FADD
FAS-associated death domain protein is a protein in humans that is encoded by FADD gene. Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.
FAS-associated death domain protein (FADD), also known as MORT1, is an adapter protein essential for the induction of extrinsic apoptosis. FADD contains a C-terminal death domain (DD) and an N-terminal death effector domain (DED). During extrinsic apoptosis, FADD acts as a bridge between the ligated death receptor and the caspases that directly propagate apoptotic signals. The receptors of the tumor necrosis factor (TNF) superfamily such as the FAS receptor, interacts with its cognate ligand to form a trimer complex. FADD binds to the FAs receptor trimer through its DD. FADD is activated and subsequently recruits apoptotic pro-caspases via DED/DED interactions to form the death-inducing signal complex (DISC), which allows cleavage and activation of initiator caspases-8 and caspases-10, ultimately leading to the apoptotic response. FADD is also involved in initiating necroptosis with serine/threonine kinases RIPK1 and RIPK3. Apart from being an essential component in death receptor-mediated apoptosis, FADD is required for T-cell proliferation, cell cycle progression, tumor development, inflammation, innate immunity, and autophagy. It has been confirmed that apoptosis is dysregulated in various pathological conditions. In cancer, loss of FADD is beneficial to the survival of malignant tumor cells by preventing apoptosis. Elevated FADD expression has been detected in human lung cancer and is correlated with poor survival. FADD expression is increased in white blood cells of multiple sclerosis relapsing patients, suggesting that FADD functions in the underlying inflammatory processes. And overexpression of FADD and caspase-8 may play a role in TNF-mediated apoptosis of dopaminergic neurons of patients with Parkinson's disease. In terms of FADD's role in numerous cell death processes, it is promising to be a therapeutic target in many conditions such as malignancy, autoimmunity, and inflammation. Marín-Rubio JL et al.proposed that FADD expression and phosphorylation may be reliable biomarkers with prognostic value for T-cell lymphoblastic lymphoma (T-LBL) stratification.
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