FAS-associated death domain protein (FADD) is a 23 kDa adaptor protein involved in initiating apoptosis. FADD is best known for its involvement in extrinsic/death receptor-mediated apoptosis, but it is also involved in initiating necroptosis with serine/threonine kinases RIPK1 and RIPK3 (1). FADD binds to receptors of the tumor necrosis factor (TNF) superfamily through its C-terminal death domain (DD). During extrinsic apoptosis, binding of the Fas-ligand causes trimerization of the Fas-receptor which then binds to FADD via the DD domain. Activated FADD recruits apoptotic pro-caspases to form the death-inducing signal complex (DISC). Formation of the DISC allows cleavage and activation of initiator caspases-8 and -10. Presence of the DD domain is critical to the formation of the DISC and initiation of apoptosis. c-FLIP, PKC, and MKRN1 have all been identified as negative regulators of FADD activity, thus inhibiting apoptosis.
Dysregulation of apoptosis has been identified in a number of pathological conditions. In cancer, loss of FADD confers a survival advantage to the malignant cells by preventing apoptosis (2). In multiple sclerosis, FADD expression is increased in the leukocytes of relapsing patients, suggesting a role for FADD in the underlying inflammatory processes (3). In Parkinson’s disease, overexpression of FADD and caspase-8 may play a role in the TNF-mediated apoptosis of dopaminergic neurons (4). Given its role in a variety of cell death processes, FADD holds promise as a therapeutic target in many conditions such as malignancy, autoimmunity, and inflammation.
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