GPAT3 is a novel inflammatory protein promoting gastric bacterial colonization and gastritis in Helicobacter pylori infection

Bacterial-modulated gastric epithelial cells (GECs) play key roles in H. pylori-associated pathology. Here we demonstrate a pro-colonization and pro-inflammation role of GEC-expressed glycerol-3-phosphate acyltransferase 3 (GPAT3), a lipid metabolism-associated protein, in H. pylori infection. GPAT3 expression was elevated in gastric mucosa of both patients and mice infected with H. pylori. GPAT3 in GECs was synergistically induced by H. pylori and IL-22 in a cagA-dependent manner. Human gastric GPAT3 correlated with H. pylori colonization and the severity of gastritis, and mouse GPAT3 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il22-/-, Gpat3-/- and Il22-/-Gpat3-/- mice. Mechanistically, GPAT3 directly interacted with CCAR1 and activated IKKγ, subsequently promoted NF-κB phosphorylation whereby NF-kB directly bound to the promoters of MMP1, CXCL11 and IL-33 to activate their transcription, which not only led to decreased E-cadherin and zonula occludens-1 proteins by MMP1, thereby resulting in gastric mucosal damage and increased H. pylori colonization; but also resulted in increased gastric influx of CD8+ T cells via CXCL11-dependent migration and their subsequent IL-33-dependent IFN-γ production, thereby promoting H. pylori-associated gastritis. Overall, we propose a model in which GPAT3 collectively ensures H. pylori persistence and promotes gastritis. To investigate the function of GPAT3 in gastric epithelial cells, AGS cells were pre-treated with GPAT3 siRNA or non-specific control siRNA (NC) (40 nM) for 24 h