scholarly journals Mycobacterial Virulence Factors: Surface-Exposed Lipids and Secreted Proteins

2020 ◽  
Vol 21 (11) ◽  
pp. 3985 ◽  
Author(s):  
Angel Ly ◽  
Jun Liu
Keyword(s):  
Outer Membrane ◽  
Virulence Factors ◽  
Structural Model ◽  
Membrane Lipids ◽  
Secretion Systems ◽  
Type Vii Secretion ◽  
System 1 ◽  
Phthiocerol Dimycocerosates ◽  
Insight Into ◽  
Phenolic Glycolipids

The clinically important Mycobacterium tuberculosis (M. tb) and related mycobacterial pathogens use various virulence mechanisms to survive and cause disease in their hosts. Several well-established virulence factors include the surface-exposed lipids in the mycobacterial outer membrane, as well as the Esx family proteins and the Pro-Glu (PE)/ Pro-Pro-Glu (PPE) family proteins secreted by type VII secretion systems (T7SS). Five ESX T7SS exist in M. tb and three—EsxA secretion system-1 (ESX-1), ESX-3, and ESX-5—have been implicated in virulence, yet only the structures of ESX-3 and ESX-5 have been solved to date. Here, we summarize the current research on three outer membrane lipids—phthiocerol dimycocerosates, phenolic glycolipids, and sulfolipids—as well as the secretion machinery and substrates of three mycobacterial T7SS—ESX-1, ESX-3, and ESX-5. We propose a structural model of the M. tb ESX-1 system based on the latest structural findings of the ESX-3 and ESX-5 secretion apparatuses to gain insight into the transport mechanism of ESX-associated virulence factors.

scholarly journals The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 666 ◽  
Author(s):  
Aïcha Bah ◽  
Merlin Sanicas ◽  
Jérôme Nigou ◽  
Christophe Guilhot ◽  
Catherine Astarie-Dequeker ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virulence Factors ◽  
Defense Mechanism ◽  
Immune Defense ◽  
Knock Out ◽  
Human Macrophages ◽  
Type Vii Secretion ◽  
Type Vii Secretion System ◽  
Phagosomal Membrane ◽  
Phthiocerol Dimycocerosates

Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of Mtb and Mycobacterium bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.

scholarly journals Structure and Function of the Mycobacterial Type VII Secretion Systems

2020 ◽  
Vol 74 (1) ◽  
pp. 315-335 ◽  
Author(s):  
Catalin M. Bunduc ◽  
W. Bitter ◽  
E.N.G. Houben
Keyword(s):  
Protein Transport ◽  
Secretion Systems ◽  
Large Molecules ◽  
Functional Studies ◽  
Type Vii Secretion ◽  
Mycobacterial Diseases ◽  
Cell Envelopes ◽  
And Function ◽  
Mycobacterial Growth ◽  
Insight Into

Bacteria have evolved intricate secretion machineries for the successful delivery of large molecules across their cell envelopes. Such specialized secretion systems allow a variety of bacteria to thrive in specific host environments. In mycobacteria, type VII secretion systems (T7SSs) are dedicated protein transport machineries that fulfill diverse and crucial roles, ranging from metabolite uptake to immune evasion and subversion to conjugation. Since the discovery of mycobacterial T7SSs about 15 y ago, genetic, structural, and functional studies have provided insight into the roles and functioning of these secretion machineries. Here, we focus on recent advances in the elucidation of the structure and mechanism of mycobacterial T7SSs in protein secretion. As many of these systems are essential for mycobacterial growth or virulence, they provide opportunities for the development of novel therapies to combat a number of relevant mycobacterial diseases.

scholarly journals Toxin secretion and trafficking by Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David Pajuelo ◽  
Uday Tak ◽  
Lei Zhang ◽  
Olga Danilchanka ◽  
Anna D. Tischler ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Molecular Mechanisms ◽  
Comprehensive Analysis ◽  
Secretion Systems ◽  
Type Vii Secretion ◽  
Toxin Secretion ◽  
Phagosomal Membrane

AbstractThe tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mycobacterium tuberculosis (Mtb) in macrophages. TNT is the C-terminal domain of the outer membrane protein CpnT and gains access to the cytosol to kill macrophages infected with Mtb. However, molecular mechanisms of TNT secretion and trafficking are largely unknown. A comprehensive analysis of the five type VII secretion systems of Mtb revealed that the ESX-4 system is required for export of CpnT and surface accessibility of TNT. Furthermore, the ESX-2 and ESX-4 systems are required for permeabilization of the phagosomal membrane in addition to the ESX-1 system. Thus, these three ESX systems need to act in concert to enable trafficking of TNT into the cytosol of Mtb-infected macrophages. These discoveries establish new molecular roles for the two previously uncharacterized type VII secretion systems ESX-2 and ESX-4 and reveal an intricate link between toxin secretion and phagosomal permeabilization by Mtb.

