Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis

Ziyu Sun, Jianyu Ye, Weimin Sun, Libo Jiang, Bing Shan, Mengmeng Zhang, Jingyi Xu, Wanjin Li, Jianping Liu, Hongyang Jing, Tian Zhang, Meiling Hou, Cen Xie, Rongling Wu, Heling Pan and Junying Yuan ()
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Ziyu Sun: Chinese Academy of Sciences
Jianyu Ye: Chinese Academy of Sciences
Weimin Sun: Chinese Academy of Sciences
Libo Jiang: Shandong University of Technology
Bing Shan: Chinese Academy of Sciences
Mengmeng Zhang: Chinese Academy of Sciences
Jingyi Xu: University of Chinese Academy of Sciences
Wanjin Li: Chinese Academy of Sciences
Jianping Liu: Chinese Academy of Sciences
Hongyang Jing: Chinese Academy of Sciences
Tian Zhang: Chinese Academy of Sciences
Meiling Hou: Chinese Academy of Sciences
Cen Xie: Chinese Academy of Sciences
Rongling Wu: Beijing Institute of Mathematical Sciences and Applications
Heling Pan: Chinese Academy of Sciences
Junying Yuan: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and TRADD-dependent colitis. These findings reveal the cooperation between RIPK1 and TRADD in mediating cell death and inflammation in IBD with NF-κB deficiency and suggest the possibility of combined inhibition of RIPK1 kinase and TRADD as a new therapeutic strategy for IBD.

Date: 2025
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DOI: 10.1038/s41467-025-57211-z

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