Intramolecular energies of the cytotoxic protein CagA of Helicobacter pylori as a possible descriptor of strains’ pathogenicity level

Rojas-Rengifo, Diana F.; Álvarez-Silva, María Camila; Ulloa-Guerrero, Cindy P.; Nuñez-Velez, Vanessa Lucía; Delgado, María del Pilar; Aguilera, Sonia Milena; Castro, Harold; Barrios, Andrés Fernando González

doi:10.1016/j.compbiolchem.2018.05.016

Cited by 3 publications

(2 citation statements)

References 30 publications

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“…Chronic infection with H. pylori is considered the most important risk factor for the development of gastric cancer [2], with previous studies demonstrating that 75% of gastric cancers are associated with it [3]. CagA protein, an important H. pylori virulence factor, has also been suggested to play an important role in the pathogenesis of gastric cancer [4,5]. After H. pylori comes into contact with the gastric mucosa, secreted CagA protein can be injected into cells through a structure called type 4 secretion system (T4SS) which interacts with various key proteins in the cell and is involved in signaling, regulation of cell polarity, proliferation and motility, and may ultimately induce cancer cell transformation [6].…”

Section: Introductionmentioning

confidence: 99%

H. pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion

Zhang

Chen

et al. 2021

Inflamm. Res.

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Objective The CagA (cytotoxin-related gene A, CagA) protein is an important factor for the pathogenicity of Helicobacter pylori (H. pylori). Although H. pylori has previously been shown to activate the NLRP3 inflammasome, it remains unclear what role CagA plays in this process. In the current study, we aimed to investigate the effect of CagA on NLRP3 activation and how it is linked to gastric cancer cell migration and invasion. Methods CagA positive H. pylori strain (Hp/CagA + ) and CagA gene knockout mutant (Hp/ΔCagA) infected and the pcDNA3.1/CagA plasmid transfected gastric epithelial cell lines, respectively. The morphological alterations of cells under a microscope; the NLRP3 inflammasome-related markers: NLRP3, caspase-1, and ASC protein levels were detected by Western blot, IL-1β and IL-18 levels were determined by ELISA; cell migration and invasion were determined by transwell assay; and the pyroptosis levels and intracellular ROS were determined by flow cytometry analysis. Then, pretreated with 5 mM NAC for 2 h and subsequently transfected with the pcDNA3.1/CagA plasmid for 48 h, the effects of NAC pretreatment on CagA-induced NLRP3 inflammasome-related markers expression and cell pyroptosis were examined, finally assessed the effect of CagA on migration and invasion in NLRP3-silenced cells. Results We found that Hp/CagA + strain infection and pcDNA3.1/CagA vector transfection result in NLRP3 inflammasome activation, generation of intracellular ROS, and increased invasion and migration of gastric cancer cells. Moreover, we found that ROS inhibition via NAC effectively blocks NLRP3 activation and pyroptosis. Silencing of NLRP3 reduces the effects of CagA on gastric cancer cell migration and invasion. ConclusionOur study shows that CagA can promote the invasion and migration of gastric cancer cells by activating NLRP3 inflammasome pathway. These findings provide novel insights into the mechanism of gastric cancer induction by H. pylori.

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Section: Introductionmentioning

confidence: 99%

H. pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion

Zhang

Chen

et al. 2021

Inflamm. Res.

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“…The main differences in the interaction were due to energy contributions of the electrostatic energy, helix dipole energy, van der Waals clashes, torsional clash, backbone clash and cis bond energy; however, the bulk free energy did not play an essential role in describing the two strains. The strain that caused the severe pathology had the highest affinity regarding the previously described energies [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Structural Analysis of Variability and Interaction of the N-terminal of the Oncogenic Effector CagA of Helicobacter pylori with Phosphatidylserine

Ulloa-Guerrero

Delgado

2018

IJMS

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Helicobacter pylori cytotoxin-associated gene A protein (CagA) has been associated with the increase in virulence and risk of cancer. It has been demonstrated that CagA’s translocation is dependent on its interaction with phosphatidylserine. We evaluated the variability of the N-terminal CagA in 127 sequences reported in NCBI, by referring to molecular interaction forces with the phosphatidylserine and the docking of three mutations chosen from variations in specific positions. The major sites of conservation of the residues involved in CagA–Phosphatidylserine interaction were 617, 621 and 626 which had no amino acid variation. Position 636 had the lowest conservation score; mutations in this position were evaluated to observe the differences in intermolecular forces for the CagA–Phosphatidylserine complex. We evaluated the docking of three mutations: K636A, K636R and K636N. The crystal and mutation models presented a ΔG of −8.919907, −8.665261, −8.701923, −8.515097 Kcal/mol, respectively, while mutations K636A, K636R, K636N and the crystal structure presented 0, 3, 4 and 1 H-bonds, respectively. Likewise, the bulk effect of the ΔG and amount of H-bonds was estimated in all of the docking models. The type of mutation affected both the ΔG (χ2(1)=93.82, p-value <2.2×10−16) and the H-bonds (χ2(1)=91.93, p-value <2.2×10−16). Overall, 76.9% of the strains that exhibit the K636N mutation produced a severe pathology. The average H-bond count diminished when comparing the mutations with the crystal structure of all the docking models, which means that other molecular forces are involved in the CagA–Phosphatidylserine complex interaction.

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Helicobacter pylori Virulence Factors, Pathogenicity, and Gastric Cancer

Elgohary,

Gomaa,

Ibrahim

et al. 2023

Interdisciplinary Cancer Research

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Intramolecular energies of the cytotoxic protein CagA of Helicobacter pylori as a possible descriptor of strains’ pathogenicity level

Cited by 3 publications

References 30 publications

H. pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion

H. pylori CagA activates the NLRP3 inflammasome to promote gastric cancer cell migration and invasion

Structural Analysis of Variability and Interaction of the N-terminal of the Oncogenic Effector CagA of Helicobacter pylori with Phosphatidylserine

Helicobacter pylori Virulence Factors, Pathogenicity, and Gastric Cancer

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