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

Autor: Ioanna S. Sougleri, Konstantinos S. Papadakos, Andreas Mentis, Mairi P. Zadik, Dionyssios N. Sgouras, Mary Mavri-Vavagianni
Přispěvatelé: Laboratoire de microbiologie médicale = Laboratory of Medical Microbiology [Athènes], Institut Pasteur Hellénique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Department of Chemistry [Athens], National and Kapodistrian University of Athens (NKUA), This report was based on work supported in part by the InfeNeutra Project, National Strategic Reference Framework (2007‐2013, project no. MIS450598) of the Ministry of Culture and Education, Greece. ISS receives a scholarship from the Hellenic Society of Gastrointestinal Oncology and Experimental Research Center (ELPEN S.A.) and KSP is supported by a studentship within the InfeNeutra project.
Rok vydání: 2015
Předmět:
0301 basic medicine
MESH: Vimentin/metabolism
MESH: Helicobacter Infections/pathology
Amino Acid Motifs
MESH: Helicobacter pylori/pathogenicity
Vimentin
MESH: Antigens
Bacterial/genetics
MESH: Amino Acid Sequence
Stem cell marker
MESH: Gastric Mucosa/microbiology
Biochemistry
MESH: Bacterial Proteins/metabolism
chemistry.chemical_compound
MESH: Amino Acid Motifs
ZEB1
MESH: Animals
CD44
Phosphorylation
biology
Chemistry
stromelysin-1/MMP-3
MESH: Epithelial-Mesenchymal Transition
Hyaluronan Receptors
MESH: Gastric Mucosa/metabolism
Host-Pathogen Interactions
Matrix Metalloproteinase 3
MMP-9
MESH: Epithelial Cells/metabolism
matrix metalloproteinase
MESH: Cell Line
Tumor
MESH: Helicobacter Infections/metabolism
Epithelial-Mesenchymal Transition
Cellular polarity
Molecular Sequence Data
MESH: Bacterial Proteins/genetics
Helicobacter Infections
MESH: Matrix Metalloproteinase 3/metabolism
03 medical and health sciences
MESH: Hyaluronan Receptors/metabolism
Bacterial Proteins
Cell Line
Tumor
CagA
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Epithelial–mesenchymal transition
Amino Acid Sequence
Molecular Biology
MESH: Antigens
Bacterial/metabolism
Antigens
Bacterial
MESH: Molecular Sequence Data
MESH: Humans
MESH: Phosphorylation
Helicobacter pylori
MESH: Host-Pathogen Interactions
Tyrosine phosphorylation
Epithelial Cells
Cell Biology
bacterial infections and mycoses
Molecular biology
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
digestive system diseases
030104 developmental biology
Gastric Mucosa
biology.protein
Cancer research
bacteria
MESH: Epithelial Cells/microbiology
Zdroj: FEBS Journal
FEBS Journal, Wiley, 2016, 283 (2), pp.206-220. ⟨10.1111/febs.13592⟩
ISSN: 1742-4658
1742-464X
DOI: 10.1111/febs.13592⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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