The Type IX Secretion System and Its Role in Bacterial Function and Pathogenesis

2021 ◽  
pp. 002203452110515
Author(s):  
P.D. Veith ◽  
M.D. Glew ◽  
D.G. Gorasia ◽  
E. Cascales ◽  
E.C. Reynolds
Keyword(s):  
Cell Surface ◽  
Outer Membrane ◽  
Virulence Factors ◽  
Secretion System ◽  
Outer Membrane Vesicles ◽  
Molecular Structures ◽  
Molecular Architecture ◽  
Cargo Proteins ◽  
Type Ix Secretion System ◽  
Insight Into

Porphyromonas, Tannerella, and Prevotella species found in severe periodontitis use the Type IX Secretion System (T9SS) to load their outer membrane surface with an array of virulence factors. These virulence factors are then released on outer membrane vesicles (OMVs), which penetrate the host to dysregulate the immune response to establish a positive feedback loop of chronic, inflammatory destruction of the tooth’s supporting tissues. In this review, we present the latest information on the molecular architecture of the T9SS and provide mechanistic insight into its role in secretion and attachment of cargo proteins to produce a virulence coat on cells and OMVs. The recent molecular structures of the T9SS motor comprising PorL and PorM as well as the secretion pore Sov, together with advances in the overall interactome, have provided insight into the possible mechanisms of secretion. We propose the presence of PorL/M motors arranged in a circle at the inner membrane with bent periplasmic rotors interacting with the PorN protein. At the outer membrane, we envisage a slide carousel model where the PorN protein is driven around a circular track composed of PorK. Cargo proteins are transported by PorN to PorW and the Sov translocon just as slides are rotated to the projection window. Secreted proteins are proposed to then be shuttled along highways consisting of the PorV shuttle protein to an array of attachment complexes distributed around the cell. The cell surface attachment of cargo is a hallmark of the T9SS, and in Porphyromonas gingivalis and Tannerella forsythia, this attachment is achieved via covalent bonding to a linking sugar synthesized by the Wbp/Vim pathway. The cell-surface attached cargo are enriched on OMVs, which are then released from the cell.

scholarly journals Species-specific secretion of ESX-5 type VII substrates is determined by the linker 2 of EccC5

2019 ◽  
Author(s):  
C. M. Bunduc ◽  
R. Ummels ◽  
W. Bitter ◽  
E.N.G. Houben
Keyword(s):  
Cell Envelope ◽  
Substrate Recognition ◽  
Effector Proteins ◽  
Specific Substrate ◽  
Secretion Systems ◽  
Binding Domains ◽  
Type Vii Secretion ◽  
Wide Range ◽  
Species Specific ◽  
System 1

AbstractType VII secretion systems (T7SSs) are used by mycobacteria to translocate a wide range of effector proteins across their diderm cell envelope. These systems, also known as ESX systems, have crucial roles for the viability and/or virulence of mycobacterial pathogens, including Mycobacterium tuberculosis and the fish pathogen Mycobacterium marinum. We previously observed species-specificity in the secretion of the PE_PGRS proteins by the ESX-5 system [1], in that the M. tuberculosis ESX-5 system was unable to fully complement an M. marinum esx-5 mutant. In this study, we established that the responsible factor for this is the central membrane ATPase EccC5, which has three nucleotide binding domains (NBDs). By creating chimeric M. marinum/M. tuberculosis EccC5 constructs, we observed that PE_PGRS secretion is mediated only in the presence of an EccC5 containing the cognate linker 2, irrespective of the origin of the EccC5 backbone. This region is responsible for linking the first two NBDs and for keeping the first NBD in an inhibited state. Notably, this region is disordered in a EccC crystal structure and is particularly extended in EccC proteins of the different ESX-5 systems. These results indicate that this region is involved in species-specific substrate recognition and might therefore be an additional substrate recognition site of EccC5.

scholarly journals Crystallographic observation of the movement of the membrane-distal domain of the T7SS core component EccB1 fromMycobacterium tuberculosis

2016 ◽  
Vol 72 (2) ◽  
pp. 139-144
Author(s):  
Xiao-Qian Xie ◽  
Xiao-Li Zhang ◽  
Chao Qi ◽  
De-Feng Li ◽  
Joy Fleming ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Atpase Activity ◽  
Virulence Factors ◽  
Conformational Changes ◽  
Secretion System ◽  
Secretion Systems ◽  
Core Component ◽  
Substrate Transport ◽  
Type Vii Secretion ◽  
Type Vii Secretion System

