cells by bead beating as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

“…ESX-1 is required for the cosecretion of two ESAT-6 family proteins, EsxA and EsxB (13). The other known substrates are Rv3881c (15) and Rv3864 (16).…”

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confidence: 99%

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A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

et al. 2015

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The ESX-5 secretion system of Mycobacterium tuberculosis is important for bacterial virulence and for the secretion of the large PE/PPE protein family, whose genes constitute 10% of the M. tuberculosis genome. A four-gene region of the ESX-5 system is duplicated three times in the M. tuberculosis genome, but the functions of these duplicates are unknown. Here we investigated one of these duplicates: the region carrying the esxI, esxJ, ppe15, and pe8 genes (ESX-5a). An ESX-5a deletion mutant in the model system M. marinum background was deficient in the secretion of some members of the PE/PPE family of proteins. Surprisingly, we also identified other proteins that are not members of this family, thus expanding the range of ESX-5 secretion substrates. In addition, we demonstrated that ESX-5a is important for the virulence of M. marinum in the zebrafish model. Furthermore, we showed the role of the M. tuberculosis ESX-5a region in inflammasome activation but not host cell death induction, which is different from the case for the M. tuberculosis ESX-5 system. In conclusion, the ESX-5a region is nonredundant with its ESX-5 paralog and is necessary for secretion of a specific subset of proteins in M. tuberculosis and M. marinum that are important for bacterial virulence of M. marinum. Our findings point to a role for the three ESX-5 duplicate regions in the selection of substrates for secretion via ESX-5, and hence, they provide the basis for a refined model of the molecular mechanism of this type VII secretion system. Mycobacterium tuberculosis is an extremely successful pathogen that employs various strategies to evade immune responses and persist within the host (1, 2). Integral to this manipulation of the host by M. tuberculosis is the secretion of virulence factors by various secretion systems (3). There are five different type VII secretion systems (T7SS) in M. tuberculosis (ESX-1 to ESX-5) (4, 5). The different ESX systems were most likely generated via duplications of the ancestral system ESX-4 in the chronological order ESX-1, ESX-3, ESX-2, and ESX-5 (6). All the ESX secretion systems have a set of common genes which encode the core components of their secretion machinery, among which are genes encoding two members of the ESAT-6-like family (Esx proteins) (5, 7).The region of difference 1 (RD1) is a 9.5-kbp stretch comprising 9 genes of ESX-1 that is deleted in all strains of the live tuberculosis vaccine M. bovis BCG (8). The importance of ESX-1 for virulence was first demonstrated by expressing the entire RD1 locus in the BCG vaccine strain and restoring virulence in the mouse model of tuberculosis (9, 10). ESX-1 is essential for full virulence of M. tuberculosis in mice (11-13). In M. marinum, it is required for the growth of bacteria within macrophages, cell-tocell spread, and virulence in the zebrafish model (14). ESX-1 is required for the cosecretion of two ESAT-6 family proteins, EsxA and EsxB (13). The other known substrates are Rv3881c (15) and Rv3864 (16).The ESX-5 system is the most recently evolve...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

et al. 2015

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“…Esx-1 is the best described. Substrates of this secretion system include the esx-1-encoded EsxB (Esat-6), EsxA (Cfp-10) and Rv3881c (6,7), and EspA and EspB, encoded by an unlinked but evolutionarily related genetic locus (8,9). Although Esx-1 and its substrates are required for virulence of pathogenic mycobacteria (10)(11)(12) and conjugation in M. smegmatis (13,14), their precise contributions to these processes have not been determined (1,2).…”

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confidence: 99%

Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition

Siegrist

Unnikrishnan

McConnell

et al. 2009

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

284

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The Esx secretion pathway is conserved across Gram-positive bacteria. Esx-1, the best-characterized system, is required for virulence of Mycobacterium tuberculosis, although its precise function during infection remains unclear. Esx-3, a paralogous system present in all mycobacterial species, is required for growth in vitro. Here, we demonstrate that mycobacteria lacking Esx-3 are defective in acquiring iron. To compete for the limited iron available in the host and the environment, these organisms use mycobactin, high-affinity iron-binding molecules. In the absence of Esx-3, mycobacteria synthesize mycobactin but are unable to use the bound iron and are impaired severely for growth during macrophage infection. Mycobacteria thus require a specialized secretion system for acquiring iron from siderophores.secretion ͉ siderophore

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“…In Mycobacterium marinum, the CFP-10/ESAT-6 secretion manipulates the phagosome-lysosome fusion. Mutations in this secretion system results in enhanced phagosome-lysosome fusion and reduced survival of mycobacteria (Tan et al, 2006;Majlessi et al, 2005;Champion et al, 2006;Xu et al, 2007;Lee et al, 2001). Analyses of deletion mutants of ESAT-6 have identified the key amino acids in complex formation, virulence and secretion (Brodin et al, 2005).…”

Section: Virulence Linked To Cfp10/esat6 Secretionmentioning

confidence: 99%

Mycobacterium tuberculosis RD-1 Secreted Antigens as Protective and Risk Factors for Tuberculosis

Ganguly¹,

Sharma²

2012

Understanding Tuberculosis - Deciphering the Secret Life of the Bacilli

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A unique Mycobacterium ESX‐1 protein co‐secretes with CFP‐10/ESAT‐6 and is necessary for inhibiting phagosome maturation

Cited by 119 publications

References 35 publications

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition

Mycobacterium tuberculosis RD-1 Secreted Antigens as Protective and Risk Factors for Tuberculosis

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