Summary
Type IV secretion systems (T4SSs) are versatile multiprotein nanomachines spanning the entire cell envelope in Gram‐negative and Gram‐positive bacteria. They play important roles through the ...contact‐dependent secretion of effector molecules into eukaryotic hosts and conjugative transfer of mobile DNA elements as well as contact‐independent exchange of DNA with the extracellular milieu. In the last few years, many details on the molecular mechanisms of T4SSs have been elucidated. Exciting structures of T4SS complexes from Escherichia coli plasmids R388 and pKM101, Helicobacter pylori and Legionella pneumophila have been solved. The structure of the F‐pilus was also reported and surprisingly revealed a filament composed of pilin subunits in 1:1 stoichiometry with phospholipid molecules. Many new T4SSs have been identified and characterized, underscoring the structural and functional diversity of this secretion superfamily. Complex regulatory circuits also have been shown to control T4SS machine production in response to host cell physiological status or a quorum of bacterial recipient cells in the vicinity. Here, we summarize recent advances in our knowledge of ‘paradigmatic’ and emerging systems, and further explore how new basic insights are aiding in the design of strategies aimed at suppressing T4SS functions in bacterial infections and spread of antimicrobial resistances.
Type IV secretion systems (T4SSs) are highly sophisticated nanomachines in the cell envelope of many bacteria. They exhibit crucial roles during infection of humans by the secretion of effector proteins, conjugative transfer of DNA and exchange of DNA with the extracellular environment. In this MicroReview, we summarize recent progress on T4SS composition, assembly and structure and highlight how basic understanding of their functions is aiding in the design of novel strategies for antimicrobial therapies.
Helicobacter pylori colonizes the gastric mucosa in the human stomach and represents a major risk factor for peptic ulcer disease and gastric cancer. Here, we summarize our current knowledge of the ...complex impact of H. pylori on manipulating host signalling networks, that is, by the cag pathogenicity island ( cag PAI)-encoded type IV secretion system (T4SS). We show that H. pylori infections reflect a paradigm for interspecies contact-dependent molecular communication, which includes the disruption of cell–cell junctions and cytoskeletal rearrangements, as well as proinflammatory, cell cycle-related, proliferative, antiapoptotic, and DNA damage responses. The contribution of these altered signalling cascades to disease outcome is discussed.
is a highly successful human bacterium, which is exceptionally equipped to persistently inhabit the human stomach. Colonization by this pathogen is associated with gastric disorders ranging from ...chronic gastritis and peptic ulcers to cancer. Highly virulent
strains express the well-established adhesins BabA/B, SabA, AlpA/B, OipA, and HopQ, and a type IV secretion system (T4SS) encoded by the
pathogenicity island (PAI). The adhesins ascertain intimate bacterial contact to gastric epithelial cells, while the T4SS represents an extracellular pilus-like structure for the translocation of the effector protein CagA. Numerous T4SS components including CagI, CagL, CagY, and CagA have been shown to target the integrin-β₁ receptor followed by translocation of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine and CagA-containing outer membrane vesicles may also play a role in the delivery process. Translocated CagA undergoes tyrosine phosphorylation in C-terminal EPIYA-repeat motifs by oncogenic Src and Abl kinases. CagA then interacts with an array of host signaling proteins followed by their activation or inactivation in phosphorylation-dependent and phosphorylation-independent fashions. We now count about 25 host cell binding partners of intracellular CagA, which represent the highest quantity of all currently known virulence-associated effector proteins in the microbial world. Here we review the research progress in characterizing interactions of CagA with multiple host cell receptors in the gastric epithelium, including integrin-β₁, EGFR, c-Met, CD44, E-cadherin, and gp130. The contribution of these interactions to
colonization, signal transduction, and gastric pathogenesis is discussed.
Infection of gastric epithelial cells with Helicobacter pylori induces strong proinflammatory responses by activating nuclear transcription factors NF-κB and AP-1. Several reports indicate that ...multiple bacterial factors and cellular molecules are involved in this signaling. Injected peptidoglycan, CagA or OipA and urease, and at least 16 different signaling cascades have been implicated in H. pylori -induced proinflammatory signaling. Many of these reports are contradictory, thus generating a highly puzzling scenario. Here we discuss the pros and cons of the multiple signaling activities in the induction of proinflammatory responses and associated problems, and give suggestions for finding ways out of this dilemma.
