Tradd, short for Tumor necrosis factor receptor type 1-associated death domain protein, is an adaptor molecule. It is involved in multiple signal pathways such as TNF-related signaling, mediating biological activities like cell survival, proliferation, differentiation, apoptosis, necroptosis, and inflammation [2]. Tradd contains an N-terminal tumor necrosis factor receptor-associated factor 2 (TRAF2) binding domain and a C-terminal death domain (DD), which interact with multiple proteins, enabling it to function as a platform for downstream signal propagation following receptor activation [2].

In various disease models, Tradd shows distinct effects. In a TAK1 IEC deficient model, phosphorylation of Tradd by TAK1 modulates RIPK1-dependent apoptosis, and Tradd and RIPK1 cooperate to mediate cell death regulated by TNF and TLR signaling, leading to different pathological manifestations in the intestine [4]. In an osteoarthritis (OA) model, Tradd deficiency or inhibition by ICCB-19 attenuates TNF-α-related OA-like phenotypes in chondrocytes, by blocking the RIPK1-TAK1-NF-κB signals and restoring autophagy [3]. In a proteinopathy mouse model induced by mutant tau(P301S), treatment with Apt-1 (which inhibits Tradd) restores proteostasis and inhibits cell death [1]. In Ripk1 -/-Ripk3 -/- mice, ablation of Tradd rescues them from perinatal lethality, and Tradd plays a more dominating role in NFκB-signaling than RIPK1 [5]. In a diabetic cardiomyopathy model, knockdown of Tradd or use of its inhibitor Apt-1 improves cardiac function and attenuates pyroptosis [6].

In conclusion, Tradd is a crucial adaptor protein involved in multiple signal pathways and biological activities. Gene knockout and inhibitor-based studies in mouse models have revealed its significance in various disease conditions, including intestinal diseases, osteoarthritis, proteinopathies, and diabetic cardiomyopathy. These findings suggest that targeting Tradd could be a potential therapeutic strategy for treating related diseases.

References:

1. Xu, Daichao, Zhao, Heng, Jin, Minzhi, Wagner, Gerhard, Yuan, Junying. 2020. Modulating TRADD to restore cellular homeostasis and inhibit apoptosis. In Nature, 587, 133-138. doi:10.1038/s41586-020-2757-z. https://pubmed.ncbi.nlm.nih.gov/32968279/

2. Chen, Yun, Gu, Yunhui, Xiong, Xing, Wang, Weiqi, Meng, Guoliang. 2022. Roles of the adaptor protein tumor necrosis factor receptor type 1-associated death domain protein (TRADD) in human diseases. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 153, 113467. doi:10.1016/j.biopha.2022.113467. https://pubmed.ncbi.nlm.nih.gov/36076575/

3. Sun, Kai, Guo, Zhou, Zhang, Jinming, Guo, Fengjing, Zhu, Wentao. 2023. Inhibition of TRADD ameliorates chondrocyte necroptosis and osteoarthritis by blocking RIPK1-TAK1 pathway and restoring autophagy. In Cell death discovery, 9, 109. doi:10.1038/s41420-023-01406-0. https://pubmed.ncbi.nlm.nih.gov/37002200/

4. Sun, Ziyu, Ye, Jianyu, Sun, Weimin, Pan, Heling, Yuan, Junying. 2025. Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis. In Nature communications, 16, 1890. doi:10.1038/s41467-025-57211-z. https://pubmed.ncbi.nlm.nih.gov/39987261/

5. Dowling, John P, Alsabbagh, Mohamed, Del Casale, Christina, Liu, Zheng-Gang, Zhang, Jianke. 2019. TRADD regulates perinatal development and adulthood survival in mice lacking RIPK1 and RIPK3. In Nature communications, 10, 705. doi:10.1038/s41467-019-08584-5. https://pubmed.ncbi.nlm.nih.gov/30741936/

6. Zheng, Yang-Yang, Shen, Dan-Ning, Peng, Xiao-Lu, Shi, Jia-Hai, Chen, Yun. 2025. TRADD-mediated pyroptosis contributes to diabetic cardiomyopathy. In Acta pharmacologica Sinica, 46, 940-950. doi:10.1038/s41401-024-01450-1. https://pubmed.ncbi.nlm.nih.gov/39753984/