I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis.
The pivotal discovery that the death proteases caspase 8 (FLICE) and caspase 10 (Mch4/FLICE2) are recruited to the CD-95 and tumor necrosis factor receptor-1 signaling complexes suggested a mechanism used by these cytotoxic receptors to initiate apoptosis. In this report, we describe the cloning and characterization of I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD-95-induced apoptosis. The overall architecture of I-FLICE is strikingly similar to that of FLICE and Mch4/FLICE2. However, I-FLICE lacks both a catalytic active site and residues that form the substrate binding pocket, in keeping with its dominant negative inhibitory function. I-FLICE is the first example of a catalytically inert caspase that can inhibit apoptosis.
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Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Vincenz
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Ni
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Gentz
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Dixit
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D000328:Adult; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry*; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002384:Catalysis; D002460:Cell Line; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry*; D047888:Receptors, Tumor Necrosis Factor, Type I; D014018:Tissue Distribution; D019014:fas Receptor / Q000378:metabolism*
D015703:Antigens, CD; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; C105036:interleukin 1beta-converting enzyme 2; C506438:CASP10 protein, human