Helicobacter pylori CagA protein induces factors involved in the epithelial to mesenchymal transition (EMT) in infected gastric epithelial cells in an EPIYA- phosphorylation-dependent manner

Ioanna Sougleri 1, * Konstantinos Papadakos 1 Mairi Zadik 1 Mary Mavri-Vavagianni 2 Andreas Mentis 1 Dionyssios Sgouras 1
* Corresponding author
1 Laboratoire de microbiologie médicale [Athènes]
2 Department of Chemistry [Athens]
National and Kapodistrian University of Athens
Abstract : As a result of Helicobacter pylori adhesion to gastric epithelial cells, the bacterial effector cytotoxin-associated gene A (CagA) is translocated intra-cellularly, and after hierarchical tyrosine phosphorylation on multiple EPIYA motifs, de-regulates cellular polarity and contributes to induction of an elongation and scattering phenotype that resembles the epithelial to mes-enchymal transition (EMT). Stromelysin-1/matrix metalloproteinase-3 (MMP-3) has been reported to induce a sequence of molecular alterations leading to stable EMT transition and carcinogenesis in epithelial cells. To identify the putative role of CagA protein in MMP-3 induction, we exploited an experimental H. pylori infection system in gastric epithelial cell lines. We utilized isogenic mutants expressing CagA protein with variable numbers of EPIYA and phosphorylation-deficient EPIFA motifs, as well as cagA knockout and translocation-deficient cagE knockout strains. Increased levels of MMP-3 transcriptional activation were demonstrated by quantitative real time-PCR for strains with more than two terminal EPIYA phos-phorylation motifs in CagA. MMP-3 expression in total cell lysates and the corresponding culture supernatants was associated with CagA expression and translocation and was dependent on CagA phosphorylation. A CagA EPIYA phosphorylation-dependent increase in gelatinase and caseinolytic activity was also detected in culture supernatants by zymography. A significant increase in the transcriptional activity of the mesenchymal markers Vimentin, Snail and ZEB1 and the stem cell marker CD44 was observed in the case of CagA containing phosphorylation-functional EPIYA motifs. Our data suggest that CagA protein induces EMT through EPIYA phos-phorylation-dependent up-regulation of MMP-3. Moreover, no significant increase in EMT and stem cell markers was observed following infection with H. pylori strains that cannot effectively translocate CagA protein.
Keywords : CD44 MMP-9 ZEB1 matrix metalloproteinase stromelysin-1/MMP-3
Document type :
Journal articles
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https://hal-riip.archives-ouvertes.fr/pasteur-02195910
Contributor : Dionyssios Sgouras <>
Submitted on : Friday, July 26, 2019 - 3:47:09 PM
Last modification on : Tuesday, July 30, 2019 - 4:59:19 PM

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Ioanna Sougleri, Konstantinos Papadakos, Mairi Zadik, Mary Mavri-Vavagianni, Andreas Mentis, et al.. Helicobacter pylori CagA protein induces factors involved in the epithelial to mesenchymal transition (EMT) in infected gastric epithelial cells in an EPIYA- phosphorylation-dependent manner. FEBS Journal, Wiley, 2016, 283 (2), pp.206-220. ⟨10.1111/febs.13592⟩. ⟨pasteur-02195910⟩

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