Intestinal Epithelial STAT6 Activation Rescues the Defective Anti-Helminth Responses Caused by Ogt Deletion

Dynamic regulation of intestinal epithelial cell (IEC) proliferation and differentiation is crucial for maintaining mucosa homeostasis and the response to helminth infection. O-GlcNAc transferase (OGT), an enzyme catalyzing the transfer of GlcNAc from the donor substrate UDP-GlcNAc onto acceptor proteins, has been proposed to promote intestinal epithelial remodeling for helminth expulsion by modifying and activating epithelial STAT6, but whether the IEC intrinsic OGT-STAT6 axis is involved in anti-helminth responses has not been tested in vivo. Here, we show that the inducible deletion of Ogt in IECs of adult mice leads to reduced tuft and goblet cell differentiation, increased crypt cell proliferation, and aberrant Paneth cell localization. By using a mouse model with concurrent Ogt deletion and STAT6 overexpression in IECs, we provide direct in vivo evidence that STAT6 acts downstream of OGT to control tuft and goblet cell differentiation in IECs. However, epithelial OGT regulates crypt cell proliferation and Paneth cell differentiation in a STAT6-independent pathway. Our results verify that protein O-GlcNAcylation in IECs is crucial for maintaining epithelial homeostasis and anti-helminthic type 2 immune responses.