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

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 XiaoOscar C. Salgado, Nicholas N. Jarjour, Kristin A. Hogquist, Xavier S. Revelo, Alma L. Burlingame, Xiang Gao, Jakob von Moltke, Zhaoyu Lin, Hai Bin Ruan

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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.

Original language	English (US)
Pages (from-to)	623-638.e5
Journal	Immunity
Volume	55
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2022.03.009
State	Published - Apr 12 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

Gasdermin
IL-10
IL-25
IL-33
O-GlcNAc
OGT
STAT6
Tuft cell
colitis
goblet cell

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Zhao, M., Ren, K., Xiong, X., Xin, Y., Zou, Y., Maynard, J. C., Kim, A., Battist, A. P., Koneripalli, N., Wang, Y., Chen, Q., Xin, R., Yang, C., Huang, R., Yu, J., Huang, Z., Zhang, Z., Wang, H., Wang, D., ... Ruan, H. B. (2022). Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C. Immunity, 55(4), 623-638.e5. https://doi.org/10.1016/j.immuni.2022.03.009

Zhao, M, Ren, K, Xiong, X, Xin, Y, Zou, Y, Maynard, JC, Kim, A, Battist, AP, Koneripalli, N, Wang, Y, Chen, Q, Xin, R, Yang, C, Huang, R, Yu, J, Huang, Z, Zhang, Z, Wang, H, Wang, D, Xiao, Y, Salgado, OC, Jarjour, NN, Hogquist, KA , Revelo, XS, Burlingame, AL, Gao, X, von Moltke, J, Lin, Z & Ruan, HB 2022, 'Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C', Immunity, vol. 55, no. 4, pp. 623-638.e5. https://doi.org/10.1016/j.immuni.2022.03.009

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

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",

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AU - Zhao, Ming

AU - Ren, Kaiqun

AU - Xiong, Xiwen

AU - Xin, Yue

AU - Zou, Yujie

AU - Maynard, Jason C.

AU - Kim, Angela

AU - Battist, Alexander P.

AU - Koneripalli, Navya

AU - Wang, Yusu

AU - Chen, Qianyue

AU - Xin, Ruyue

AU - Yang, Chenyan

AU - Huang, Rong

AU - Yu, Jiahui

AU - Huang, Zan

AU - Zhang, Zengdi

AU - Wang, Haiguang

AU - Wang, Daoyuan

AU - Xiao, Yihui

AU - Salgado, Oscar C.

AU - Jarjour, Nicholas N.

AU - Hogquist, Kristin A.

AU - Revelo, Xavier S.

AU - Burlingame, Alma L.

AU - Gao, Xiang

AU - von Moltke, Jakob

AU - Lin, Zhaoyu

AU - Ruan, Hai Bin

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N2 - 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.

AB - 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.

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KW - IL-25

KW - IL-33

KW - O-GlcNAc

KW - OGT

KW - STAT6

KW - Tuft cell

KW - colitis

KW - goblet cell

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AN - SCOPUS:85127492845

SN - 1074-7613

VL - 55

SP - 623-638.e5

JO - Immunity

JF - Immunity

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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