The protein EccB1, a core component of the type VII secretion system (T7SS) ofMycobacterium tuberculosis, has been identified as an ATPase and is essential for the secretion of virulence factors by the ESX-1 system. In a previous study, EccB1 structures were determined in two different conformations. Here, two new conformations are identified and described. These four conformations present snapshots of the swinging movement of the membrane-distal domain A2. The movement of this domain involves conformational changes in two flexible loops (loop A, residues 243–264, and loop B, residues 324–341) which are rich in proline and glycine residues and connect domain A2 to domains C1 and B2. It is proposed that the movement of this domain is related to the ATPase activity of EccB1 and its homologues, as well as to the substrate transport of ESX secretion systems.

scholarly journals Discovery of Salmonella Virulence Factors Translocated via Outer Membrane Vesicles to Murine Macrophages

2011 ◽  
Vol 79 (6) ◽  
pp. 2182-2192 ◽  
Author(s):  
Hyunjin Yoon ◽  
Charles Ansong ◽  
Joshua N. Adkins ◽  
Fred Heffron
Keyword(s):  
Outer Membrane ◽  
Virulence Factors ◽  
Outer Membrane Proteins ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Secretion Systems ◽  
Homologous Proteins ◽  
Content Type ◽  
Small Proteins

ABSTRACTSalmonella entericaserovar Typhimurium, an intracellular pathogen and leading cause of food-borne illness, encodes a plethora of virulence effectors.Salmonellavirulence factors are translocated into host cells and manipulate host cellular activities, providing a more hospitable environment for bacterial proliferation. In this study, we report a new set of virulence factors that is translocated into the host cytoplasm via bacterial outer membrane vesicles (OMV). PagK (or PagK1), PagJ, and STM2585A (or PagK2) are small proteins composed of ∼70 amino acids and have high sequence homology to each other (>85% identity).Salmonellalacking all three homologues was attenuated for virulence in a mouse infection model, suggesting at least partial functional redundancy among the homologues. While each homologue was translocated into the macrophage cytoplasm, their translocation was independent of all threeSalmonellagene-encoded type III secretion systems (T3SSs)–Salmonellapathogenicity island 1 (SPI-1) T3SS, SPI-2 T3SS, and the flagellar system. Selected methods, including direct microscopy, demonstrated that the PagK-homologous proteins were secreted through OMV, which were enriched with lipopolysaccharide (LPS) and outer membrane proteins. Vesicles produced by intracellular bacteria also contained lysosome-associated membrane protein 1 (LAMP1), suggesting the possibility of OMV convergence with host cellular components during intracellular trafficking. This study identified novelSalmonellavirulence factors secreted via OMV and demonstrated that OMV can function as a vehicle to transfer virulence determinants to the cytoplasm of the infected host cell.

scholarly journals Campylobacter jejuni Outer Membrane Vesicles Play an Important Role in Bacterial Interactions with Human Intestinal Epithelial Cells

2012 ◽  
Vol 80 (12) ◽  
pp. 4089-4098 ◽  
Author(s):  
Abdi Elmi ◽  
Eleanor Watson ◽  
Pamela Sandu ◽  
Ozan Gundogdu ◽  
Dominic C. Mills ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Campylobacter Jejuni ◽  
Virulence Factors ◽  
Intestinal Epithelial Cells ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Intestinal Epithelial ◽  
Secretion Systems ◽  
Content Type

ABSTRACTCampylobacter jejuniis the most prevalent cause of food-borne gastroenteritis in the developed world; however, the molecular basis of pathogenesis is unclear. Secretion of virulence factors is a key mechanism by which enteric bacterial pathogens interact with host cells to enhance survival and/or damage the host. However,C. jejunilacks the virulence-associated secretion systems possessed by other enteric pathogens. Many bacterial pathogens utilize outer membrane vesicles (OMVs) for delivery of virulence factors into host cells. In the absence of prototypical virulence-associated secretion systems, OMVs could be an important alternative for the coordinated delivery ofC. jejuniproteins into host cells. Proteomic analysis ofC. jejuni11168H OMVs identified 151 proteins, including periplasmic and outer membrane-associated proteins, but also many determinants known to be important in survival and pathogenesis, including the cytolethal distending toxin (CDT).C. jejuniOMVs contained 16N-linked glycoproteins, indicating a delivery mechanism by which these periplasm-located yet immunogenic glycoproteins can interact with host cells.C. jejuniOMVs possess cytotoxic activity and induce a host immune response from T84 intestinal epithelial cells (IECs), which was not reduced by OMV pretreatment with proteinase K or polymyxin B prior to coincubation with IECs. Pretreatment of IECs with methyl-beta-cyclodextrin partially blocks OMV-induced host immune responses, indicating a role for lipid rafts in host cell plasma membranes during interactions withC. jejuniOMVs. OMVs isolated from aC. jejuni11168HcdtAmutant induced interleukin-8 (IL-8) to the same extent as did wild-type OMVs, suggesting OMV induction of IL-8 is independent of CDT.

