The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.
Death receptors, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand receptors, recruit Fas-associated death domain and pro-caspase-8 homodimers, which are then autoproteolytically activated. Active caspase-8 is released into the cytoplasm, where it cleaves various proteins including pro-caspase-3, resulting in apoptosis. The cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein long ... form (FLIP(L)), a structural homologue of caspase-8 lacking caspase activity because of several mutations in the active site, is a potent inhibitor of death receptor-induced apoptosis. FLIP(L) is proposed to block caspase-8 activity by forming a proteolytically inactive heterodimer with caspase-8. In contrast, we propose that FLIP(L)-bound caspase-8 is an active protease. Upon heterocomplex formation, a limited caspase-8 autoprocessing occurs resulting in the generation of the p43/41 and the p12 subunits. This partially processed form but also the non-cleaved FLIP(L)-caspase-8 heterocomplex are proteolytically active because they both bind synthetic substrates efficiently. Moreover, FLIP(L) expression favors receptor-interacting kinase (RIP) processing within the Fas-signaling complex. We propose that FLIP(L) inhibits caspase-8 release-dependent pro-apoptotic signals, whereas the single, membrane-restricted active site of the FLIP(L)-caspase-8 heterocomplex is proteolytically active and acts on local substrates such as RIP.
Mesh Terms:
Amino Acid Sequence, Antigens, CD95, Apoptosis, Binding Sites, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins, Caspase 3, Caspase 8, Caspase 9, Caspases, Cell Line, Cell Size, Dimerization, Enzyme Activation, Enzyme Inhibitors, Fas Ligand Protein, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Macromolecular Substances, Membrane Glycoproteins, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Sequence Alignment, Signal Transduction
Amino Acid Sequence, Antigens, CD95, Apoptosis, Binding Sites, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins, Caspase 3, Caspase 8, Caspase 9, Caspases, Cell Line, Cell Size, Dimerization, Enzyme Activation, Enzyme Inhibitors, Fas Ligand Protein, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Macromolecular Substances, Membrane Glycoproteins, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Sequence Alignment, Signal Transduction
J. Biol. Chem.
Date: Nov. 22, 2002
PubMed ID: 12215447
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