Modulating TRADD to restore cellular homeostasis and inhibit apoptosis

Area of Science:

• Molecular Biology
• Cell Biology
• Neuroscience

Background:

• Cell death is a hallmark of human diseases, often stemming from disrupted cellular homeostasis.
• While cell death mechanisms are understood, restoring homeostasis after cell death inhibition remains unclear.
• TRADD (TRAF-associated NF-κB activator domain-containing protein) is an adaptor protein implicated in cellular signaling pathways.

Purpose of the Study:

• To identify regulators of cellular homeostasis and apoptosis.
• To investigate the role of TRADD in maintaining cellular balance and preventing cell death.
• To explore pharmacological strategies targeting TRADD for therapeutic benefit.

Main Methods:

• Investigated TRADD's role in regulating K63-linked ubiquitination of beclin 1 and autophagy.
• Assessed the impact of TRADD deficiency on RIPK1-dependent apoptosis and proteasomal stress-induced apoptosis.
• Utilized small molecules ICCB-19 and Apt-1 to inhibit TRADD function in cellular and animal models.

Main Results:

• TRADD inhibits autophagy by modulating beclin 1 ubiquitination, thereby influencing cell death pathways.
• TRADD deficiency leads to increased apoptosis, while its inhibition blocks apoptosis and restores homeostasis.
• Small molecules ICCB-19 and Apt-1 bind to TRADD, inhibiting its function and activating autophagy.
• TRADD inhibition restored proteostasis and reduced cell death in a mouse model of tauopathy.

Conclusions:

• TRADD is a critical regulator of both cellular homeostasis and apoptosis.
• Pharmacological inhibition of TRADD by ICCB-19 or Apt-1 shows therapeutic potential for diseases characterized by cell death and homeostasis disruption.
• Targeting TRADD offers a promising strategy for treating proteinopathies and other human diseases.