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1.
Biochem Biophys Res Commun ; 618: 79-85, 2022 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-35716599

RESUMO

Arteriosclerosis is intimately associated with cardiovascular diseases. Recently, evidence accumulated that infection with Helicobacter pylori cagA-positive strains, which causes gastritis, peptic ulceration, and gastric cancer, is also involved in the development of arteriosclerosis. The cagA-encoded CagA protein is injected into the attached gastric epithelial cells via the type IV secretion system. We previously showed that CagA-containing exosomes are secreted from CagA-injected gastric epithelial cells and enter the systemic blood circulation, delivering CagA into endothelial cells. In the present study, transgenic mice were established in which CagA was selectively expressed in endothelial cells by Cre-loxP system. Treatment of the mice with a high-fat diet revealed that atherogenic lesions were induced in mice expressing CagA in vascular endothelial cells but not in CagA-nonexpressing mice. To investigate the effects of CagA on endothelial cells, we also established conditional CagA-expressing human vascular endothelial cells using the Tet-on system. Upon induction of CagA, a dramatic change in cell morphology was observed that was concomitantly associated with the loss of the endothelial cells to form tube-like structures. Induction of CagA also activated the pro-inflammatory transcription factor STAT3. Thus, exosome-delivered CagA deregulates signals that activates STAT3 in endothelial cells, which accelerates inflammation that promotes arteriosclerosis/atherosclerosis.


Assuntos
Arteriosclerose , Infecções por Helicobacter , Helicobacter pylori , Animais , Antígenos de Bactérias/metabolismo , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Proteínas de Bactérias/metabolismo , Células Endoteliais/metabolismo , Células Epiteliais/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Camundongos
2.
Cell Host Microbe ; 29(6): 941-958.e10, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-33989515

RESUMO

Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis.


Assuntos
Antígenos de Bactérias/metabolismo , Proteína BRCA1/metabolismo , Proteínas de Bactérias/metabolismo , Células Epiteliais/metabolismo , Instabilidade Genômica , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Neoplasias Gástricas/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinogênese/metabolismo , Linhagem Celular , Quebras de DNA de Cadeia Dupla , Células Epiteliais/microbiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Serina-Treonina Quinase 3 , Transdução de Sinais , Estômago/microbiologia , Proteína Supressora de Tumor p53/metabolismo
3.
Sci Rep ; 8(1): 15981, 2018 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374120

RESUMO

Helicobacter pylori cagA-positive strains are critically involved in the development of gastric cancer. Upon delivery into gastric epithelial cells via type IV secretion, the cagA-encoded CagA interacts with and thereby perturbs the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1b via the tyrosine-phosphorylated EPIYA-C/D segment and the CM sequence, respectively. Importantly, sequences spanning these binding regions exhibit variations among CagA proteins, which influence the pathobiological/oncogenic potential of individual CagA. Here we isolated an H. pylori strain (Hp_TH2099) naturally infecting the stomach of a housed macaque, indicating a zoonotic feature of H. pylori infection. Whole genome sequence analysis revealed that Hp_TH2099 belongs to the hpAsia2 cluster and possesses ABC-type Western CagA, which contains hitherto unreported variations in both EPIYA-C and CM sequences. The CM variations almost totally abolished PAR1b binding. Whereas pTyr + 5 variation in the EPIYA-C segment potentiated SHP2-binding affinity, pTyr-2 variation dampened CagA tyrosine phosphorylation and thus impeded CagA-SHP2 complex formation. As opposed to the H. pylori standard strain, infection of mouse ES cell-derived gastric organoids with Hp_TH2099 failed to elicit CagA-dependent epithelial destruction. Thus, the macaque-isolated H. pylori showed low virulence due to attenuated CagA activity through multiple substitutions in the sequences involved in binding with SHP2 and PAR1b.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Infecções por Helicobacter/veterinária , Helicobacter pylori/isolamento & purificação , Macaca/microbiologia , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/química , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Suco Gástrico/microbiologia , Genes Bacterianos , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/transmissão , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Humanos , Camundongos , Modelos Moleculares , Organoides/microbiologia , Fenótipo , Conformação Proteica , Mapeamento de Interação de Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Recombinantes/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Virulência , Zoonoses
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