title: FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens.
abstract: Engagement of CD95 or tumor necrosis factor 1 receptor (TNFR-1) by ligand or agonist antibodies is capable of activating the cell death program, the effector arm of which is composed of mammalian interleukin-1beta converting enzyme (ICE)-like cysteine proteases (designated caspases) that are related to the Caenorhabditis elegans death gene, CED-3. Caspases, unlike other mammalian cysteine proteases, cleave their substrates following aspartate residues. Furthermore, proteases belonging to this family exist as zymogens that in turn require cleavage at internal aspartate residues to generate the two-subunit active enzyme. As such, family members are capable of activating each other. Remarkably, both CD95 and TNFR-1 death receptors initiate apoptosis by recruiting a novel ICE/CED-3 family member, designated FLICE/MACH, to the receptor signaling complex. Therefore, FLICE/MACH represents the apical triggering protease in the cascade. Consistent with this, recombinant FLICE was found capable of proteolytically activating downstream caspases. Furthermore, CrmA, a pox virus-encoded serpin that inhibits Fas and tumor necrosis factor-induced cell death attenuates the ability of FLICE to activate downstream caspases.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: M
authors.initials: M
authors.lastname: Muzio
authors.forename: G S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: V M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D029742:Caenorhabditis elegans Proteins; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002467:Cell Nucleus / Q000378:metabolism*; D002474:Cell-Free System; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D006367:HeLa Cells; D015801:Helminth Proteins / Q000378:metabolism; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D011212:Poxviridae / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D014162:Transfection; D014764:Viral Proteins; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D029742:Caenorhabditis elegans Proteins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D015801:Helminth Proteins; D009842:Oligopeptides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D015843:Serpins; D014764:Viral Proteins; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans