Even though chronic gastritis was well established as a risk factor for the development of several gastric pathologies, such as peptic ulceration, gastric carcinoma, and lymphoma, before the discovery of
It is estimated that almost half of the world’s population is infected with
The development of gastritis associated with the infection is a multifactorial process, where the bacterium and host factors influence the pathogenesis of the disease. Colonization by
Helicobacter pylori virulence factors in gastritis and gastric cancer
Researchers have studied
To colonize the stomach,
4. Lipopolysaccharides (LPS) and peptidoglycan
Approximately 4% of the
The outer membrane inflammatory protein (OipA), identified in 2000 (Yamaoka et al., 2000), is involved in the attachment of
Blood group antigen binding adhesin (BabA), has been thought to be the primary protein involved in adherence to the gastric mucosa (Boren et al., 1993). It is encoded by the
Sialic acid-binding adhesin (SabA) is responsible of
6. Vacuolating cytotoxin (VacA)
VacA is a pore-forming cytotoxin identified in supernatants of
VacA induces multiple cellular activities, the best studied is the alteration on endosomal maturation which consequently leads to vacuolation of epithelial cells, VacA is also capable of induce membrane-channel formation, cytochrome c release from mitochondria, and binding to cell-membrane receptors activating a proinflammatory response (Amieva & El-Omar, 2008). VacA has the ability to cause leakage of ions and small molecules, by disrupting the barrier function of tight junctions (Papini et al., 1998) and also inhibit T-cell activation and proliferation (Gebert et al., 2003).
All strains of
The amino terminus contains the signal sequence that shows allelic variability and has been classified into different types. Strains with s1 allele secrete an active toxin and are also highly associated with ulcers and gastric cancer (Atherton et al., 1995), however, s1/s2 combination or s2 genotypes are found in patients with gastric cancer (Lopez-Vidal et al., 2008). The middle region of the gene also shows allelic variation, with m1 subtype having stronger vacuolating activity and it is associated with an increased risk for development of gastric epithelial injury and gastric cancer (Yamaoka, 2010).
The clinical isolates of
7. Cytotoxin associated gen-Pathogenicity Island (
Colonization of the human stomach by
The presence of flanking direct repeated sequences 605 (IS605) in the
T4SSs are a large group of highly versatile secretion machineries in many Gram-negative pathogenic bacteria that are evolutionarily related to bacterial conjugative systems (Fronzes et al., 2009). Although the
A systematic mutagenesis study with isogenic mutants in each of the
Twelve genes out of 27 of
The prototypical (macromolecular complex) T4SS of
8. Cytotoxin-associated protein (CagA)
CagA protein is the only known effector protein translocated to the host cell by the T4SS (Backert et al., 2010). It was firstly described as a very immunogenic protein in humans infected with cytotoxin-producing strains (Covacci et al., 1993). After that, its association with gastric cancer and peptic ulcer was well established.
Recent reports suggest that CagA is able to down regulate the vacuolation effects of VacA on host cells, and conversely, VacA is able to down regulates CagA activity (Oldani et al., 2009, Tegtmeyer et al., 2009). Clinical isolates that contain the
CagA is encoded by the
Other main feature of CagA protein is its high variable size, which range from 120-145 kDa (Covacci et al., 1993, Tummuru et al., 1993). This variation is due to the presence of polymorphism at the carboxy-terminal region given by the presence of repeat sequences called EPIYA motifs, which are present in a copy number varying from one to seven (Xia et al., 2009). Four major types of EPIYA motifs (A, B, C, and D) have been described based on the specific amino acid sequence that flanks the Glu-Pro-Ile-Tyr-Ala motif at both sides (Hatakeyama, 2004).
The EPIYA-repeat region of CagA is made of tandem alignment of the four distinct EPIYA segments (A, B, C, D) in various combinations (Hatakeyama, 2011). CagA molecules containing the EPIYA-A, EPIYA-B and EPIYA-C segments in tandem are denoted as ‘‘western type’’, and are found in many
The EPIYA-C segment in "Western type" isolates can be present in up to five copies which might be due to recombination mediated by a 16 amino acid sequence designated CagA multimerization sequence that is present at both sides of EPIYA-C motif. The CagA multimerization sequence is also present in EPIYA-D but only at one end, therefore cannot duplicate by this mechanism (Furuta et al., 2011). Other implications of CagA multimerization sequence in the bacterial pathogenicity will be discussed later in the text.
It has been proposed that EPIYA motifs of CagA act as ‘‘master keys’’ that can potentially be tyrosine-phosphorylated by host kinases and are capable to interact with a wide range of different host cell proteins (Backert et al., 2010). In the same way, the observation that the EPIYA-region is unstructured and can adopt multiple conformations mimicking host substrates of kinase families, thus manipulating eukaryotic cellular biochemistry during infection, provides further support for this "master key" hypothesis (Nesic et al., 2010).
