B3GNT7 regulates mucin glycosylation and protects against colitis and infection

Mucus covers and protects colonic epithelial cells. Mucus is mainly composed of heavily O-glycosylated proteins called mucins, and disruption of normal mucin glycosylation occurs in ulcerative colitis (UC). Mucin-2 (MUC2) is the major colonic mucin, and MUC2 O-glycans are often extended with sulfated polyLacNAc, also known as keratan sulfate (KS). The GlcNAc residues in KS are added by B3GNT family members. B3GNT7 is highly expressed in the colon, and B3GNT7 expression is dramatically reduced in UC. However, the function of B3GNT7 in colonic physiology is unexplored. Here we show that B3gnt7 is a key player in colonic physiology through its function in controlling the structure of mucus glycans. We found that B3GNT7 prefers to extend a sulfated acceptor substrate and is required for production of polyLacNAc-modified mucus in a human goblet cell model. In vivo, B3GNT7 regulates Muc2, Muc13, and Muc17 O-glycosylation. Intestinal B3GNT7 deficiency increases susceptibility to colitis and enteric infection in mice, showing that B3GNT7-dependent glycosylation confers protective properties to colonic mucus. Taken together, these results demonstrate that B3GNT7 has a function distinct from other B3GNT family members and is critical for maintaining colonic homeostasis. SIGNIFICANCE STATEMENTUlcerative colitis is a chronic inflammatory bowel disease that affects 5 million people globally. The colonic mucus layer forms a protective barrier over colonic epithelial cells and is disrupted in ulcerative colitis. Mucus is composed of mucin proteins decorated by carbohydrates, called glycans. Glycans confer protective properties to the mucus barrier, and mucin glycans change in ulcerative colitis. B3GNT7 is an enzyme that elongates glycans and is downregulated in ulcerative colitis. In this study, we use in vitro and in vivo models to demonstrate that B3GNT7 regulates colonic mucus glycans and protects mice against colitis and infection. Our findings provide molecular insight into the contributions of B3GNT7-dependent glycans to colonic homeostasis.