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; Qingzhi Wang

doi:10.1038/s41467-022-32846-4

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 SongHai Bin Ruan, Qingzhi Wang

Physiology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	5192
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32846-4
State	Published - Dec 2022

Bibliographical note

Funding Information:
C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the scientific advisory board of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; has received research funding from Boehringer-Ingelheim and Treeline Biosciences; and has a stock option from Treeline Biosciences. All other authors declare no competing interests.

Funding Information:
We thank Ms. Xiyu Yang for animal husbandry and Dr. Yinming Liang for helpful discussions on flow cytometry. This work was supported by grants from Program for Science & Technology Innovation Talents in Higher Education of Henan Province (20HASTIT046 to X.X.), National Natural Science Foundation of China (U1904132 to X.X.), Key Scientific and Technological Project of Xinxiang (GG2019008 to Q.W.), Outstanding Youth Foundation of Jiangsu Province (BK20190043 to W.-Q.H.), International Joint Research Center for Genomic Resources (2017B01012 to W.-Q.H.), National Institute of Health/National Institute of Allergy and Infectious Diseases (R01 AI162791 to H.-B.R.), Key Scientific and Technological Research Project in Henan Province (222102310048 to G.Z.).

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© 2022, The Author(s).

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Xiong, X., Yang, C., He, W. Q., Yu, J., Xin, Y., Zhang, X., Huang, R., Ma, H., Xu, S., Li, Z., Ma, J., Xu, L., Wang, Q., Ren, K., Wu, X. S., Vakoc, C. R., Zhong, J., Zhong, G., Zhu, X., ... Wang, Q. (2022). Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity. Nature communications, 13(1), Article 5192. https://doi.org/10.1038/s41467-022-32846-4

Xiong, X, Yang, C, He, WQ, Yu, J, Xin, Y, Zhang, X, Huang, R, Ma, H, Xu, S, Li, Z, Ma, J, Xu, L, Wang, Q, Ren, K, Wu, XS, Vakoc, CR, Zhong, J, Zhong, G, Zhu, X, Song, Y, Ruan, HB & Wang, Q 2022, 'Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity', Nature communications, vol. 13, no. 1, 5192. https://doi.org/10.1038/s41467-022-32846-4

@article{b7acafe947424956876786ffa4ab2e6f,

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

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.",

author = "Xiwen Xiong and Chenyan Yang and He, {Wei Qi} and Jiahui Yu and Yue Xin and Xinge Zhang and Rong Huang and Honghui Ma and Shaofang Xu and Zun Li and Jie Ma and Lin Xu and Qunyi Wang and Kaiqun Ren and Wu, {Xiaoli S.} and Vakoc, {Christopher R.} and Jiateng Zhong and Genshen Zhong and Xiaofei Zhu and Yu Song and Ruan, {Hai Bin} and Qingzhi Wang",

note = "Funding Information: C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the scientific advisory board of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; has received research funding from Boehringer-Ingelheim and Treeline Biosciences; and has a stock option from Treeline Biosciences. All other authors declare no competing interests. Funding Information: We thank Ms. Xiyu Yang for animal husbandry and Dr. Yinming Liang for helpful discussions on flow cytometry. This work was supported by grants from Program for Science & Technology Innovation Talents in Higher Education of Henan Province (20HASTIT046 to X.X.), National Natural Science Foundation of China (U1904132 to X.X.), Key Scientific and Technological Project of Xinxiang (GG2019008 to Q.W.), Outstanding Youth Foundation of Jiangsu Province (BK20190043 to W.-Q.H.), International Joint Research Center for Genomic Resources (2017B01012 to W.-Q.H.), National Institute of Health/National Institute of Allergy and Infectious Diseases (R01 AI162791 to H.-B.R.), Key Scientific and Technological Research Project in Henan Province (222102310048 to G.Z.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32846-4",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

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TY - JOUR

T1 - Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity

AU - Xiong, Xiwen

AU - Yang, Chenyan

AU - He, Wei Qi

AU - Yu, Jiahui

AU - Xin, Yue

AU - Zhang, Xinge

AU - Huang, Rong

AU - Ma, Honghui

AU - Xu, Shaofang

AU - Li, Zun

AU - Ma, Jie

AU - Xu, Lin

AU - Wang, Qunyi

AU - Ren, Kaiqun

AU - Wu, Xiaoli S.

AU - Vakoc, Christopher R.

AU - Zhong, Jiateng

AU - Zhong, Genshen

AU - Zhu, Xiaofei

AU - Song, Yu

AU - Ruan, Hai Bin

AU - Wang, Qingzhi

N1 - Funding Information: C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the scientific advisory board of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; has received research funding from Boehringer-Ingelheim and Treeline Biosciences; and has a stock option from Treeline Biosciences. All other authors declare no competing interests. Funding Information: We thank Ms. Xiyu Yang for animal husbandry and Dr. Yinming Liang for helpful discussions on flow cytometry. This work was supported by grants from Program for Science & Technology Innovation Talents in Higher Education of Henan Province (20HASTIT046 to X.X.), National Natural Science Foundation of China (U1904132 to X.X.), Key Scientific and Technological Project of Xinxiang (GG2019008 to Q.W.), Outstanding Youth Foundation of Jiangsu Province (BK20190043 to W.-Q.H.), International Joint Research Center for Genomic Resources (2017B01012 to W.-Q.H.), National Institute of Health/National Institute of Allergy and Infectious Diseases (R01 AI162791 to H.-B.R.), Key Scientific and Technological Research Project in Henan Province (222102310048 to G.Z.). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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

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