In contrast to the polymorphic C-terminal EPIYA region of CagA, N-terminal region is well conserved among CagA proteins (Hatakeyama, 2011). The N-terminal CagA region is required for the membrane association of CagA in polarized epithelial cells (Bagnoli et al., 2005) and is important for its translocation into host cells (Murata-Kamiya et al., 2010), the first 200 amino acids at the N-terminus of CagA form a membrane-binding domain in
9. CagA tridimensional structure and membrane localization
It has been shown that CagA targeting to the epithelial cell membrane is important for host signaling (Higashi et al., 2002, Bagnoli et al., 2005, Higashi et al., 2005) and there is evidence that membrane binding of CagA is important for its translocation into host cells (Murata-Kamiya et al., 2010, Steininger et al., 2011).
Recently, it has been proposed that interaction of CagA with host cell proteins depends on the localization of CagA into distinct compartments in host cells (Pelz et al., 2011). The model proposed states that membrane localization is mediated by two membrane domains, one composed by residues 1-200 (N-terminal domain) and the other from 200-1216 (C-terminal domain), detailed description of the function of these domains are described in the Figure 2. In addition, C-terminal domain is comprised of two regions that interact with each other and are located in the membrane together when linked to N terminal domain, the first region is from amino acids 200-800 containing phosphatidyl serine binding domain and the second from 800-1216 containing EPIYA and CagA multimerization motifs. The region from 800-1216 when expressed alone localizes in cytosol and produces a strong alteration in cell morphology (Steininger et al., 2011).
According with the above-mentioned model, CagA spatial conformation may play an important role for the proper translocation and compartmentalization, so a tridimentional structure prediction of CagA was made using I-TASSER, which has been ranked as the best method for the automated protein structure prediction in the last two community-wide critical assessment of protein structure prediction (CASP) experiments (Roy et al., 2010). The best predicted model for both East-Asia and Western type of CagA consists of a sinuous super helical structure in which N-terminal region protrudes at one side and C-terminal region forms a loop (Figure 3). These predicted structural models agree with the model proposed of Steininger et al., in which amino acids 200-1216 forms two domains that interact with each other (Steininger et al., 2011). According to the results obtained with I-TASSER the most similar structure available in the PDB database (www.rcsb.org/pdb/home/home.do) is from Cand1 protein, however the only function similarity shared with CagA is the capacity of protein binding.
Interestingly, it is also proposed that N-terminal membrane-binding domain functions as an inhibitory domain of the C-terminal region effects, and that region from 800-1216 when expressed alone induces the highest percentage of epithelial cell elongation (Pelz et al., 2011). Also it has been proposed that CagA is cleaved by proteases in human cells yielding two fragments of about 100-105 kDa and 35-40 kDa (Moese et al., 2001), the last would correspond to the region from amino acid 800-1216. This leads to the question if some structural variants of CagA are better cleaved inside the host cell so that can not be totally inhibited by the N-terminal membrane-binding domain, but this requires investigation.
10. Phosphorylation-dependent cell signaling of CagA
Phosphorylation of CagA deregulates several signaling pathways leading to modification in host cell shape and adhesion, contributing to the transformation of cells (Hatakeyama, 2011, Jones et al., 2010). All of the EPIYA motifs in the four distinct EPIYA segments serve as tyrosine phosphorylation sites of CagA in host cells (Hatakeyama, 2011). Enzymes that can phosphorylate CagA
Once tyrosine phosphorylated, EPIYA-C or -D can bind to SHP-2 phosphatase (Hatakeyama, 2011) and activates the phosphatase activity of Shp2 producing an extremely elongated cell shape known as the hummingbird phenotype and altered cell motility (Backert et al., 2010, Higashi et al., 2004, Tsutsumi et al., 2006). SHP2 is required for full activation of the MAPK/ERK pathway, which conveys a potent mitogenic signal (Matozaki et al., 2009) and for direct dephosphorylation and inactivation of focal adhesion kinase, FAK, that deregulates integrin signaling (Tsutsumi et al., 2006).
Carrying the type EPIYA-D or multiple EPIYA-C repeats is associated with increased SHP-2 phosphatase activity induced by CagA, increasing the risk of precancerous and cancer lesions. This is because East-specific D segment shows higher binding affinity to SHP2 than the West-specific C segment but the C-type motif is variable in copy number and sequence, which can provide more sites for SHP2 binding.
