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

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. Vakoc, Jiateng Zhong, Genshen Zhong, Xiaofei Zhu, Yu Song, Hai-Bin Ruan and Qingzhi Wang ()
Additional contact information
Xiwen Xiong: Xinxiang Medical University
Chenyan Yang: Xinxiang Medical University
Wei-Qi He: Suzhou Medical College of Soochow University
Jiahui Yu: Xinxiang Medical University
Yue Xin: Xinxiang Medical University
Xinge Zhang: Xinxiang Medical University
Rong Huang: Xinxiang Medical University
Honghui Ma: Xinxiang Medical University
Shaofang Xu: Suzhou Medical College of Soochow University
Zun Li: 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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32846-4

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