FADD

FADD, or Fas-Associated protein with Death Domain, is a human adaptor protein that mediates signaling in the extrinsic pathway of apoptosis. It serves as a link between death receptors—such as Fas (CD95) and other members of the TNF receptor superfamily—and downstream caspases, enabling the execution of programmed cell death in response to receptor activation.

Structurally, FADD contains two functional domains: a death effector domain (DED) and a death domain (DD). The death domain mediates interaction with the cytoplasmic tails of activated death receptors, while the death effector domain recruits procaspase-8 or procaspase-10 to form the death-inducing signaling complex (DISC). This assembly leads to caspase-8 activation and the downstream caspase cascade that commits the cell to apoptosis. FADD can also participate in signaling cross-talk, influencing other pathways such as NF-κB and influencing cell fate decisions in a context-dependent manner.

Regulation of FADD activity is achieved through post-translational modifications and interactions with other proteins. Phosphorylation and ubiquitination can influence DISC assembly and signaling outcomes. Inhibitory proteins such as c-FLIP can compete with procaspases for binding to FADD, modulating the strength and duration of apoptotic signaling. In addition to promoting apoptosis, FADD is implicated in maintaining cellular homeostasis by restricting necroptotic pathways under certain conditions; genetic models show that loss of FADD can shift cells toward necroptosis, affecting development and immune function.

Clinical relevance of FADD includes associations with cancer, immune disorders, and dysregulated cell death. Altered FADD expression or function can impact tumorigenesis, immune cell turnover, and responses to stress. Research into FADD continues to explore its therapeutic potential in diseases characterized by aberrant apoptosis or necroptosis.