A Specific A/T Polymorphism in Western Tyrosine Phosphorylation B-Motifs Regulates CagA Epithelial Cell Interactions

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As the dominant bacterium living in the human stomach, Helicobacter pylori has mixed roles in host health. One significant pathogenic risk factor is the CagA protein, which interferes with multiple host cell signaling pathways through its EPIYA tyrosine phosphorylation motifs (TPMs). Through database searching and silico analysis, we reveal a strong non-random distribution of the EPIYA B motif polymorphisms (including EPIYT and EPIYA) in Western H. pylori isolates, and provide evidence that the EPIYT are significantly less associated with gastric cancer than the EPIYA. By constructing a series of H. pylori cagA isogenic mutants and isogenic complementation plasmids, generating specific antibodies, co-culturing with human AGS cells, performing biochemical and modeling analysis, we demonstrate that CagA B-motif phosphorylation status is essential for its interaction with host PI3-kinase during colonization and that CagA with an EPIYT B-motif had significantly attenuated induction of interleukin-8 and the hummingbird phenotype, had higher affinity with PI3-kinase, and enhanced induction of AKT compared to the EPIYA. These findings provide insight into how Western H. pylori CagA regulates cancer-related activity inside host cells through the A/T polymorphisms at the functionally important B motif.

Vyšlo v časopise: A Specific A/T Polymorphism in Western Tyrosine Phosphorylation B-Motifs Regulates CagA Epithelial Cell Interactions. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004621
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004621

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