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

Xiong, Xiwen, Yang, Chenyan, He, Wei-Qi, Yu, Jiahui, Xin, Yue, Zhang, Xinge, Huang, Rong, Ma, Honghui, Xu, Shaofang, Li, Zun, Ma, Jie, Xu, Lin, Wang, Qunyi, Ren, Kaiqun, Wu, Xiaoli S, Vakoc, Christopher R, Zhong, Jiateng, Zhong, Genshen, Zhu, Xiaofei, Song, Yu, Ruan, Hai-Bin, Wang, Qingzhi (September 2022) Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity. Nature Communications, 13 (1). p. 5192. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > immunity organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:	Wu, Xiaoli Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 September 2022
Date Deposited:	06 Sep 2022 21:51
Last Modified:	17 Jan 2024 19:28
PMCID:	PMC9440928
URI:	https://repository.cshl.edu/id/eprint/40707

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