Role of type IV secretion in<i>Helicobacter pylori</i>pathogenesis

Backert, Steffen; Selbach, Matthias

doi:10.1111/j.1462-5822.2008.01156.x

Cited by 228 publications

(229 citation statements)

References 83 publications

(127 reference statements)

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“…One candidate is H. pylori peptidoglycan, which is translocated into host cells by the cag type IV secretion system and sensed by intracellular Nod1, which then activates NF-B-dependent responses such as secretion of interleukin-8 and ␤-defensin 2 (Viala et al, 2004;Boughan et al, 2006). Another possibility based on a recent investigation (Kwok et al, 2007) is that binding of CagL to cell surface ␣ 5 ␤ 1 integrins can alter local membrane dynamics and eventuate in the assembly of focal adhesions that trigger integrin signaling cascades (Backert and Selbach, 2008), which may aberrantly activate p120.…”

Section: Discussionmentioning

confidence: 99%

“…dependent delivery of CagA and other cag island substrates from the bacterial cytoplasm directly into host cells (Backert and Selbach, 2008). Inactivation of cagE, therefore, results in a nonfunctional type IV cag secretion system.…”

Section: Molecular Biology Of the Cell 4112mentioning

confidence: 99%

“…cagE encodes a homologue of VirB4, a protein involved in toxin export in Bordetella pertussis. Based on homology, CagE is postulated to function as a NTPase, which is required for energy-dependent delivery of CagA and other cag island substrates from the bacterial cytoplasm directly into host cells (Backert and Selbach, 2008). Inactivation of cagE, therefore, results in a nonfunctional type IV cag secretion system.…”

Section: H Pylori-mediated Mmp-7 Expression Is Transcriptionally Regmentioning

confidence: 99%

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p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Ogden

Wroblewski

Weydig

et al. 2008

MBoC

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Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons develop cancer. One H. pylori constituent that augments disease risk is the cytotoxin-associated gene (cag) pathogenicity island, which encodes a secretion system that translocates bacterial effector molecules into host cells. Matrix metalloproteinase (MMP)-7, a member of a family of enzymes with tumor-initiating properties, is overexpressed in premalignant and malignant gastric lesions, and H. pylori cag ؉ strains selectively increase MMP-7 protein levels in gastric epithelial cells in vitro and in vivo. We now report that H. pylori-mediated mmp-7 induction is transcriptionally regulated via aberrant activation of p120-catenin (p120), a component of adherens junctions. H. pylori increases mmp-7 mRNA levels in a cagand p120-dependent manner and induces translocation of p120 to the nucleus in vitro and in a novel ex vivo gastric gland culture system. Nuclear translocation of p120 in response to H. pylori relieves Kaiso-mediated transcriptional repression of mmp-7, which is implicated in tumorigenesis. These results indicate that selective and coordinated induction of mmp-7 expression by H. pylori cag ؉ isolates may explain in part the augmentation in gastric cancer risk associated with these strains. INTRODUCTIONHelicobacter pylori induces an inflammatory response in the stomach that persists for decades, and biological costs incurred by this pathogen include an increased risk for gastric adenocarcinoma and non-Hodgkins lymphoma of the stomach (Nomura et al., 1991;Parsonnet et al., 1991;Peterson, 1991;Hansson et al., 1993;Correa, 1996;Uemura et al., 2001;Peek and Blaser, 2002;Moss and Sood, 2003). However, only a fraction of colonized persons ever develop neoplasia, and enhanced cancer risk is related to strain-specific differences, aberrant host responses, and/or specific interactions between microbial and host determinants.H. pylori strains that possess the cytotoxin-associated gene (cag) pathogenicity island increase the risk for cancer compared with strains that lack this genetic locus (Peek and Blaser, 2002). The cag island encodes proteins, such as CagE, that form a type IV secretion system that translocates components of bacterial peptidoglycan and CagA, the product of the terminal gene of the island, into host cells (Asahi et al., 2000;Backert et al., 2000;Odenbreit et al., 2000;Stein et al., 2000;Selbach et al., 2002;Viala et al., 2004). After translocation, peptidoglycan initiates innate immune signaling via activation of the intracellular pattern recognition receptor, Nod-1, and the transcriptional activator nuclear factor-B (NF-B) (Viala et al., 2004). Intracellular CagA undergoes Src-dependent tyrosine phosphorylation and activates a eukaryotic phosphatase, leading to dephosphorylation of host cell proteins and cellular morphological changes (Backert et al., 2000;Higashi et al., 2002;Selbach et al., 2002;Stein et al., 2002). Recently, CagA has been shown to activate ␤-catenin and...

