The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.

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Date

2002

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Périmètre
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Serveur académique Lausannois

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Ce document est lié à :
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M206882200

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/pmid/12215447

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/pissn/0021-9258

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_5A5C5C71FE167

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , Copying allowed only for non-profit organizations , https://serval.unil.ch/disclaimer

Mots-clés 0

Amino Acid Sequence; Antigens, CD95/metabolism; Apoptosis/physiology; Binding Sites; CASP8 and FADD-Like Apoptosis Regulating Protein; Carrier Proteins/chemistry; Carrier Proteins/genetics; Caspase 3; Caspase 8; Caspase 9; Caspases/antagonists & inhibitors; Caspases/chemistry; Cell Line; Cell Size; Dimerization; Enzyme Activation; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Fas Ligand Protein; Humans; Intracellular Signaling Peptides and Proteins; Ligands; Macromolecular Substances; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; Sequence Alignment; Signal Transduction/physiology

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Death--Philosophy Dying End of life

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O. Micheau et al., « The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. », Serveur académique Lausannois, ID : 10.1074/jbc.M206882200

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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.

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