Polar Localization of Virulence-Related Esx-1 Secretion in Mycobacteria

Carlsson, Fredric; Joshi, S.N.; Rangell, Linda; Brown, Eric J.

doi:10.1371/journal.ppat.1000285

Cited by 102 publications

(138 citation statements)

References 34 publications

(57 reference statements)

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“…In the ESX-1 mutant the detection levels of MmPE35 were lower than in the WT and ESX-5 mutant strains. As discussed above for PE25/PPE41, this is likely due to MmPE35's instability in the absence of a functional ESX-1 system (5,11,13,33). These results show that MmPE35 is indeed secreted via ESX-1.…”

Section: Esx-5 Secretion Of M Tuberculosis Lipy Depends On a Similarsupporting

confidence: 56%

“…This secretion defect was not accompanied by an increase in cellular levels of PE25 and PPE41. This phenomenon is often observed for ESX-1 and ESX-5 substrates and indicates that the stability of the substrates depends on the presence of the T7S systems in the bacterial cell (5,11,13,33). PPE41 was detected in two forms, a 25-kDa band, which represents full-length PPE41, and a smaller form of ∼19 kDa, which probably represents degraded PPE41 (20).…”

Section: Resultsmentioning

confidence: 78%

“…The archetypical T7S system, ESX-1, is responsible for the secretion of several proteins, including the ESX-1-encoded T-cell antigens ESAT-6 (early secreted antigenic target of 6 kDa) and CFP-10 (culture filtrate protein of 10 kDa) (7,(11)(12)(13)(14)(15). ESX-1 and its substrates play an important, albeit not yet fully understood role in M. tuberculosis virulence.…”

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confidence: 99%

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General secretion signal for the mycobacterial type VII secretion pathway

Daleke

Ummels

Bawono³

et al. 2012

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

182

224

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Mycobacterial pathogens use specialized type VII secretion (T7S) systems to transport crucial virulence factors across their unusual cell envelope into infected host cells. These virulence factors lack classical secretion signals and the mechanism of substrate recognition is not well understood. Here we demonstrate that the model T7S substrates PE25/PPE41, which form a heterodimer, are targeted to the T7S pathway ESX-5 by a signal located in the C terminus of PE25. Site-directed mutagenesis of residues within this C terminus resulted in the identification of a highly conserved motif, i.e., YxxxD/E, which is required for secretion. This motif was also essential for the secretion of LipY, another ESX-5 substrate. Pathogenic mycobacteria have several different T7S systems and we identified a PE protein that is secreted by the ESX-1 system, which allowed us to compare substrate recognition of these two T7S systems. Surprisingly, this ESX-1 substrate contained a C-terminal signal functionally equivalent to that of PE25. Exchange of these C-terminal secretion signals between the PE proteins restored secretion, but each PE protein remained secreted via its own ESX secretion system, indicating that an additional signal(s) provides system specificity. Remarkably, the YxxxD/E motif was also present in and required for efficient secretion of the ESX-1 substrates CFP-10 and EspB. Therefore, our data show that the YxxxD/E motif is a general secretion signal that is present in all known mycobacterial T7S substrates or substrate complexes.

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Section: Esx-5 Secretion Of M Tuberculosis Lipy Depends On a Similarsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 78%

mentioning

confidence: 99%

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General secretion signal for the mycobacterial type VII secretion pathway

Daleke

Ummels

Bawono³

et al. 2012

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

182

224

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“…The virulence secretion system ESX-1 localizes to the poles of M. marinum (25) and is encoded in the RD1-region. Involvement of this secretion system in ejection has been demonstrated before (17) in particular the secreted factor ESAT-6.…”

Section: Discussionmentioning

confidence: 99%

“…The specific recruitment of the autophagy machinery to the distal pole of ejecting bacteria raises the question whether polar mycobacterial virulence factors are involved in this recruitment and whether this is specific for pathogenic M. marinum. The virulence secretion system ESX-1 is enriched at the poles of M. marinum (25) and is encoded in the RD1-region. Involvement of this secretion system in ejection has been demonstrated before (17).…”

Section: Atg1-mentioning

confidence: 99%

The autophagic machinery ensures nonlytic transmission of mycobacteria

Gerstenmaier

Pilla

Herrmann

et al. 2015

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

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In contrast to mechanisms mediating uptake of intracellular bacterial pathogens, bacterial egress and cell-to-cell transmission are poorly understood. Previously, we showed that the transmission of pathogenic mycobacteria between phagocytic cells also depends on nonlytic ejection through an F-actin based structure, called the ejectosome. How the host cell maintains integrity of its plasma membrane during the ejection process was unknown. Here, we reveal an unexpected function for the autophagic machinery in nonlytic spreading of bacteria. We show that ejecting mycobacteria are escorted by a distinct polar autophagocytic vacuole. If autophagy is impaired, cell-to-cell transmission is inhibited, the host plasma membrane becomes compromised and the host cells die. These findings highlight a previously unidentified, highly ordered interaction between bacteria and the autophagic pathway and might represent the ancient way to ensure nonlytic egress of bacteria.autophagy | Dictyostelium discoideum | Mycobacterium marinum | ejection

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Systematic review on the proteomic profile of Mycobacterium tuberculosis exposed to drugs

Campanerut‐Sá

Ghiraldi-Lopes

Meneguello

et al. 2017

Proteomics Clinical Apps

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The authors present an overview about proteomics studies in Mycobacterium tuberculosis exposed to some anti-tuberculosis drugs and new candidates, using two-dimensional gel electrophoresis and mass spectrometry. To date, that the authors have knowledge, this is the first studies that was performed specifically in M. tuberculosis using systematic review on electronic literature conducted in three databases using the following search terms: tuberculosis OR mycobacterium tuberculosis, proteome OR proteomics, and mass spectrometry electrospray ionization OR matrix-assisted laser desorption ionization OR two-dimensional gel electrophoresis. By electronic search, 622 abstracts of the original articles published from November 2003 to March 2016 were selected. After the selection, four articles fulfill proposed criteria and were included in this study. The studies reported changes in the protein profile of M. tuberculosis after exposure to isoniazid, ethambutol, streptomycin, ofloxacin, moxifloxacin and two new drugs candidates, SQ109 and ATB107. In conclusion, the proteins changes were related to the synthesis of mycolic acids, cellular metabolism pathways, bacterial stress and starvation.

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Polar Localization of Virulence-Related Esx-1 Secretion in Mycobacteria

Cited by 102 publications

References 34 publications

General secretion signal for the mycobacterial type VII secretion pathway

General secretion signal for the mycobacterial type VII secretion pathway

The autophagic machinery ensures nonlytic transmission of mycobacteria

Systematic review on the proteomic profile of Mycobacterium tuberculosis exposed to drugs

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