Inflammasome-mediated production of mature IL-1β and IL-18 cytokines represents an important innate immune response against infecting pathogens. Helicobacter pylori, one of the most successful and ...persistent human pathogens, induces severe inflammation leading to gastritis and more serious gastric diseases. H. pylori modulates different immune responses for its survival and inflammasome signaling is manipulated by the cag pathogenicity island (cagPAI), urease and VacA cytotoxin. Here we report that H. pylori regulates NLRP3 expression, an inflammasome forming regulator, in infected THP-1 monocytes. This response was independent of the major H. pylori pathogenicity-associated factors CagA, VacA, Cgt, FlaA and cagPAI. Two NLRP3 expression controlling factors, the NLRP3 mRNA targeting microRNA hsa-miR-223-3p and cytokine IL-10, were found to work in tandem for its regulation. H. pylori infection also induced copious amount of pro-IL-1β in THP-1 monocytes/macrophages but secreted a very low amount of mature IL-1β. Moreover, secreted IL-10 correlated with the down-regulation of nigericin-induced NLRP3 inflammasome activation of LPS-primed THP-1 monocytes and human PBMCs from volunteers. However, H. pylori-treated PBMCs secreted significantly more mature IL-1β throughout the infection period, which suggests a different mode of activation. Taken together, this study demonstrates targeting of inflammasome-forming NLRP3, an important innate immunity component, and crucial manipulation of pro- and anti-inflammatory cytokines in H. pylori infection.
Helicobacter pylori is a very successful human-specific bacterium worldwide. Infections of the stomach with this pathogen can induce pathologies, including chronic gastritis, peptic ulcers and even ...gastric cancer. Highly virulent H. pylori strains encode the cytotoxin-associated gene (cag)-pathogenicity island, which expresses a type IV secretion system (T4SS). This T4SS forms a syringe-like pilus structure for the injection of virulence factors such as the CagA effector protein into host target cells. This is achieved by a number of T4SS proteins, including CagI, CagL, CagY and CagA, which by itself binds the host cell integrin member β₁ followed by delivery of CagA across the host cell membrane. A role of CagA interaction with phosphatidylserine has also been shown to be important for the injection process. After delivery, CagA becomes phosphorylated by oncogenic tyrosine kinases and mimics a host cell factor for the activation or inactivation of some specific intracellular signalling pathways. We review recent progress aiming to characterize the CagA-dependent and CagA-independent signalling capabilities of the T4SS, which include the induction of membrane dynamics, disruption of cell-cell junctions and actin-cytoskeletal rearrangements, as well as pro-inflammatory, cell cycle-related and anti-apoptotic transcriptional responses. The contribution of these signalling pathways to pathogenesis during H. pylori infections is discussed.
Summary
Helicobacter pylori is a paradigm of persistent pathogens and major risk factor for developing severe diseases including adenocarcinoma in the human stomach. An important bacterial factor ...linked to gastric disease progression is the cag pathogenicity island‐encoded type‐IV secretion system (T4SS) effector protein CagA. Translocated CagA undergoes tyrosine phosphorylation at EPIYA‐motifs and then activates or inactivates multiple host signaling proteins in a phosphorylation‐dependent and phosphorylation‐independent fashion. In this way, intracellular CagA acts as a ‘masterkey’ or ‘picklock’, which evolved during evolution to hijack key host cell signal transduction functions. Crucial targets of CagA represent a variety of serine/threonine and tyrosine kinases, which control major checkpoints of eukaryotic signaling. Here we review the signal transmission by translocated CagA on multiple receptor kinases (c‐Met and EGFR) and non‐receptor kinases (Src, Abl, Csk, aPKC, Par1, PI3K, Akt, FAK, GSK‐3, JAK, PAK1, PAK2 and MAP kinases), manipulating a selection of fundamental processes in the human gastric epithelium such as cell adhesion, polarity, proliferation, motility, receptor endocytosis, cytoskeletal rearrangements, apoptosis, inflammation and cell cycle progression. This enormous complexity generates a highly remarkable and puzzling scenario during H. pylori infection. The contribution of these signaling pathways to bacterial survival, persistence and gastric pathogenesis is discussed.
