Modulating TRADD to restore cellular homeostasis and inhibit apoptosis

Daichao Xu, Heng Zhao, Minzhi Jin, Hong Zhu, Bing Shan, Jiefei Geng, Slawomir A. Dziedzic, Palak Amin, Lauren Mifflin, Masanori Gomi Naito, Ayaz Najafov, Jing Xing, Lingjie Yan, Jianping Liu, Ying Qin, Xinqian Hu, Huibing Wang, Mengmeng Zhang, Vica Jean Manuel, Li Tan, Zhuohao He, Zhenyu J. Sun, Virginia M. Y. Lee, Gerhard Wagner and Junying Yuan ()
Additional contact information
Daichao Xu: Harvard Medical School
Heng Zhao: Harvard Medical School
Minzhi Jin: Harvard Medical School
Hong Zhu: Harvard Medical School
Bing Shan: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Jiefei Geng: Harvard Medical School
Slawomir A. Dziedzic: Harvard Medical School
Palak Amin: Harvard Medical School
Lauren Mifflin: Harvard Medical School
Masanori Gomi Naito: Harvard Medical School
Ayaz Najafov: Harvard Medical School
Jing Xing: Michigan State University
Lingjie Yan: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Jianping Liu: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Ying Qin: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Xinqian Hu: Harvard Medical School
Huibing Wang: Harvard Medical School
Mengmeng Zhang: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Vica Jean Manuel: Harvard Medical School
Li Tan: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Zhuohao He: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Zhenyu J. Sun: Dana Farber Cancer Institute
Virginia M. Y. Lee: University of Pennsylvania School of Medicine
Gerhard Wagner: Harvard Medical School
Junying Yuan: Harvard Medical School

Nature, 2020, vol. 587, issue 7832, 133-138

Abstract: Abstract Cell death in human diseases is often a consequence of disrupted cellular homeostasis. If cell death is prevented without restoring cellular homeostasis, it may lead to a persistent dysfunctional and pathological state. Although mechanisms of cell death have been thoroughly investigated1–3, it remains unclear how homeostasis can be restored after inhibition of cell death. Here we identify TRADD4–6, an adaptor protein, as a direct regulator of both cellular homeostasis and apoptosis. TRADD modulates cellular homeostasis by inhibiting K63-linked ubiquitination of beclin 1 mediated by TRAF2, cIAP1 and cIAP2, thereby reducing autophagy. TRADD deficiency inhibits RIPK1-dependent extrinsic apoptosis and proteasomal stress-induced intrinsic apoptosis. We also show that the small molecules ICCB-19 and Apt-1 bind to a pocket on the N-terminal TRAF2-binding domain of TRADD (TRADD-N), which interacts with the C-terminal domain (TRADD-C) and TRAF2 to modulate the ubiquitination of RIPK1 and beclin 1. Inhibition of TRADD by ICCB-19 or Apt-1 blocks apoptosis and restores cellular homeostasis by activating autophagy in cells with accumulated mutant tau, α-synuclein, or huntingtin. Treatment with Apt-1 restored proteostasis and inhibited cell death in a mouse model of proteinopathy induced by mutant tau(P301S). We conclude that pharmacological targeting of TRADD may represent a promising strategy for inhibiting cell death and restoring homeostasis to treat human diseases.

Date: 2020
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DOI: 10.1038/s41586-020-2757-z

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