On the other hand, phosphorylated EPIYA-A and EPIYA-B have been shown ability to bind to Csk (Tsutsumi et al., 2003). Interaction of CagA with Csk stimulates the kinase activity of Csk, which in turn inhibits Src in a negative feedback loop that constrains the phosphorylation-dependent CagA activity below a certain threshold to ensure long-term colonization of
11. Phosphorylation-independent cell signaling of CagA
Recent studies have shown that not all cellular interactions exerted by CagA depend on its tyrosine phosphorylation so far more than 13 cellular interaction partners of non-phosphorylated CagA have been identified (Backert et al., 2010, Tegtmeyer et al., 2009, Mimuro et al., 2002). It has been shown that these interactions exert effects such as pro-inflammatory and mitogenic responses, disruption of cell-to-cell junctions or loss of cell polarity.
The first cellular interaction partner described of non-phosphorylated CagA was the adapter protein Gbr2 (Mimuro et al., 2002). Recently, it was reported that Gbr2 is the only host factor that interacts with both phosphorylated and non-phosphorylated EPIYA motifs (Selbach et al., 2009). Non-phosphorylated CagA was shown to interact with Gbr2
On the other hand, Chang YJ, et al., 2006, reported that
Yokoyama et al., 2005, found that CagA can stimulate the calcium-dependent serine/threonine phosphatase calcineurin in gastric epithelial cells, inducing translocation of the nuclear factor of activated T cells (NFAT) from the cytoplasm to the nucleus, where activates NFAT-dependent genes (Yokoyama et al., 2005). It is possible that the reported CagA-PLC interaction triggers Ca2+ mobilization and subsequent activation of calcineurin.
One of the NFAT-dependent genes activated by CagA in gastric epithelial cells is p21Cip1, a cyclin-dependent kinase inhibitor. Accordingly, although CagA activates a growth-promoting signal via the SHP-2-MAP kinase pathway or the Grb2-Ras-MAP kinase pathway, it simultaneously inhibits cell proliferation through NFAT-dependent p21Cip1 induction. Intriguingly, the
The CagA multimerization sequence mediates a stable binding with SHP-2 protein potentiating CagA virulence and is also responsible of the phosphorylation-independent activity of CagA (Ren et al., 2006, Nagase et al., 2011). Furthermore, it has been shown that CagA binds and inhibits the polarity-regulating kinase partitioning-defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) through CagA multimerization sequence (Nagase et al., 2011). Kurashima et al., showed that CagA multimerization sequence destabilizes the E-cadherin/beta-catenin complex to trigger aberrant activation of the beta-catenin signal that underlies intestinal metaplasia (Kurashima et al., 2008). Recently, it was shown that the diversity in the structure and number of CagA multimerization sequences influence the strength of pathological activities of individual CagA with its cellular targets (PAR1b and SHP-2), emphasising its importance as a determinant of the degree of virulence of CagA (Lu et al., 2008) for development of gastric cancer.
A recent study shows that CagA can also interact with runt-related transcription factor gene 3 (RUNX3, a tumor suppressor that is frequently inactivated in gastric cancer) by a novel identified WW domain in the amino-terminal region of CagA (Tsang et al., 2010). In particular, CagA induces the ubiquitination and degradation of RUNX3, thereby extinguishing its ability to inhibit the transcriptional activation of RUNX3; currently, functional inactivation of RUNX3 can be caused by mutation, epigenetic gene silencing (promoter methylation) or cytoplasmic protein mislocalization (Ito, 2011). Recent evidence shows a strong association between methylation of the RUNX3 promoter and gastric cancer (Fan et al., 2011, Li et al., 2011). Recently, Lin et al., found that loss of RUNX3 in gastric cancer prevents G1 phase arrest and promotes tumorigenesis through Akt1/ß-catenin/cyclin D1 signaling pathway (Lin et al., 2012).
A consequence of non-phosphorylated CagA interactions in polarized epithelial cells is the disruption of cell junctions. In particular, tight and adherence junctions are essential for the integrity of the gastric epithelium (Wessler & Backert, 2008). CagA interferes with these intercellular junctions via several pathways. 1) Injected CagA associates with the epithelial tight-junction scaffolding protein, zone occludens-1 (ZO-1), and the transmembrane protein, junction adhesion molecule (JAM2), causing an ectopic assembly of tight-junction components at sites of bacterial attachment (Amieva & El-Omar, 2008), leading to alterations of cell polarity. 2) Non-phosphorylated CagA can interact with the transmembrane cell-cell junction protein E-cadherin (Hatakeyama, 2008). Subsequently, it was found that CagA forms a complex with c-Met recruiting E-cadherin and the Armadillo-domain protein, catenin delta, indicating that the interaction between CagA and E-cadherin is not direct (Oliveira et al., 2009). Baek et al., in 2007, reported that the interaction of alpha-Pix (PAK-interactive exchange factor) with CagA activates PAK1, ERK and NF-κB, which induces IL-8 expression (Baek et al., 2007, Lim et al., 2009); beta 1 integrin (integrin ß1) is another CagA-independent signaling that promotes cell motility (Snider et al., 2008), although the functional importance of this interaction needs to be investigated.
12. Concluding remarks
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