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Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity

Author

Listed:
  • Xiwen Xiong

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Chenyan Yang

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Wei-Qi He

    (Suzhou Medical College of Soochow University)

  • Jiahui Yu

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Yue Xin

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Xinge Zhang

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Rong Huang

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Honghui Ma

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Shaofang Xu

    (Suzhou Medical College of Soochow University)

  • Zun Li

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Jie Ma

    (Xinxiang Medical University)

  • Lin Xu

    (Xinxiang Medical University)

  • Qunyi Wang

    (The Third Affiliated Hospital of Xinxiang Medical University)

  • Kaiqun Ren

    (Hunan Normal University School of Medicine)

  • Xiaoli S. Wu

    (Cold Spring Harbor Laboratory)

  • Christopher R. Vakoc

    (Cold Spring Harbor Laboratory)

  • Jiateng Zhong

    (Xinxiang Medical University)

  • Genshen Zhong

    (Xinxiang Medical University)

  • Xiaofei Zhu

    (Xinxiang Medical University)

  • Yu Song

    (Xinxiang Medical University)

  • Hai-Bin Ruan

    (University of Minnesota Medical School)

  • Qingzhi Wang

    (Xinxiang Medical University)

Abstract

Dynamic regulation of intestinal epithelial cell (IEC) differentiation is crucial for both homeostasis and the response to helminth infection. SIRT6 belongs to the NAD+-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Here, we report that IEC Sirt6 deletion leads to impaired tuft cell development and type 2 immunity in response to helminth infection, thereby resulting in compromised worm expulsion. Conversely, after helminth infection, IEC SIRT6 transgenic mice exhibit enhanced epithelial remodeling process and more efficient worm clearance. Mechanistically, Sirt6 ablation causes elevated Socs3 expression, and subsequently attenuated tyrosine 641 phosphorylation of STAT6 in IECs. Notably, intestinal epithelial overexpression of constitutively activated STAT6 (STAT6vt) in mice is sufficient to induce the expansion of tuft and goblet cell linage. Furthermore, epithelial STAT6vt overexpression remarkedly reverses the defects in intestinal epithelial remodeling caused by Sirt6 ablation. Our results reveal a novel function of SIRT6 in regulating intestinal epithelial remodeling and mucosal type 2 immunity in response to helminth infection.

Suggested Citation

  • Xiwen Xiong & Chenyan Yang & Wei-Qi He & Jiahui Yu & Yue Xin & Xinge Zhang & Rong Huang & Honghui Ma & Shaofang Xu & Zun Li & Jie Ma & Lin Xu & Qunyi Wang & Kaiqun Ren & Xiaoli S. Wu & Christopher R. , 2022. "Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32846-4
    DOI: 10.1038/s41467-022-32846-4
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