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Dehio C 《Cellular microbiology》2008,10(8):1591-1598
Type IV secretion systems (T4SSs) are transporters of Gram-negative bacteria that mediate interbacterial DNA transfer, and translocation of virulence factors into eukaryotic host cells. The α-proteobacterial genus Bartonella comprises arthropod-borne pathogens that colonize endothelial cells and erythrocytes of their mammalian reservoir hosts, thereby causing long-lasting intraerythrocytic infections. The deadly human pathogen Bartonella bacilliformis holds an isolated position in the Bartonella phylogeny as a sole representative of an ancestral lineage. All other species evolved in a separate 'modern' lineage by radial speciation and represent highly host-adapted pathogens of limited virulence potential. Unlike B. bacilliformis , the species of the modern lineage encode at least one of the closely related T4SSs, VirB/VirD4 or Vbh. These VirB-like T4SSs represent major host adaptability factors that contributed to the remarkable evolutionary success of the modern lineage. At the molecular level, the VirB/VirD4 T4SS was shown to translocate several effector proteins into endothelial cells that subvert cellular functions critical for establishing chronic infection. A third T4SS, Trw, is present in a sub-branch of the modern lineage. Trw does not translocate any known effectors, but produces multiple variant pilus subunits critically involved in the invasion of erythrocytes. The T4SSs laterally acquired by the bartonellae have thus adopted highly diverse functions during infection, highlighting their versatility as pathogenicity factors. 相似文献
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Bacterial type IV secretion: conjugation systems adapted to deliver effector molecules to host cells 总被引:32,自引:0,他引:32
Several bacterial pathogens utilize conjugation machines to export effector molecules during infection. Such systems are members of the type IV or 'adapted conjugation' secretion family. The prototypical type IV system is the Agrobacterium tumefaciens T-DNA transfer machine, which delivers oncogenic nucleoprotein particles to plant cells. Other pathogens, including Bordetella pertussis, Legionella pneumophila, Brucellaspp. and Helicobacter pylori, use type IV machines to export effector proteins to the extracellular milieu or the mammalian cell cytosol. 相似文献
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Type IV secretion systems (T4SSs) are transport machineries of Gram-negative bacteria that mediate interbacterial DNA-transfer, and secretion of virulence factors into eukaryotic target cells. A growing number of human pathogenic bacteria use T4SSs for intercellular delivery of effector molecules that modify host cellular functions in favour of the pathogen. Recent advances in studying the molecular mechanisms of Bartonella pathogenesis have provided evidence for the central roles of two distinct T4SSs, VirB/VirD4 and Trw, in the ability of the bacteria to colonize, invade and persist within either vascular endothelial cells or erythrocytes, respectively. The identification of VirB/VirD4-transported substrates and the delineation of their secretion signal have paved the way towards understanding the molecular mechanisms underlying Bartonella-host cell interaction and modulation, as well as the exploitation of this system for engineered substrate delivery into mammalian target cells. 相似文献
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Bacteria use type IV secretion systems (T4SS) to translocate macromolecular substrates destined for bacterial, plant or human target cells. The T4SS are medically important, contributing to virulence-gene spread, genome plasticity and the alteration of host cellular processes during infection. The T4SS are ancestrally related to bacterial conjugation machines, but present-day functions include (i) conjugal transfer of DNA by cell-to-cell contact, (ii) translocation of effector molecules to eukaryotic target cells, and (iii) DNA uptake from or release to the extracellular milieu. Rapid progress has been made toward identification of type IV secretion substrates and the requirements for substrate recognition. 相似文献
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Bacteria use type IV secretion systems for two fundamental objectives related to pathogenesis--genetic exchange and the delivery of effector molecules to eukaryotic target cells. Whereas gene acquisition is an important adaptive mechanism that enables pathogens to cope with a changing environment during invasion of the host, interactions between effector and host molecules can suppress defence mechanisms, facilitate intracellular growth and even induce the synthesis of nutrients that are beneficial to bacterial colonization. Rapid progress has been made towards defining the structures and functions of type IV secretion machines, identifying the effector molecules, and elucidating the mechanisms by which the translocated effectors subvert eukaryotic cellular processes during infection. 相似文献
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Helicobacter pylori is a human-specific gastric pathogen that colonizes over half the world's population. Infection with this bacterium is associated with a spectrum of gastric pathologies ranging from mild gastritis to peptic ulcers and gastric cancer. A strong predictor of severe disease outcome is infection with a bacterial strain harbouring the cag (cytotoxin associated gene) pathogenicity island (PAI), a 40 kb stretch of DNA that encodes homologues of several components of a type IV secretion system (TFSS). One gene within the cag PAI, cagA, has been shown to encode a substrate for the TFSS which is translocated into host cells and causes multiple changes in host cell signalling. Here we review recent advances in the characterization of type IV secretion, the activities of CagA and CagA-independent effects of the TFSS, which are contributing to our understanding of H. pylori pathogenesis. 相似文献
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Bacterial type IV secretion systems (T4SSs) are a versatile group of nanomachines that can horizontally transfer DNA through conjugation and deliver effector proteins into a wide range of target cells. The components of T4SSs in gram-negative bacteria are organized into several large subassemblies: an inner membrane complex, an outer membrane core complex, and, in some species, an extracellular pilus. Cryo-electron tomography has been used to define the structures of T4SSs in intact bacteria, and high-resolution structural models are now available for isolated core complexes from conjugation systems, the Xanthomonas citri T4SS, the Helicobacter pylori Cag T4SS, and the Legionella pneumophila Dot/Icm T4SS. In this review, we compare the molecular architectures of these T4SSs, focusing especially on the structures of core complexes. We discuss structural features that are shared by multiple T4SSs as well as evolutionary strategies used for T4SS diversification. Finally, we discuss how structural variations among T4SSs may confer specialized functional properties. 相似文献
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Type IV secretion (T4S) systems are versatile machines involved in many processes relevant to bacterial virulence, such as horizontal DNA transfer and effector translocation into human cells. A recent workshop organized by the International University of Andalousia in Baeza, Spain, covered most aspects of bacterial T4S relevant to human disease, ranging from the structural and mechanistic analysis of the T4S systems to the physiological roles of the translocated effector proteins in subverting cellular functions in infected humans. This review reports the highlights from this workshop, which include the first visualization of a T4S system core complex spanning both membranes of Gram-negative bacteria, the identification of the first host receptors for T4S systems, the identification and characterization of novel T4S effector proteins, the analysis of the molecular function of effector proteins in subverting human cellular functions and an analysis of the role of T4S systems in the evolution of pathogenic bacteria. Our increasing knowledge of the biology of T4S systems improves our ability to exploit them as biotechnological tools or to use them as novel targets for a new generation of antimicrobials. 相似文献
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Peter J. Christie Neal WhitakerChristian González-Rivera 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2014
The bacterial type IV secretion systems (T4SSs) translocate DNA and protein substrates to bacterial or eukaryotic target cells generally by a mechanism dependent on direct cell-to-cell contact. The T4SSs encompass two large subfamilies, the conjugation systems and the effector translocators. The conjugation systems mediate interbacterial DNA transfer and are responsible for the rapid dissemination of antibiotic resistance genes and virulence determinants in clinical settings. The effector translocators are used by many Gram-negative bacterial pathogens for delivery of potentially hundreds of virulence proteins to eukaryotic cells for modulation of different physiological processes during infection. Recently, there has been considerable progress in defining the structures of T4SS machine subunits and large machine subassemblies. Additionally, the nature of substrate translocation sequences and the contributions of accessory proteins to substrate docking with the translocation channel have been elucidated. A DNA translocation route through the Agrobacterium tumefaciens VirB/VirD4 system was defined, and both intracellular (DNA ligand, ATP energy) and extracellular (phage binding) signals were shown to activate type IV-dependent translocation. Finally, phylogenetic studies have shed light on the evolution and distribution of T4SSs, and complementary structure-function studies of diverse systems have identified adaptations tailored for novel functions in pathogenic settings. This review summarizes the recent progress in our understanding of the architecture and mechanism of action of these fascinating machines, with emphasis on the ‘archetypal’ A. tumefaciens VirB/VirD4 T4SS and related conjugation systems. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. 相似文献
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Type IV secretion systems (T4SSs) are used by various bacteria to deliver protein and DNA molecules to a wide range of target cells. These include systems that are directly involved in pathogenesis, such as the secretion of pertussis toxin by Bordetella pertussis into human cells and the delivery of single-stranded DNA (ssDNA) into plants by Agrobacterium. These complex systems are composed of proteins that span the bacterial cytoplasm. The Agrobacterium T4SS is composed of 12 virulence proteins and delivers its transferred ssDNA and several virulence protein substrates to a variety of eukaryotic cells. Recent studies on the Agrobacterium T4SS have revealed new information on the localization and structure of its proteins in the bacteria, the biochemical properties of its transport signal, the route of a DNA substrate through the secretion system, and the initial point of contact of the system with its host. These findings have expanded our knowledge and understanding of the still mostly obscure structure and function of the T4SSs. 相似文献
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Marchesini MI Herrmann CK Salcedo SP Gorvel JP Comerci DJ 《Cellular microbiology》2011,13(8):1261-1274
Type IV secretion systems (T4SS) are specialized protein complexes used by many bacterial pathogens for the delivery of effector molecules that subvert varied host cellular processes. Brucella spp. are facultative intracellular pathogens capable of survival and replication inside mammalian cells. Brucella T4SS (VirB) is essential to subvert lysosome fusion and to create an organelle permissive for replication. One possible role for VirB is to translocate effector proteins that modulate host cellular functions for the biogenesis of the replicative organelle. We hypothesized that proteins with eukaryotic domains or protein-protein interaction domains, among others, would be good candidates for modulation of host cell functions. To identify these candidates, we performed an in silico screen looking for proteins with distinctive features. Translocation of 84 potential substrates was assayed using adenylate cyclase reporter. By this approach, we identified six proteins that are delivered to the eukaryotic cytoplasm upon infection of macrophage-like cells and we could determine that four of them, encoded by genes BAB1_1043, BAB1_2005, BAB1_1275 and BAB2_0123, require a functional T4SS for their delivery. We confirmed VirB-mediated translocation of one of the substrates by immunofluorescence confocal microscopy, and we found that the N-terminal 25 amino acids are required for its delivery into cells. 相似文献
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Type IV secretion systems (T4SSs) are large protein complexes which traverse the cell envelope of many bacteria. They contain a channel through which proteins or protein–DNA complexes can be translocated. This translocation is driven by a number of cytoplasmic ATPases which might energize large conformational changes in the translocation complex. The family of T4SSs is very versatile, shown by the great variety of functions among family members. Some T4SSs are used by pathogenic Gram‐negative bacteria to translocate a wide variety of virulence factors into the host cell. Other T4SSs are utilized to mediate horizontal gene transfer, an event that greatly facilitates the adaptation to environmental changes and is the basis for the spread of antibiotic resistance among bacteria. Here we review the recent advances in the characterization of the architecture and mechanism of substrate transfer in a few representative T4SSs with a particular focus on their diversity of structure and function. 相似文献
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The type IV secretion system (TFSSs) is a multifunctional family of translocation pathways that mediate the transfer of DNA among bacteria and deliver DNA and proteins to eukaryotic cells during bacterial infections. Horizontal transmission has dominated the evolution of the TFSS, as demonstrated here by a lack of congruence between the tree topology inferred from components of the TFSS and the presumed bacterial species divergence pattern. A parsimony analysis suggests that conjugation represents the ancestral state and that the divergence from conjugation to secretion of effector molecules has occurred independently at multiple sites in the tree. The result shows that the nodes at which functional shifts have occurred coincide with those of horizontal gene transfers among distantly related bacteria. We suggest that it is the transfer between species that paved the way for the divergence of the TFSSs and discuss the general role of horizontal gene transfers for the evolution of novel gene functions. 相似文献
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Silvia Lang Christian J. Gruber Maya Topf Klaus Zangger Ellen L. Zechner Gabriel Waksman 《Molecular microbiology》2013,89(2):324-333
Relaxases are proteins responsible for the transfer of plasmid and chromosomal DNA from one bacterium to another during conjugation. They covalently react with a specific phosphodiester bond within DNA origin of transfer sequences, forming a nucleo‐protein complex which is subsequently recruited for transport by a plasmid‐encoded type IV secretion system. In previous work we identified the targeting translocation signals presented by the conjugative relaxase TraI of plasmid R1. Here we report the structure of TraI translocation signal TSA. In contrast to known translocation signals we show that TSA is an independent folding unit and thus forms a bona fide structural domain. This domain can be further divided into three subdomains with striking structural homology with helicase subdomains of the SF1B family. We also show that TSA is part of a larger vestigial helicase domain which has lost its helicase activity but not its single‐stranded DNA binding capability. Finally, we further delineate the binding site responsible for translocation activity of TSA by targeting single residues for mutations. Overall, this study provides the first evidence that translocation signals can be part of larger structural scaffolds, overlapping with translocation‐independent activities. 相似文献
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Lori L. Burrows 《Molecular microbiology》2012,86(4):765-769
The type II secretion system (T2SS) exports folded proteins from the periplasms of Gram‐negative bacteria. The type IV pilus system (T4PS) is a multifunctional machine used for adherence, motility and DNA transfer in bacteria and archaea. Partial sequence identity between the two systems suggests that they are related and might function via a similar mechanism, the dynamic assembly and disassembly of pseudopilus (T2SS) or pilus (T4PS) filaments. The major subunit in each system is thought to form the bulk of the (pseudo)pilus, while minor (low‐abundance) subunits have proposed roles in assembly initiation, antagonism of disassembly, or modulation of (pseudo)pilus functional properties. In this issue, Cisneros et al. ( 2012 ) extend their previous finding that pseudopilus assembly is primed by the minor pseudopilins, showing that the same proteins can initiate assembly of Escherichia coli T4P. Similarly, they show that the E. coli minor pilins prime the polymerization of T2S pseudopili, although unlike genuine pseudopili, the chimeric filaments did not support secretion. This work reinforces the notion of a common assembly mechanism for the T2S and T4P systems. 相似文献