TY - JOUR
T1 - Modulating TRADD to restore cellular homeostasis and inhibit apoptosis
AU - Xu, Daichao
AU - Zhao, Heng
AU - Jin, Minzhi
AU - Zhu, Hong
AU - Shan, Bing
AU - Geng, Jiefei
AU - Dziedzic, Slawomir A.
AU - Amin, Palak
AU - Mifflin, Lauren
AU - Naito, Masanori Gomi
AU - Najafov, Ayaz
AU - Xing, Jing
AU - Yan, Lingjie
AU - Liu, Jianping
AU - Qin, Ying
AU - Hu, Xinqian
AU - Wang, Huibing
AU - Zhang, Mengmeng
AU - Manuel, Vica Jean
AU - Tan, Li
AU - He, Zhuohao
AU - Sun, Zhenyu J.
AU - Lee, Virginia M.Y.
AU - Wagner, Gerhard
AU - Yuan, Junying
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/11/5
Y1 - 2020/11/5
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85091354953&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2757-z
DO - 10.1038/s41586-020-2757-z
M3 - Article
C2 - 32968279
AN - SCOPUS:85091354953
SN - 0028-0836
VL - 587
SP - 133
EP - 138
JO - Nature
JF - Nature
IS - 7832
ER -