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

Zhao, Mingli; Ren, Kai; Xiong, Xin; Yue, Xin; Zou, Yujie; Maynard, Jason C.; Kim, Angela; Battist, Alexander P; Koneripalli, Navya; Wang, Yusu; Chen, Qianyue; Xin, Ruyue; Yang, Chenyan; Huang, Rong; Yu, Jin; Huang, Zan; Zhang, Zengdi; Wang, Haiguang; Wang, Daoyuan; Xiao, Yihui; Salgado, Oscar Camilo; Jarjour, Nicholas N.; Hogquist, Kristin A.; Revelo, Xavier S.; Burlingame, Alma L.; Gao, Xiang; Moltke, Jakob von; Lin, Zhaoyu; Ruan, Hai Bin

doi:10.1016/j.immuni.2022.03.009

Cited by 65 publications

(45 citation statements)

References 86 publications

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“…In response to IL4/IL13, STAT6 proteins undergo tyrosine phosphorylation and are transported to the nucleus, where along with co-factors, STAT6 regulates the expression of its target genes 16 . Confirming the requirement for STAT6 in anti-helminth responses, mice lacking STAT6 show abrogated expansion of tuft and goblet cells and compromised worm expulsion after helminth infections 12 , 17 – 19 . Although STAT6 has been mainly shown to function in immune cells, there is a growing appreciation of its role in non-immune cells, including IECs.…”

Section: Introductionmentioning

confidence: 70%

“…STAT6 is activated by type 2 cytokines and essential for anti-helminth epithelial remodeling 15 . Stat6 −/− mice failed to generate helminth infection-induced tuft and goblet cell hyperplasia, demonstrating a requirement for STAT6 activity in the protective type 2 immune responses 12 , 17 – 19 . Importantly, the sufficiency of intestinal epithelial STAT6 in driving tuft and goblet cell hyperplasia has been demonstrated by IEC specific expression of constitutively activated STAT6 (STAT6vt) in two mouse models generated by Schubart et al .…”

Section: Discussionmentioning

confidence: 99%

“…But it should be pointed out that Sirt6 ablation in IECs also results in reduced intestinal tuft cell abundance in naive mice or in vehicle-treated organoids, suggesting epithelial SIRT6 is also required for intestinal tuft cell development at the steady-state when type 2 immunity is not activated. So far, the mechanisms that give rise to the tuft cell lineage are less well understood, and STAT6 and POU2F3 are known transcription factors to be essential for tuft cell differentiation 12 , 13 , 19 . The necessity of STAT6 for helminth-associated epithelial remodeling is supported by the findings from Stat6 -/- mice 12 , 17 – 19 .…”

Section: Discussionmentioning

confidence: 99%

“…So far, the mechanisms that give rise to the tuft cell lineage are less well understood, and STAT6 and POU2F3 are known transcription factors to be essential for tuft cell differentiation 12 , 13 , 19 . The necessity of STAT6 for helminth-associated epithelial remodeling is supported by the findings from Stat6 -/- mice 12 , 17 – 19 . However, we found comparable tuft cell frequency between intestinal organoids isolated from Stat6 -/- mice and WT controls in the absence of IL4/IL13 stimulation, indicating STAT6 is not required for tuft cell differentiation at the steady-state.…”

Section: Discussionmentioning

confidence: 99%

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

Xiong

Yang

et al. 2022

Nat Commun

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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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Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Xiong

Yang

et al. 2022

Nat Commun

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“…Nonetheless, it is unclear if cold or b3adrenergic activation could directly modulate the hexosamine biosynthetic pathway, OGT activity, and protein O-GlcNAcylation in Treg cells. Other work in our laboratory has revealed a pivotal role of O-GlcNAcylation on STAT6 signaling and type 2 immunity (57). It is warranted in the future to determine if OGT also regulates the STAT6-Pten axis in tissue-specific Treg cells and adipose tissue function.…”

Section: Discussionmentioning

confidence: 92%

An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism

et al. 2022

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The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.

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Activation of STAT6 in Intestinal Epithelial Cells Predisposes to Gut Inflammation

Westermann,

Radtke,

Kramer

et al. 2024

Eur J Immunol

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Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) often associated with a Type 2 immune response. Although previous reports hint at a role for signal transducer and activator of transcription (STAT) 6 signaling in non‐immune cells, the contribution of STAT6‐activation particularly in intestinal epithelial cells (IECs) is still unknown. Dextran sodium sulfate (DSS)‐induced colitis is a model for UC in mice that we applied here on animals with expression of a constitutively active version of STAT6 in IECs (VillinCre_STAT6vt mice). We report increased pathology and mortality due to enhanced and systemic inflammation in these mice. Bulk RNA sequencing of colonic tissue from naïve VillinCre_STAT6vt mice showed differential expression of more than 140 genes compared to control mice. Gene set enrichment analysis revealed STAT6‐regulated expression of the unfolded protein response, MTORC‐ and MYC‐signaling, and protein secretion pathways. A comparison of gene expression in the colon of naïve VillinCre_STAT6vt mice and a human single‐cell RNA sequencing dataset of a patient cohort with IBD revealed overlapping changes in the epithelial and macrophage compartment compared to corresponding controls. In conclusion, we found that activation of STAT6 in the intestinal epithelium predisposes to exacerbated colitis and gut inflammation.

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

Cited by 65 publications

References 86 publications

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

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

An OGT-STAT5 Axis in Regulatory T Cells Controls Energy and Iron Metabolism

Activation of STAT6 in Intestinal Epithelial Cells Predisposes to Gut Inflammation

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