2. Academic Validation
  3. Modulating TRADD to restore cellular homeostasis and inhibit apoptosis

Modulating TRADD to restore cellular homeostasis and inhibit apoptosis

  • Nature. 2020 Nov;587(7832):133-138. doi: 10.1038/s41586-020-2757-z.
Daichao Xu  # 1 2,  Heng Zhao  # 1,  Minzhi Jin 1,  Hong Zhu 1,  Bing Shan 2,  Jiefei Geng 1,  Slawomir A Dziedzic 1,  Palak Amin 1,  Lauren Mifflin 1,  Masanori Gomi Naito 1,  Ayaz Najafov 1,  Jing Xing 3,  Lingjie Yan 2,  Jianping Liu 4,  Ying Qin 2,  Xinqian Hu 1,  Huibing Wang 1,  Mengmeng Zhang 2,  Vica Jean Manuel 1,  Li Tan 2,  Zhuohao He 2 5,  Zhenyu J Sun 6,  Virginia M Y Lee 5,  Gerhard Wagner 7,  Junying Yuan 8
Affiliations

Affiliations

  • 1 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI, USA.
  • 4 State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 5 Center for Neurodegenerative Disease Research, Institute on Aging, Department of Pathology and Laboratory, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
  • 6 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 8 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 32968279 DOI: 10.1038/s41586-020-2757-z
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.

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