<i>Helicobacter pylori</i>outer membrane protein HopQ identified as a novel T4SS-associated virulence factor

Belogolova, Elena; Bauer, Bianca; Pompaiah, Malvika; Asakura, Hiroshi; Brinkman, Volker; Ertl, Claudia; Bartfeld, Sina; Nechitaylo, Taras Y.; Haas, Rainer; Machuy, Nikolaus; Salama, Nina R.; Churin, Y; Meyer, Thomas F.

doi:10.1111/cmi.12158

Cited by 65 publications

(73 citation statements)

References 93 publications

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“…VacA is a toxin that is secreted through an autotransporter pathway (5,52) and subsequently can be released as a soluble protein into the extracellular space or remain attached to the bacterial surface (5,53). BabA is an H. pylori adhesin that binds to the Lewis b antigen on host cells (8), and HopQ is an outer membrane protein that influences the activity of the cag type IV secretion system (14). In contrast to VacA, BabA, and HopQ, virtually nothing is known about the functions of BabB, BabC, HomA, and HomD.…”

Section: Discussionmentioning

confidence: 99%

“…For example, H. pylori outer membrane protein adhesins mediate H. pylori adherence to gastric epithelial cells (8)(9)(10), and surface-exposed components of the cag type IV secretion system (T4SS) have important roles in engaging receptors on host cells (11,12). Some H. pylori outer membrane proteins (OMPs) can stimulate or inhibit inflammatory responses (13), and others can modulate the activity of the cag type IV secretion system (14)(15)(16).…”

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confidence: 99%

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Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

et al. 2014

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More than 50Helicobacter pylori genes are predicted to encode outer membrane proteins (OMPs), but there has been relatively little experimental investigation of the H. pylori cell surface proteome. In this study, we used selective biotinylation to label proteins localized to the surface of H. pylori, along with differential detergent extraction procedures to isolate proteins localized to the outer membrane. Proteins that met multiple criteria for surface-exposed outer membrane localization included known adhesins, as well as Cag proteins required for activity of the cag type IV secretion system, putative lipoproteins, and other proteins not previously recognized as cell surface components. We identified sites of nontryptic cleavage consistent with signal sequence cleavage, as well as C-terminal motifs that may be important for protein localization. A subset of surface-exposed proteins were highly susceptible to proteolysis when intact bacteria were treated with proteinase K. Most Hop and Hom OMPs were susceptible to proteolysis, whereas Hor and Hof proteins were relatively resistant. Most of the protease-susceptible OMPs contain a large protease-susceptible extracellular domain exported beyond the outer membrane and a protease-resistant domain at the C terminus with a predicted ␤-barrel structure. These features suggest that, similar to the secretion of the VacA passenger domain, the N-terminal domains of protease-susceptible OMPs are exported through an autotransporter pathway. Collectively, these results provide new insights into the repertoire of surface-exposed H. pylori proteins that may mediate bacterium-host interactions, as well as the cell surface topology of these proteins.

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Section: Discussionmentioning

confidence: 99%

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Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

et al. 2014

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“…However, very recent studies also suggest that even some non-cagPAI encoded factors such as HopI, HopQ, and LPS biosynthesis genes are also involved in host cell interaction and injection of CagA. 16,17 If these bacterial factors can bind to other host receptors assisting in T4SS function is yet unclear and awaits further investigation. However, it can be assumed that the T4SS injection mechanism is much more complicated than originally proposed 52 and requires even multiple cagPAIindependent factors, probably acting cooperatively.…”

Section: Discussionmentioning

confidence: 99%

“…It has been found that some of the adhesion factors discussed below act in conjunction with other proteins, e.g., from the cagPAI, in order to hijack several host cell processes including varied transcription, opening of cell-to-cell junctions, cytoskeletal rearrangements, onset of inflammation, and others. [14][15][16][17] In addition to the above carbohydrate binders, intensive research in recent years has demonstrated that H. pylori also targets host cholesterol, heparan sulfate, phosphatidylserine, sphingomyelin, and other lipids 1,7,13,18,19 as well as a broad variety of host protein receptors. For 25 of these protein receptors the corresponding bacterial factor has been identified (summarized in Table 1), while for at least 19 others the matching bacterial factors remain unknown (Table S1).…”

