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

Shah, Swati; Cannon, Joe R.; Fenselau, Catherine; Briken, Volker

doi:10.1128/iai.00827-15

Cited by 50 publications

(50 citation statements)

References 63 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The PE and PPE proteins encoded by such operons are thought to be exclusively secreted as PE and PPE heterodimers that may not be promiscuous to other secretion partners (Ekiert and Cox, ; Korotkova et al , ; Chen et al , ; Phan et al , ; Phan and Houben, ). A notable example of such operonic organization is the PE8‐PPE15‐EsxI‐EsxJ operon, which was shown to facilitate protein secretion of other TypeVII and non‐TypeVII substrates (Shah et al , ). Similarly, the PE13‐PPE18‐EsxK‐EsxL is another well‐studied operon, of which PPE18 represents an important antigen component of the M72/AS01E subunit vaccine candidate (Meeren et al , ).…”

Section: Secretion and Functions Of Specific Pe And Ppe Protein Subgrmentioning

confidence: 99%

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

Ates

2019

Molecular Microbiology

View full text Add to dashboard Cite

The PE and PPE proteins of Mycobacterium tuberculosis have been studied with great interest since their discovery. Named after the conserved proline (P) and glutamic acid (E) residues in their N-terminal domains, these proteins are postulated to perform wide-ranging roles in virulence and immune modulation. However, technical challenges in studying these proteins and their encoding genes have hampered the elucidation of molecular mechanisms and leave many open questions regarding the biological functions mediated by these proteins. Here, I review the shared and unique characteristics of PE and PPE proteins from a molecular perspective linking this information to their functions in mycobacterial virulence. I discuss how the different subgroups (PE_PGRS, PPE-PPW, PPE-SVP and PPE-MPTR) are defined and why this classification of paramount importance to understand the PE and PPE proteins as individuals and or groups. The goal of this MicroReview is to summarize and structure the existing information on this gene family into a simplified framework of thinking about PE and PPE proteins and genes. Thereby, I hope to provide helpful starting points in studying these genes and proteins for researchers with different backgrounds. This has particular implications for the design and monitoring of novel vaccine candidates and in understanding the evolution of the M. tuberculosis complex.

show abstract

Section: Secretion and Functions Of Specific Pe And Ppe Protein Subgrmentioning

confidence: 99%

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

Ates

2019

Molecular Microbiology

View full text Add to dashboard Cite

show abstract

“…The Δ pstA1 mutant could also interfere with IFN-γ production or signaling due to constitutive ESX-5 secretion. Manipulation of cytokine responses is a plausible explanation considering that ESX-5 has previously been implicated in activating the inflammasome and triggering IL-1β production by infected cells (18, 19). Finally, the susceptibility of Irgm1 -/- mice to infection with intracellular pathogens can be reversed by deletion of a second IFN-γ regulated GTPase Irgm3 (44).…”

Section: Discussionmentioning

confidence: 99%

“…Though the precise function of ESX-5 remains unclear, it appears to influence nutrient acquisition to enable M. tuberculosis replication (15-17) and to promote host cell necrosis by activating the inflammasome and stimulating IL-1β secretion (18, 19). In the related pathogen Mycobacterium marinum , ESX-5 secretes most proteins that belong to the mycobacteria-specific PE and PPE protein families (16, 20).…”

Section: Introductionmentioning

confidence: 99%

The Mycobacterium tuberculosis Phosphate-Sensing Pst/SenX3-RegX3 System Regulates ESX-5 Secretion to Evade Host Immunity

