LOX-1 acts as an N⁶-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase.

Abstract

The role of N⁶-methyladenosine (m⁶A) modification of host mRNA during bacterial infection is unclear. Here, we show that Helicobacter pylori infection upregulates host m⁶A methylases and increases m⁶A levels in gastric epithelial cells. Reducing m⁶A methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interfering RNAs targeting m⁶A methylases, enhances H. pylori colonization. We identify LOX-1 mRNA as a key m⁶A-regulated target during H. pylori infection. m⁶A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate that m⁶A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downregulating LOX-1 and thus reducing H. pylori adhesion.