Modulating TRADD to restore cellular homeostasis and inhibit apoptosis

Nature. 2020 Nov;587(7832):133-138. doi: 10.1038/s41586-020-2757-z. Epub 2020 Sep 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Autophagy / drug effects
  • Baculoviral IAP Repeat-Containing 3 Protein / metabolism
  • Beclin-1 / chemistry
  • Beclin-1 / metabolism
  • Bortezomib / antagonists & inhibitors
  • Bortezomib / pharmacology
  • Cell Line
  • Homeostasis / drug effects*
  • Humans
  • Huntingtin Protein / metabolism
  • Inhibitor of Apoptosis Proteins / metabolism
  • Male
  • Mice
  • Models, Molecular
  • Neurofibrillary Tangles / metabolism
  • Proteome / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • TNF Receptor-Associated Death Domain Protein / antagonists & inhibitors*
  • TNF Receptor-Associated Death Domain Protein / chemistry
  • TNF Receptor-Associated Death Domain Protein / deficiency
  • TNF Receptor-Associated Death Domain Protein / metabolism*
  • TNF Receptor-Associated Factor 2 / metabolism
  • Ubiquitination
  • alpha-Synuclein / metabolism
  • tau Proteins / metabolism


  • Beclin-1
  • Huntingtin Protein
  • Inhibitor of Apoptosis Proteins
  • Proteome
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 2
  • alpha-Synuclein
  • tau Proteins
  • Bortezomib
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Receptor-Interacting Protein Serine-Threonine Kinases