Section: Introductionmentioning

confidence: 99%

Signal transduction ofHelicobacter pyloriduring interaction with host cell protein receptors of epithelial and immune cells

Pachathundikandi

Tegtmeyer²,

Backert³

2013

Gut Microbes

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“…H. pylori requires ␣ 5 ␤ 1 integrin for the efficient injection of CagA (18). Additional interactions between H. pylori adhesins and other host cell proteins can also promote cag PAI delivery (19)(20)(21). A number of H. pylori proteins have been shown to bind to ␣ 5 ␤ 1 integrin, on the basis of the findings of studies that focused on proteins encoded within the cag PAI.…”

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The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α ₅ β ₁ Integrin

et al. 2017

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The human pathogen Helicobacter pylori uses the host receptor ␣ 5 ␤ 1 integrin to trigger inflammation in host cells via its cag pathogenicity island (cag PAI) type IV secretion system (T4SS). Here, we report that the H. pylori ImaA protein (HP0289) decreases the action of the cag PAI T4SS via tempering the bacterium's interaction with ␣ 5 ␤ 1 integrin. Previously, imaA-null mutants were found to induce an elevated inflammatory response that was dependent on the cag PAI T4SS; here we extend those findings to show that the elevated response is independent of the CagA effector protein. To understand how ImaA could be affecting cag PAI T4SS activity at the host cell interface, we utilized the Phyre structural threading program and found that ImaA has a region with remote homology to bacterial integrinbinding proteins. This region was required for ImaA function. Unexpectedly, we observed that imaA mutants bound higher levels of ␣ 5 ␤ 1 integrin than wild-type H. pylori, an outcome that required the predicted integrin-binding homology region of ImaA. Lastly, we report that ImaA directly affected the amount of host cell ␤1 integrin but not other cellular integrins. Our results thus suggest a model in which H. pylori employs ImaA to regulate interactions between integrin and the T4SS and thus alter the host inflammatory strength.KEYWORDS autotransporter proteins, inflammation, pathogenesis, secretion systems, virulence factors T he human pathogen Helicobacter pylori is one of the world's most common pathogens, chronically colonizing the stomachs of at least one-third of the world's population, with the populations of many countries experiencing rates of colonization of over 50% (1, 2). The outcomes of this infection vary on the basis of a combination of bacterial genetics, host genetics, and environmental factors (3). Ten to 15% of those infected go on to develop severe diseases, including ulcers and gastric adenocarcinoma (4-6). H. pylori-triggered diseases cause significant mortality and morbidity worldwide. For example, gastric adenocarcinoma killed over 700,000 people worldwide in 2012, and in the United States, 26,370 people were expected to have been diagnosed with this disease in 2016 (7,8).One of the main factors that influences the H. pylori disease outcome is whether a person is infected with a strain that possesses the cytotoxin-associated gene (cag) pathogenicity island (cag PAI). cag PAI-positive strains are associated with severe inflammation, peptic ulcers, and gastric cancer (9). The cag PAI encodes a type IV secretion system (T4SS), a large multiprotein system that triggers a host inflammatory response directly via interactions with the host cells (10) and also via delivery of proinflammatory cargo: the protein CagA and the bacterial molecule peptidoglycan (11,12).Given the cost and consequence of producing an active cag PAI T4SS, its function is controlled at several levels (2, 13, 14). While there is some transcriptional modulation

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Helicobacter pyloriouter membrane protein HopQ identified as a novel T4SS-associated virulence factor

Cited by 65 publications

References 93 publications

Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

Signal transduction ofHelicobacter pyloriduring interaction with host cell protein receptors of epithelial and immune cells

The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α ₅ β ₁ Integrin

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Helicobacter pyloriouter membrane protein HopQ identified as a novel T4SS-associated virulence factor

Cited by 65 publications

References 93 publications

Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

Signal transduction ofHelicobacter pyloriduring interaction with host cell protein receptors of epithelial and immune cells

The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α 5 β 1 Integrin

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The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α ₅ β ₁ Integrin