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
  • 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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