Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C

Ming Zhao; Kaiqun Ren; Xiwen Xiong; Yue Xin; Yujie Zou; Jason C Maynard; Angela Kim; Alexander P Battist; Navya Koneripalli; Yusu Wang; Qianyue Chen; Ruyue Xin; Chenyan Yang; Rong Huang; Jiahui Yu; Zan Huang; Zengdi Zhang; Haiguang Wang; Daoyuan Wang; Yihui Xiao; Oscar C Salgado; Nicholas N Jarjour; Kristin A Hogquist; Xavier S Revelo; Alma L Burlingame; Xiang Gao; Jakob von Moltke; Zhaoyu Lin; Hai-Bin Ruan

doi:10.1016/j.immuni.2022.03.009

Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C

Immunity. 2022 Apr 12;55(4):623-638.e5. doi: 10.1016/j.immuni.2022.03.009. Epub 2022 Apr 5.

Authors

Ming Zhao¹, Kaiqun Ren², Xiwen Xiong³, Yue Xin³, Yujie Zou⁴, Jason C Maynard⁵, Angela Kim¹, Alexander P Battist¹, Navya Koneripalli¹, Yusu Wang⁴, Qianyue Chen⁴, Ruyue Xin⁴, Chenyan Yang³, Rong Huang³, Jiahui Yu³, Zan Huang¹, Zengdi Zhang¹, Haiguang Wang¹, Daoyuan Wang⁶, Yihui Xiao⁶, Oscar C Salgado⁷, Nicholas N Jarjour⁷, Kristin A Hogquist⁸, Xavier S Revelo⁹, Alma L Burlingame⁵, Xiang Gao⁴, Jakob von Moltke¹⁰, Zhaoyu Lin¹¹, Hai-Bin Ruan¹²

Affiliations

¹ Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
² Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA; College of Medicine, Hunan Normal University, Changsha, Hunan, China.
³ School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
⁴ MOE Key Laboratory of Model Animals for Disease Study, State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
⁶ College of Medicine, Hunan Normal University, Changsha, Hunan, China.
⁷ Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
⁸ Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
⁹ Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA; Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
¹⁰ Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
¹¹ MOE Key Laboratory of Model Animals for Disease Study, State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China. Electronic address: linzy@nju.edu.cn.
¹² Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA; Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA. Electronic address: hruan@umn.edu.

Abstract

The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (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 cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.

Keywords: Gasdermin; IL-10; IL-25; IL-33; O-GlcNAc; OGT; STAT6; Tuft cell; colitis; goblet cell.

MeSH terms

Acylation
Alarmins* / immunology
Anthelmintics / immunology
Biomarkers, Tumor
Cytokines
DNA-Binding Proteins
Helminthiasis / immunology
Humans
Hyperplasia
Inflammation
Interleukin-33
Intestinal Mucosa* / immunology
Mebendazole
N-Acetylglucosaminyltransferases / immunology
Pore Forming Cytotoxic Proteins
STAT6 Transcription Factor / immunology

Substances

Alarmins
Anthelmintics
Biomarkers, Tumor
Cytokines
DNA-Binding Proteins
GSDMC protein, human
Interleukin-33
Pore Forming Cytotoxic Proteins
STAT6 Transcription Factor
STAT6 protein, human
Mebendazole
N-Acetylglucosaminyltransferases
O-GlcNAc transferase

Abstract

MeSH terms

Substances

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