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Biology Of the Cell 4112mentioning

confidence: 99%

Section: H Pylori-mediated Mmp-7 Expression Is Transcriptionally Regmentioning

confidence: 99%

See 1 more Smart Citation

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Ogden

Wroblewski

Weydig

et al. 2008

MBoC

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“…Adherent of bacterium to gastric epithelial cells is critical to initiate the gastric inflammatory response with different clinical outcomes in humans (Hessey et al, 1990;Logan, 1996;Segal et al, 1996;Rieder et al, 1997). CagL (a VirB5 ortholog) is a bacterial factor that is known as a pilus protein Backert and Selbach, 2008;Backert et al, 2011), Integrin α5β1 is a receptor on gastric epithelial cell that CagL binds to; by its arginineglycine-aspartate (RGD) motif, this interaction activates α5β1 receptor and facilitates the delivery of CagA oncoprotein through type 4 secretion system (T4SS) into the epithelial cell (Parsonnet et al, 1997;Kwok et al, 2007;Backert and Selbach, 2008;Backert et al, 2011;Shaffer et al, 2011). CagL is associated with two other cag PAI proteins; CagI and CagH.…”

Section: Genotypes Predict Risk Of Peptic Ulcerations But Not Gastricmentioning

confidence: 99%

Helicobacter pylori cag Pathogenicity Island cagL and orf17 Genotypes Predict Risk of Peptic Ulcerations but not Gastric Cancer in Iran

Raei¹,

Latifi‐Navid²,

Zahri³

2015

Asian Pacific Journal of Cancer Prevention

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Background: Gastric cancer (GC) is the third most common cancer regarding mortality in the world. The cag pathogenicity island (PAI) of Helicobacter pylori which contains genes associated with a more aggressive phenotype may involve in the pathogenesis of gastrointestinal disease. We here aimed to examine the associations of cagH, cagL, orf17, and cagG genotypes of H. pylori cag PAI with severe gastrointestinal disease. Materials and Methods: A total of 242 H. pylori strains were genotyped. Histopathological examination and classification of subjects were performed. Results: The frequencies of the cagH, cagL, cagG, and orf17 genotypes were 40/54 (74.1%), 53/54 (98.1%), 38/54 (70.4%), and 43/54 (79.6%), respectively, in patients with peptidic ulceration (PU),while in the control group, the frequencies were 87/147 (59.6%) for cagH, 121/146 (82.9%) for cagL, 109/146 (74.7%) for cagG, and 89/146 (61.0%) for orf17. The results of simple logistic regression analysis showed that the cagL and orf17 genotypes were significantly associated with an increased risk of PU not GC; the ORs (95% CI) were 10.950 (1.446-82.935), and 2.504 (1.193-5.253), respectively. No significant association was found between the cagH and cagG genotypes and the risk of both the PU and the GC in Iran (P>0.05). Finally, multiple logistic regression analysis showed that the cagL genotype was independently and significantly associated with the ageand sex-adjusted risk for PU; the OR (95% CI) was 9.557 (1.219-17.185). Conclusions: We conclude that the orf17 and especially cagL genotypes of H. pylori cag PAI could be factors for risk prediction of PU, but not GC in Iran.

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“…The only reported effector protein translocated into the host cell by the cag-PAI T4SS is CagA [28]. Therefore, CagA has been recognized as a genetic marker for the cagPAI locus [29] and H. pylori-associated disease development [1,2]. Sequence comparison of the cagPAI genes of more than 30 H. pylori isolates have shown that the gene order and content are highly conserved [30].…”

Section: General Role Of Type IV Secretion Systems (T4sss) In Dna Excmentioning

confidence: 99%

DNA transfer in the gastric pathogen Helicobacter pylori

Fernández-González

Backert

2014

J Gastroenterol

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The gastric pathogen Helicobacter pylori is one of the most genetically diverse bacteria. Recombination and DNA transfer contribute to its genetic variability and enhance host adaptation. Among the strategies described to increase genetic diversity in bacteria, DNA transfer by conjugation is one of the best characterized. Using this mechanism, a fragment of DNA from a donor cell can be transferred to a recipient, always mediated by a conjugative nucleoprotein complex, which is evolutionarily related to type IV secretion systems (T4SSs). Interestingly, the H. pylori chromosomes can encode up to four T4SSs, including the cagPAI, comB, tfs3, and tfs4 genes, some of which are known to promote chronic H. pylori infection. The T4SS encoded by the cagPAI mediates the injection of the effector protein CagA and proinflammatory signaling, and the comB system is involved in DNA uptake from the environment. However, the role of tfs3 and tfs4 is not yet clear. The presence of a functional XerD tyrosine recombinase and 5 0 AAAGAATG-3 0 border sequences as well as two putative conjugative relaxases (Rlx1 and Rlx2), a coupling protein (TraG), and a chromosomal region carrying a putative origin of transfer (oriT) suggest the existence of a DNA transfer apparatus in tfs4. Moreover, a conjugation-like DNA transfer mechanism in H. pylori has already been described in vitro, but whether this occurs in vivo is still unknown. Some extrachromosomal plasmids and phages are also present in various H. pylori strains. Genetic exchange among plasmids and chromosomes, and involved DNA mobilization events, could explain part of H. pylori's genetic diversity. Here, we review our knowledge about the possible DNA transfer mechanisms in H. pylori and its implications in bacterial adaptation to the host environment.

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Role of type IV secretion inHelicobacter pyloripathogenesis

Cited by 228 publications

References 83 publications

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

p120 and Kaiso RegulateHelicobacter pylori-induced Expression of Matrix Metalloproteinase-7

Helicobacter pylori cag Pathogenicity Island cagL and orf17 Genotypes Predict Risk of Peptic Ulcerations but not Gastric Cancer in Iran

DNA transfer in the gastric pathogen Helicobacter pylori

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