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 investigated 1 – 3 , it remains unclear how homeostasis can be restored after inhibition of cell death. Here we identify TRADD 4 – 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. The adaptor protein TRADD is a regulator of both cellular homeostasis and apoptosis, and represents a potential therapeutic target for human diseases.

中文翻译：

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调节 TRADD 以恢复细胞稳态并抑制细胞凋亡

人类疾病中的细胞死亡通常是细胞稳态破坏的结果。如果在不恢复细胞稳态的情况下阻止细胞死亡，则可能导致持续的功能障碍和病理状态。尽管已经彻底研究了细胞死亡的机制 1 – 3 ，但仍不清楚如何在抑制细胞死亡后恢复体内平衡。在这里，我们确定 TRADD 4 – 6，一种衔接蛋白，作为细胞稳态和细胞凋亡的直接调节剂。TRADD 通过抑制由 TRAF2、cIAP1 和 cIAP2 介导的 K63 连接的 beclin 1 泛素化来调节细胞稳态，从而减少自噬。TRADD 缺乏抑制 RIPK1 依赖的外在细胞凋亡和蛋白酶体应激诱导的内在细胞凋亡。我们还表明小分子 ICCB-19 和 Apt-1 与 TRADD (TRADD-N) 的 N 端 TRAF2 结合域上的口袋结合，后者与 C 端域 (TRADD-C) 和 TRAF2 相互作用调节 RIPK1 和 beclin 的泛素化 1. ICCB-19 或 Apt-1 对 TRADD 的抑制通过激活具有累积突变 tau、α-突触核蛋白或亨廷顿蛋白的细胞中的自噬来阻止细胞凋亡并恢复细胞稳态。在由突变 tau (P301S) 诱导的蛋白质病小鼠模型中，用 Apt-1 处理恢复蛋白质稳态并抑制细胞死亡。我们得出结论，TRADD 的药理学靶向可能代表抑制细胞死亡和恢复体内平衡以治疗人类疾病的有希望的策略。衔接蛋白 TRADD 是细胞稳态和细胞凋亡的调节剂，