Fas activated death domain

Mechanisms underlying SM-induced apoptosis have been carefully explored using primary cultures of human keratinocytes. Treatment of keratinocytes with 100-300 pM SM resulted in activation of caspase 8, which initiates the Fas-dependent death receptor pathway, and caspase 9, which initiates the mitochondrial apoptotic pathway (Rosenthal et al., 2003). Fas and Fas ligand were upregulated in a concentration-dependent manner by SM leading to activation of caspase 3, the central executioner protease. Transfection of immortalized keratinocytes with a dominant-negative Fas-activated death domain resulted in a blunted caspase response to SM. Micro vesication and tissue injury produced in vivo by SM exposure of transfected cells after grafting onto athymic nude mice was also reduced by this treatment. 

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. 

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). 

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.

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...

NEMO kinase (regulatory subunit IKKy), NFkB (nuclear factor kappa B lymphoma) essential modulator, inhibitor of kappa kinase gamma (IKKy). Protein kinase C-interacting protein p62/sequestosome-l, is activated by interleukin IL-IP in sequence, it activates of nuclear factor NFkB in TNFa-stimulated cells (Zotti T et al Mol Immunol 2014 58 27-31). NEMO promotes vFFlP (Fas-associated death domain-like interleukin-1-converting enzyme inhibitory protein) expression by Kaposi sarcoma associated herpesvirus (KSHV) (Tolani B et al J Virol 2014 March 26 PMID 24672029). 

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 is a highly conserved cascade of events resnlting in cell destruction without associated inflammation or damage to surrounding tissnes. The executioner enzymes are cysteine-aspartic proteases (caspases) that are normally present as inactive proenzymes (procaspases). Apoptotic stimnli activate initiator caspases (caspase-8, caspase-9, caspase-12) which, in turn, activate effector caspases (caspase-3, caspase-6, caspase-7) that actually dismantle the cell [43]. The apoptotic cascade can be triggered by extrinsic or intrinsic pathways. In the extrinsic pathway, activation of the Fas receptor and tumor necrosis factor receptor (TNF-R) on the cell surface leads to recruitment of adaptor proteins, such as the Fas-associated death domain (FADD), whose death... 

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