Cooperation of TRADD- and RIPK1-dependent Cell Death Pathways in Maintaining Intestinal Homeostasis

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Feb 22

PMID 39987261

Authors

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

Junying Yuan

Affiliations

Soon will be listed here.

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.

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