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

Abstract

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.

ASPP2/PP1 complexes maintain the integrity of pseudostratified epithelia undergoing remodelling during morphogenesis

“…1a). As seen in other examples of polarised epithelia 13,14,16,22 , ASPP2 was strongly localised to the apical junction in the trophectoderm from the 32-cell stage onwards (Fig. 1a).…”

ASPP2/PP1 complexes maintain the integrity of pseudostratified epithelia undergoing remodelling during morphogenesis

“…In support of this, we found that ASPP2 could start to be detected as early as E2.5 at cell-cell junctions ( Figure S1A). As seen in other examples of polarised epithelia 13,14,16,22 , ASPP2 was strongly localised to the apical junction in the TE from the 32-cell stage onwards ( Figure 1A). This localisation pattern was similar in human blastocysts, suggesting that ASPP2 behaves in a similar way across mammals ( Figure S1B).…”

A meta‐analysis of the association between Helicobacter pylori infection and risk of atherosclerotic cardiovascular disease

“…Helicobacter pylori ( H pylori ) is a spiral, gram‐negative microaerobic bacterium and has infected about half of the world’s population 1,2 . Its infection can cause a variety of symptoms, including gastritis, peptic ulcer, and neoplastic disease 3‐5 . Recent researches have found that H pylori infection can not only cause digestive problems, but also be closely related to many diseases outside the digestive system 6 …”