Goblet cell-expressed microprotein FXYD3 determines gut homeostasis by maintaining mucus barrier integrity

The intestinal mucus layer produced by goblet cells is a critical component of innate immunity. The key host factors and regulatory mechanisms controlling goblet cell function in mucus layer formation remain poorly understood. This study identifies a function for the microprotein FXYD domain-containing transport regulator 3 (FXYD3) in goblet cells in regulating mucus layer formation to maintain intestinal homeostasis. Deficiency of FXYD3 in mouse intestinal epithelial cells results in a damaged mucus barrier, leading to dysbiosis and increased susceptibility to colitis. Mechanistically, FXYD3 interacts with endoplasmic reticulum Ca²⁺-ATPase SERCA2 to enhance its pump activity. FXYD3 deficiency causes defects in ER Ca²⁺ homeostasis and mucin glycosylation, impairing mucus layer integrity. Furthermore, metabolites of gut microbiota, propionate, and butyrate promote FXYD3 expression. In ulcerative colitis patients, FXYD3 expression is significantly downregulated and correlates with disease severity. These findings indicate FXYD3 is a key mediator of host-microbiota interactions for intestinal health.