CagA–ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids

CagA–ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids

The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 5; pp. 2645 - 2655
Main Authors: Buti, Ludovico, Ruiz-Puig, Carlos, Sangberg, Dennis, Leissing, Thomas M., Brewer, R. Camille, Owen, Richard P., Sgromo, Bruno, Royer, Christophe, Ebner, Daniel, Lu, Xin
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 04-02-2020
Series:PNAS Plus
Subjects:
Apoptosis
Bacteria
Biological Sciences
Cancer
Colonization
Epidermal growth factor
Epidermal growth factor receptors
Epithelial cells
Gastric cancer
Growth factors
Health risks
Helicobacter pylori
Infections
Invasiveness
Mesenchyme
Mucosa
Organoids
p53 Protein
Phenotypes
PNAS Plus
Polarity
Risk analysis
Risk factors
Signal transduction
Signaling
Survival
Tumor suppressor genes
tumor suppressors
cell polarity
microbial pathogenesis
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Summary:The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by promoting an epithelial-to-mesenchymal transition (EMT)-like phenotype that disrupts junctions and enhances motility and invasiveness of the infected cells. However, the mechanism by which CagA disrupts gastric epithelial cell polarity to achieve its oncogenicity is not fully understood. Here we found that the apoptosis-stimulating protein of p53 2 (ASPP2), a host tumor suppressor and an important CagA target, contributes to the survival of cagA-positive H. pylori in the lumen of infected gastric organoids. Mechanistically, the CagA–ASPP2 interaction is a key event that promotes remodeling of the partitioning-defective (PAR) polarity complex and leads to loss of cell polarity of infected cells. Blockade of cagA-positive H. pylori ASPP2 signaling by inhibitors of the EGFR (epidermal growth factor receptor) signaling pathway—identified by a high-content imaging screen—or by a CagA-binding ASPP2 peptide, prevents the loss of cell polarity and decreases the survival of H. pylori in infected organoids. These findings suggest that maintaining the host cell-polarity barrier would reduce the detrimental consequences of infection by pathogenic bacteria, such as H. pylori, that exploit the epithelial mucosal surface to colonize the host environment.
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Author contributions: L.B. and X.L. designed research; L.B., C.R.-P., T.M.L., and R.C.B. performed research; D.S., R.P.O., B.S., C.R., and D.E. contributed new reagents/analytic tools; L.B., C.R.-P., D.S., T.M.L., D.E., and X.L. analyzed data; and L.B. and X.L. wrote the paper.
1Present address: Charles River Nederland B.V., 2333CR Leiden, The Netherlands.
Edited by Ralph R. Isberg, Tufts University School of Medicine, Boston, MA, and approved December 16, 2019 (received for review May 25, 2019)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1908787117