Helicobacter pylori is a paradigm of persistent human pathogens and major risk factor for developing severe gastric diseases including adenocarcinoma. An important factor associated with disease progression is the type‐IV secretion effector protein CagA, which evolved during evolution to hijack key host signal transduction functions. Here we review the signal transmission by translocated CagA on multiple receptor kinases (c‐Met and EGFR) and non‐receptor kinases (Src, Abl, Csk, aPKC, Par1, PI3K, Akt, FAK, GSK‐3, JAK, PAK1, PAK2 and MAP kinases), manipulating fundamental processes in the gastric epithelium including cell adhesion, polarity, proliferation, motility, receptor endocytosis, cytoskeletal rearrangements, apoptosis, inflammation and cell cycle progression as well as bacterial survival.
The pathogenic bacterium
Helicobacter pylori
is genetically highly diverse and a major risk factor for the development of peptic ulcer disease and gastric adenocarcinoma in humans. During evolution,
...H. pylori
has acquired multiple type IV secretion systems (T4SSs), and then adapted for various purposes. These T4SSs represent remarkable molecular transporter machines, often associated with an extracellular pilus structure present in many bacteria, which are commonly composed of multiple structural proteins spanning the inner and outer membranes. By definition, these T4SSs exhibit central functions mediated through the contact-dependent conjugative transfer of mobile DNA elements, the contact-independent release and uptake of DNA into and from the extracellular environment as well as the secretion of effector proteins in mammalian host target cells. In recent years, numerous features on the molecular functionality of these T4SSs were disclosed.
H. pylori
encodes up to four T4SSs on its chromosome, namely the Cag T4SS present in the
cag
pathogenicity island (
cag
PAI), the ComB system, as well as the Tfs3 and Tfs4 T4SSs, some of which exhibit unique T4SS functions. The Cag T4SS facilitates the delivery of the CagA effector protein and pro-inflammatory signal transduction through translocated ADP-heptose and chromosomal DNA, while various structural pilus proteins can target host cell receptors such as integrins or TLR5. The ComB apparatus mediates the import of free DNA from the extracellular milieu, whereas Tfs3 may accomplish the secretion or translocation of effector protein CtkA. Both Tfs3 and Tfs4 are furthermore presumed to act as conjugative DNA transfer machineries due to the presence of tyrosine recombinases with cognate recognition sequences, conjugational relaxases, and potential origins of transfer (
oriT)
found within the
tfs3
and
tfs4
genome islands. In addition, some extrachromosomal plasmids, transposons and phages have been discovered in multiple
H. pylori
isolates. The genetic exchange mediated by DNA mobilization events of chromosomal genes and plasmids combined with recombination events could account for much of the genetic diversity found in
H. pylori
. In this review, we highlight our current knowledge on the four T4SSs and the involved mechanisms with consequences for
H. pylori
adaptation to the hostile environment in the human stomach.
Helicobacter pylori is estimated to infect more than half of the worlds human population and represents a major risk factor for chronic gastritis, peptic ulcer disease, MALT lymphoma, and gastric ...adenocarcinoma. H. pylori infection and clinical consequences are controlled by highly complex interactions between the host, colonizing bacteria, and environmental parameters. Important bacterial determinants linked with gastric disease development include the cag pathogenicity island encoding a type IV secretion system (T4SS), the translocated effector protein CagA, vacuolating cytotoxin VacA, adhesin BabA, urease, serine protease HtrA, secreted outer membrane vesicles, and many others. The high quantity of these factors and allelic changes in the corresponding genes reveals a sophisticated picture and problems in evaluating the impact of each distinct component. Extensive work has been performed to pinpoint molecular processes related to H. pylori‐triggered pathogenesis using Mongolian gerbils, mice, primary tissues, as well as novel in vitro model systems such as gastroids. The manipulation of host signaling cascades by the bacterium appears to be crucial for inducing pathogenic downstream activities and gastric disease progression. Here, we review the most recent advances in this important research area.
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