Modulating TRADD to restore cellular homeostasis and inhibit apoptosis

Abstract

Cell death in human disease is often a consequence of disrupted cellular homeostasis. Preventing cell death without restoring cellular homeostasis may lead to a persistent dysfunctional state that remains pathologically significant. While mechanisms of cell death have been thoroughly investigated1-3, how to restore homeostasis after inhibition of cell death remains unclear. Here we identify TRADD4-6, an adaptor protein, as a direct regulator of both cellular homeostasis and apoptosis. TRADD modulates cellular homeostasis by inhibiting TRAF2/cIAP1/2-mediated K63 ubiquitination of Beclin 1, thus reducing autophagy. TRADD deficiency inhibits RIPK1-dependent extrinsic apoptosis and proteasomal stress-induced intrinsic apoptosis. Furthermore, we identify small molecules ICCB-19 and Apt-1 that bind to a pocket on TRADD’s N-terminal TRAF2 binding domain (TRADD-N) involved in interacting with TRADD-C and TRAF2 to modulate ubiquitination of RIPK1 and Beclin 1. Inhibition of TRADD by ICCB-19/Apt-1 blocks apoptosis and restores cellular homeostasis by activating autophagy in cells with accumulated mutant tau, -synuclein, and Huntingtin. Treatment with Apt-1 restored proteostasis and inhibited cell death in a proteinopathy animal model induced by mutant TauP301S. We conclude that pharmacological targeting of TRADD may represent a promising strategy to inhibit cell death and restore homeostasis for treatment of human disease.