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

As a result of Helicobacter pylori adhesion to gastric epithelial cells, the bacterial effector cytotoxin‐associated gene A (CagA) is translocated intracellularly, and after hierarchical tyrosine phosphorylation on multiple EPIYA motifs, de‐regulates cellular polarity and contributes to induction of...

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Bibliographic Details
Published in:The FEBS journal 2016-01, Vol.283 (2), p.206-220
Main Authors: Sougleri, Ioanna S, Papadakos, Konstantinos S, Zadik, Mairi P, Mavri‐Vavagianni, Mary, Mentis, Andreas F, Sgouras, Dionyssios N
Format: Article
Language:English
Subjects:
adhesion
Amino Acid Motifs
Amino Acid Sequence
Animals
Antigens, Bacterial - genetics
Antigens, Bacterial - metabolism
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Bacteriology
Biochemistry, Molecular Biology
carcinogenesis
CD44
Cell Line, Tumor
cell polarity
epithelial cells
Epithelial Cells - metabolism
Epithelial Cells - microbiology
Epithelial-Mesenchymal Transition
Gastric Mucosa - metabolism
Gastric Mucosa - microbiology
genes
Helicobacter Infections - metabolism
Helicobacter Infections - pathology
Helicobacter pylori
Helicobacter pylori - pathogenicity
Host-Pathogen Interactions
Humans
Hyaluronan Receptors - metabolism
Kinases
Life Sciences
matrix metalloproteinase
Matrix Metalloproteinase 3 - metabolism
Microbiology and Parasitology
MMP‐9
Molecular Sequence Data
mutants
phenotype
Phosphorylation
Proteins
Stem cells
stromelysin‐1/MMP‐3
transcription (genetics)
transcriptional activation
tyrosine
Ulcers
vimentin
Vimentin - metabolism
ZEB1
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Summary:As a result of Helicobacter pylori adhesion to gastric epithelial cells, the bacterial effector cytotoxin‐associated gene A (CagA) is translocated intracellularly, 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 mesenchymal 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 phosphorylation 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 phosphorylation‐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.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.13592