Elliott

2018

Preprint

View full text Add to dashboard Cite

15The Mycobacterium tuberculosis Type VII secretion system ESX-5, which has been implicated 16 in virulence, is activated at the transcriptional level by the phosphate starvation responsive 17 Pst/SenX3-RegX3 signal transduction system. Deletion of pstA1, which encodes a Pst 18 phosphate transporter component, causes constitutive activation of the response regulator 19 RegX3, hyper-secretion of ESX-5 substrates and attenuation in the mouse infection model. We 20 hypothesized that constitutive activation of ESX-5 secretion causes attenuation of the ∆pstA1 21 mutant. To test this, we uncoupled ESX-5 from regulation by RegX3. Using electrophoretic 22 mobility shift assays, we defined a RegX3 binding site in the esx-5 locus. Deletion or mutation of 23 the RegX3 binding site reversed hyper-secretion of the ESX-5 substrate EsxN by the ∆pstA1 24 mutant and abrogated induction of EsxN secretion in response to phosphate limitation by wild-25 type M. tuberculosis. Deletion of the esx-5 RegX3 binding site (∆BS) suppressed attenuation of 26 the ∆pstA1 mutant in Irgm1 -/mice, suggesting that constitutive ESX-5 secretion limits M.27 tuberculosis evasion of host immune responses that are independent of Irgm1. However, the 28 ∆pstA1∆BS mutant remained attenuated in both NOS2 -/and C57BL/6 mice, suggesting that 29 factors other than ESX-5 secretion also contribute to attenuation of the ∆pstA1 mutant. In 30 addition, a ∆pstA1∆esxN mutant lacking the hyper-secreted ESX-5 substrate EsxN remained 31 attenuated in Irgm1 -/mice, suggesting that ESX-5 substrates other than EsxN cause increased 32 susceptibility to host immunity. Our data indicate that while M. tuberculosis requires ESX-5 for 33 virulence, it tightly controls secretion of ESX-5 substrates to avoid elimination by host immune 34 responses. 35 INTRODUCTION 36Pathogenic bacteria often regulate the activity of specialized protein secretion systems 37 that are required for virulence to ensure release of secreted effectors only at the appropriate 38 stage of infection. Tight control of secretion system activity may limit recognition by the host 39 immune system or prevent expression of complex secretion machines that restrict growth (1, 2). 3Mycobacterium tuberculosis, the causative agent of tuberculosis, encodes five Type VII or ESX 41 specialized protein secretion systems, of which ESX-1, ESX-3 and ESX-5 have been shown to 42 promote pathogenesis (3). M. tuberculosis regulates activity of each of these secretion systems 43 in response to signals encountered in the host. Iron limitation activates ESX-3 (4), which plays a 44 role in both iron scavenging and inhibiting phagosome maturation (5, 6). ESX-1 permeabilizes 45 the phagosomal membrane to allow bacterial access to the host cell cytoplasm (7-9). ESX-1 46 secretion is regulated by two signal transduction systems, PhoPR and MprAB, that respond to 47 acidic pH and cell wall stress, respectively, signals that M. tuberculosis encounters in the 48 phagosome (10-13). We recently demonstrated that M. tuberculosis activates ESX-5 ...

show abstract

“…In MTB, disruption of ESX-5 showed a strong attenuation, failure in the cell wall integrity and the loss of the secretion of the PPE protein [57]. ESX-5a region, from ESX5 is composed by duplicated genes and had been related with inflammasome activation [58]. Also, mutations in the ESX-5 system components as esxC5 are related with ofloxacin resistance in MTB [59].…”

Section: Esx-5mentioning

confidence: 99%

Virulence Factors and Pathogenicity of Mycobacterium

Echeverría-Valencia¹,

Flores-Villalva²,

Espitia³

2018

Mycobacterium - Research and Development

View full text Add to dashboard Cite

Virulence, is referred as the ability of a pathogen to cause disease, and for mycobacteria it depends on their ability to reside within host cells and evade the microbicidal mechanisms of macrophages. The outcome of tuberculosis (TB) infection is highly variable and it seems that the closest relationship between the Mycobacterium genre and humans has shaped the mycobacterial genome to encode bacterial factors that reflects a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity causing disease even in fully immunocompetent host. Although Mycobacterium tuberculosis (MTB) does not have classical virulence factors, it has described many virulence-associated genes and virulence lifestyle genes from Mycobacterium tuberculosis complex (MTBC). In this chapter, we describe the most important gene/molecule involved in the host defense modulation response, also the plethora of strategies to evade immune mechanisms of macrophage. We review the main genes whose inactivation in the mycobacterial genome leads to a measurable loss in virulence in the different validated TB models.

show abstract

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

Cited by 50 publications

References 63 publications

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

The Mycobacterium tuberculosis Phosphate-Sensing Pst/SenX3-RegX3 System Regulates ESX-5 Secretion to Evade Host Immunity

Virulence Factors and Pathogenicity of Mycobacterium

Contact Info

Product

Resources

About