Modulating TRADD to restore cellular homeostasis and inhibit apoptosis.
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, ?-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.
Mesh Terms:
Animals, Apoptosis, Autophagy, Baculoviral IAP Repeat-Containing 3 Protein, Beclin-1, Bortezomib, Cell Line, Homeostasis, Humans, Huntingtin Protein, Inhibitor of Apoptosis Proteins, Male, Mice, Models, Molecular, Neurofibrillary Tangles, Proteome, Receptor-Interacting Protein Serine-Threonine Kinases, TNF Receptor-Associated Death Domain Protein, TNF Receptor-Associated Factor 2, Ubiquitination, alpha-Synuclein, tau Proteins
Animals, Apoptosis, Autophagy, Baculoviral IAP Repeat-Containing 3 Protein, Beclin-1, Bortezomib, Cell Line, Homeostasis, Humans, Huntingtin Protein, Inhibitor of Apoptosis Proteins, Male, Mice, Models, Molecular, Neurofibrillary Tangles, Proteome, Receptor-Interacting Protein Serine-Threonine Kinases, TNF Receptor-Associated Death Domain Protein, TNF Receptor-Associated Factor 2, Ubiquitination, alpha-Synuclein, tau Proteins
Nature
Date: Dec. 01, 2019
PubMed ID: 32968279
View in: Pubmed Google Scholar
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