scholarly journals Structural insights into substrate recognition by the type VII secretion system

2019 ◽  
Vol 11 (2) ◽  
pp. 124-137 ◽  
Author(s):  
Shuhui Wang ◽  
Kaixuan Zhou ◽  
Xiaolin Yang ◽  
Bing Zhang ◽  
Yao Zhao ◽  
...  
Keyword(s):  
Substrate Recognition ◽  
Secretion Systems ◽  
Atp Binding Site ◽  
Type Vii Secretion ◽  
The Family ◽  
Type Vii Secretion System ◽  
Pass Through ◽  
System 1 ◽  
Substrate Proteins ◽  
Structural Insights

AbstractType VII secretion systems (T7SSs) are found in many disease related bacteria including Mycobacterium tuberculosis (Mtb). ESX-1 [early secreted antigen 6 kilodaltons (ESAT-6) system 1] is one of the five subtypes (ESX-1~5) of T7SSs in Mtb, where it delivers virulence factors into host macrophages during infection. However, little is known about the molecular details as to how this occurs. Here, we provide high-resolution crystal structures of the C-terminal ATPase3 domains of EccC subunits from four different Mtb T7SS subtypes. These structures adopt a classic RecA-like ɑ/β fold with a conserved Mg-ATP binding site. The structure of EccCb1 in complex with the C-terminal peptide of EsxB identifies the location of substrate recognition site and shows how the specific signaling module “LxxxMxF” for Mtb ESX-1 binds to this site resulting in a translation of the bulge loop. A comparison of all the ATPase3 structures shows there are significant differences in the shape and composition of the signal recognition pockets across the family, suggesting that distinct signaling sequences of substrates are required to be specifically recognized by different T7SSs. A hexameric model of the EccC-ATPase3 is proposed and shows the recognition pocket is located near the central substrate translocation channel. The diameter of the channel is ~25-Å, with a size that would allow helix-bundle shaped substrate proteins to bind and pass through. Thus, our work provides new molecular insights into substrate recognition for Mtb T7SS subtypes and also a possible transportation mechanism for substrate and/or virulence factor secretion.

scholarly journals Two-Partner Secretion Systems of Neisseria meningitidis Associated with Invasive Clonal Complexes

2008 ◽  
Vol 76 (10) ◽  
pp. 4649-4658 ◽  
Author(s):  
Peter van Ulsen ◽  
Lucy Rutten ◽  
Moniek Feller ◽  
Jan Tommassen ◽  
Arie van der Ende
Keyword(s):  
Neisseria Meningitidis ◽  
Outer Membrane ◽  
Open Reading Frames ◽  
Gram Negative Bacteria ◽  
Secretion Systems ◽  
Gram Negative ◽  
System 1 ◽  
Related Proteins ◽  
Encoding Genes ◽  
Reading Frames

ABSTRACT The two-partner secretion (TPS) pathway is widespread among gram-negative bacteria and facilitates the secretion of very large and often virulence-related proteins. TPS systems consist of a secreted TpsA protein and a TpsB protein involved in TpsA transport across the outer membrane. Sequenced Neisseria meningitidis genomes contain up to five TpsA- and two TpsB-encoding genes. Here, we investigated the distribution of TPS-related open reading frames in a collection of disease isolates. Three distinct TPS systems were identified among meningococci. System 1 was ubiquitous, while systems 2 and 3 were significantly more prevalent among isolates of hyperinvasive clonal complexes than among isolates of poorly invasive clonal complexes. In laboratory cultures, systems 1 and 2 were expressed. However, several sera from patients recovering from disseminated meningococcal disease recognized the TpsAs of systems 2 and 3, indicating the expression of these systems during infection. Furthermore, we showed that the major secreted TpsAs of systems 1 and 2 depend on their cognate TpsBs for transport across the outer membrane and that the system 1 TpsAs undergo processing. Together, our data indicate that TPS systems may contribute to the virulence of N. meningitidis.

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