FADD Fas-associated death domain

An important trigger for apoptosis is known as the Fas system. This is used by cytotoxic Tcells, for example, which eliminate infected cells in this way (top left). Most of the body s cells have Fas receptors (CD 95) on their plasma membrane. If a T cell is activated by contact with an MHC presenting a viral peptide (see p. 296), binding of its Fas ligands occurs on the target cell s Fas receptors. Via the mediator protein FADD ( Fas-associated death domain ), this activates cas-pase-8 inside the cell, setting in motion the apoptotic process. 

FADD Fas-associated death domain, an adapter protein... 

Death domain receptors. The cytokine TNF (tumor necrosis factor) uses a type of receptor called the death domain receptor (Fig. 11.21). These receptors function as a trimer when they bind TNF (which is also a trimer). On TNF binding, an inhibitory protein called the silencer of death is released from the receptor. The receptor then binds and activates several adaptor proteins. One adaptor protein, FADD (fas-associated death domain), recruits and activates the zymogen form of a proteolytic enzyme called caspase. Caspases... 

Fig. 1. Modulation of apoptosis by v-FLIP and v-Bcl-2. v-FLIPs specifically inhibit apoptosis mediated by death receptors. v-lCA specifically targets caspase-8 and inhibits its activation. v-Bcl-2 and vMIA inhibit those apoptotic pathways that are signaled through mitochondrial release of cytochrome c. FADD, Fas-associated death domain FLICE, FADD-like interleukin-converting enzyme CARD, cas-pase-recruiting domain PTPC. permeability transition pore complex FLIP, FLICE-inhibitory protein vie A, viral inhibitor of caspase 8-induced-apoptosis MIA. viral mitochondrial inhibitor of apoptosis Apcif-l, apoptotic protease-activating factor 1...

Fas, fragment apoptosis stimulator FADD, Fas-associated death domain FLICE, FADD-like Interleukin-Ibeta (IL-ip) converting enzyme. Click for human B-cell lymphoblasts producing constitutively Fas-Ugand (FasL) to kill Fas-receptor positive (FasR CIM" (cluster of differentiation) immune T cells (Klinker MW et al Front Immunol 2014 Apr 4. doi 10.3389/fimmu.2014.00144. 

Synergistic anti-tumor interactions between sig-naUng/cell cycle inhibitors and TRAIL have also been reported. Upon binding to its cognate receptor, TRAIL activates, through the FADD (Fas-associated death domain)-related component of death receptors, procas-pase-8, which in turn cleaves and activates Bid, a potent... 

Apoptosis can be induced by two pathways the extrinsic pathway starts with an activation of death receptors on the cell surface, which leads to the activation of caspases (Figure 5). Death receptors are a subgroup of the tumor necrosis factor (TNF) receptor family that have an intracellular death domain. Death receptors include CD95, TRAIL-Rl, and TRAIL-R2 (TNF-related apoptosis inducing ligand). The stimulated death receptors activate an adaptor protein FADD (Fas-associated death domain protein), which, in turn, activates the inactive form of caspase-8 (cysteine-aspartyl-specific proteases). Caspase-8 activates pro-caspase-3 and also the protein Bid (a member of the Bcl-2 family) that can stimulate and amplify the intrinsic pathway. 

In the case of the death receptor Fas (see 15.4), activation of the caspase involves a protein that interacts with the cytoplasmic part of the receptor and is known as FADD protein (Fas-associated death domain). The FADD protein has distinct structural motives that mediate specific interactions with other proteins. It interacts via the death domain with the receptor and via the death effector domain with the corresponding caspase (here caspase 8). 

Extrinsic (death receptor) pathway of caspase activation during apoptosis involves the binding of death ligands to cell surface receptors (e.g., Fas/ CD95/Apo-l or TNF receptor), recruitment of adaptor molecules Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD) to the cytosolic end of the receptor, and formation of the death-inducing signaling complex (DISC) at the plasma membrane. DISC recruits and activates the initiator caspases, caspase-8 or -10. 

TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF TNF-Rl and TNF-R2. The binding of TNF to TNF-Rl has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain (FADD). The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially autoimmune diseases (see Chapter 15). 

A similar process occurs for caspase-8 activation. In this case, oligomerization of the death adaptor protein Fas-Associated Death Domain (FADD) recruits procaspase-8 into the death-inducing signalling complex (DISC) allowing caspase-8 dimerization and subsequent activation (Shi, 2006). 

Thorburn J, et al. Selective inactivation of a Fas-associated death domain protein (FADD)-dependent apoptosis and autophagy pathway in immortal epithelial cells. Mol. Biol. Cell 2005 16 1189-1199. 

Fig. 3. Schematic representation of extrinsic cell death signaling mediated by Fas ligand (FasL). Binding of FasL to Fas receptor initiates cytosolic aggregation of multiple death domains (e.g. Fas-associated death domains (FADDs)), initiating caspase activation, and subsequent apoptotic death of the cell.

Fas protein was rarely expressed on thyroid epithelial cells from each group, except that increasing Fas expression was noticed at the 32nd week in the 1000-fold high iodine group. The expression of Fas was related to the duration and the dosage of exposure. No FasL expression was found, no whether matter autoimmune thyroiditis existed or not. FLIP acts as an intracellular apoptosis-suppression protein, which can competitively bind to the Fas-associated death domain (FADD), the apoptosis-mediated protein in the death receptor apoptosis pathway, hence blocking the Fas—FasL mediated apoptosis pathway. 

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