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

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.

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Publication Details

Journal
Nature Communications
Published
2025-02-22
DOI
https://doi.org/10.1038/s41467-025-57211-z
Citations
12
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
9.67
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article

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

Cen Xie, Libo Jiang, Zongping Sun, Heling Pan et al.
12 citations
Nature Communications
Gut microbiota and health
9.67
article

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

Cen Xie, Libo Jiang, Zongping Sun, Heling Pan, Hongyang Jing, Mengmeng Zhang, Bing Shan, Junying Yuan, Rongling Wu, Wanjin Li, Jianping Liu, Jingyi Xu, Min Hou, Jiaxing Ye, Wei Jia Sun, Tian Zhang
article en
12 citations

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.

Nature CommunicationsVol. 16(1)
Shandong University of Technology (CN), Chinese Academy of Sciences (CN), Shanghai Institute of Materia Medica (CN), Shanghai Institute of Organic Chemistry (CN), Shanghai Institute of Computing Technology (CN), University of Chinese Academy of Sciences (CN), Tsinghua University (CN)
Zero hunger
Openalex Percentile: Top 2%
Gut microbiota and health
9.67
DOIOpen Access PDFOpenAlex
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