Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer
Yadong Xie, … , Huabin Li, Hui Xiao
Yadong Xie, … , Huabin Li, Hui Xiao
Published January 21, 2020
Citation Information: J Clin Invest. 2020;130(4):2111-2128. https://doi.org/10.1172/JCI133264.
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Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer

Abstract

Although Western diet and dysbiosis are the most prominent environmental factors associated with inflammatory bowel diseases (IBDs), the corresponding host factors and cellular mechanisms remain poorly defined. Here we report that the TSC1/mTOR pathway in the gut epithelium represents a metabolic and innate immune checkpoint for intestinal dysfunction and inflammation. mTOR hyperactivation triggered by Western diet or Tsc1 ablation led to epithelium necroptosis, barrier disruption, and predisposition to dextran sulfate sodium–induced colitis and inflammation-associated colon cancer. Mechanistically, our results uncovered a critical role for TSC1/mTOR in restraining the expression and activation of RIPK3 in the gut epithelium through TRIM11-mediated ubiquitination and autophagy-dependent degradation. Notably, microbiota depletion by antibiotics or gnotobiotics attenuated RIPK3 expression and activation, thereby alleviating epithelial necroptosis and colitis driven by mTOR hyperactivation. mTOR primarily impinged on RIPK3 to potentiate necroptosis induced by TNF and by microbial pathogen-associated molecular patterns (PAMPs), and hyperactive mTOR and aberrant necroptosis were intertwined in human IBDs. Together, our data reveal a previously unsuspected link between the Western diet, microbiota, and necroptosis and identify the mTOR/RIPK3/necroptosis axis as a driving force for intestinal inflammation and cancer.

Authors

Yadong Xie, Yifan Zhao, Lei Shi, Wei Li, Kun Chen, Min Li, Xia Chen, Haiwei Zhang, Tiantian Li, Yu Matsuzawa-Ishimoto, Xiaomin Yao, Dianhui Shao, Zunfu Ke, Jian Li, Yan Chen, Xiaoming Zhang, Jun Cui, Shuzhong Cui, Qibin Leng, Ken Cadwell, Xiaoxia Li, Hong Wei, Haibing Zhang, Huabin Li, Hui Xiao

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Figure 3

Aberrant epithelial necroptosis contributes to heightened colitis in Tsc1IEC-KO mice.

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Aberrant epithelial necroptosis contributes to heightened colitis in Tsc...
Tsc1fl/fl and Tsc1IEC-KO mice were treated with 2.5% DSS for 5 days and then with regular water. (A and B) Body weight (A) and survival (B) of the treated mice (n = 16–18) were documented daily. (C) Leakage of FITC-dextran from the GI tract to the bloodstream was measured in DSS-treated mice for 3 days (n = 6). (D) qPCR analysis of proinflammatory gene expression (normalized to β-actin) in colons treated with DSS for 5 days (n = 6). (E) Immunoblots of colonic epithelial lysates from mice treated with DSS for 5 days (n = 3). p-RIPK1 (S166), p-RIPK3 (S232), and p-MLKL (S345) antibodies were used. Numbers under Western blot bands represent relative quantifications over actin. (F) IF staining on colon sections from various genotypes of mice treated with DSS for 5 days (n = 6). Double-positive cells were counted over 5 high-power fields (×400) per sample (n = 30). Scale bars: 20 μm. (G) Body weight of mice treated with DSS for 5 days (n = 7–8). Data were pooled from 3 independent experiments (A, B, and G) or are representative of 3 independent experiments (C–F) and are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by log-rank test (B), unpaired Student’s t test (C, D, and G), or 1-way ANOVA (F).