University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology; University of Minnesota - Minneapolis - Department of Integrative Biology and Physiology
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.
Zhao, Ming and Ren, Kaiqun and Ren, Kaiqun and Xiong, Xiwen and Xiong, Xiwen and Xin, Yue and Xin, Yue and Kim, Angela and Maynard, Jason C. and Zou, Yujie and Zou, Yujie and Battist, Alexander P. and Battist, Alexander P. and Koneripalli, Navya and Huang, Zan and Zhang, Zengdi and Zhang, Zengdi and Yu, Jiahui and Wang, Haiguang and Wang, Haiguang and Salgado, Oscar C. and Salgado, Oscar C. and Hogquist, Kristin A. and Hogquist, Kristin A. and Revelo, Xavier S. and Revelo, Xavier S. and Burlingame, Alma L. and Gao, Xiang and Gao, Xiang and Lin, Zhaoyu and Lin, Zhaoyu and von Moltke, Jakob and von Moltke, Jakob and Ruan, Hai-Bin, Epithelial STAT6 O-GlcNAcylation Drives Anti-Helminth Immunity via a Concerted Alarmin Response. Available at SSRN: https://ssrn.com/abstract=3917158 or http://dx.doi.org/10.2139/ssrn.3917158
This version of the paper has not been formally peer reviewed.
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