TRADDmediated

TRADD-mediated signaling refers to the cellular signaling events initiated by the adaptor protein TRADD (TNFR1-associated death domain protein) in response to tumor necrosis factor (TNF) receptor 1 activation. TRADD integrates receptor proximal signals to downstream pathways that govern cell fate, including NF-κB activation, MAP kinase signaling, and apoptotic or necroptotic death programs.

Upon TNF binding to TNFR1, TRADD is recruited via death-domain interactions. In Complex I, it recruits TRAF2, RIPK1, and cIAP1/2; RIPK1 ubiquitination promotes NF-κB and MAPK activation and survival. The complex can convert to Complex II, where TRADD associates with FADD and caspase-8 to trigger apoptosis.

TRADD also influences necroptosis. When caspase-8 is inhibited, RIPK1 interacts with RIPK3 to drive necroptosis; TRADD’s early recruitment and the ubiquitination state of RIPK1 help determine whether survival or death signaling predominates.

Regulation includes ubiquitination by cIAPs and deubiquitination by CYLD; post-translational modifications and competition with other adaptors modulate TRADD signaling, influencing the balance between pro-survival and pro-death outcomes.

Dysregulation of TRADD-mediated signaling has been linked to inflammatory diseases, autoimmune conditions, and cancer. As a central hub in TNF signaling, TRADD represents a potential target for therapies aimed at modulating TNF-driven inflammation and cell death.