Epithelial STAT6 O-GlcNAcylation Drives Anti-Helminth Immunity via a Concerted Alarmin Response

The epithelium is an integral component of mucosal barrier and host immunity. Following helminth parasite infection, the intestinal epithelial cells secrete "alarmin” cytokines, such as interleukin (IL)-25 and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting type 2 cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here we report that, intestinal epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification is induced upon helminth infections. By modifying and activating STAT6, O-GlcNAc transferase (OGT) promotes the transcription of lineage-defining transcription factor Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activates the expression of Gsdmc family genes. The resulting membrane pore formed by GSDMC facilitates the unconventional secretion of IL-33 from goblet cells. GSDMC-mediated IL-33 secretion is indispensable for the host to mount effective antihelminth immunity and support intestinal homeostasis. Protein O-GlcNAcylation can be harnessed for the future treatment of type 2 inflammation-associated human diseases.