title: Death effector domain-only polypeptides of caspase-8 and -10 specifically inhibit death receptor-induced cell death.
abstract: Caspase-8 and -10 are thought to be involved in a signaling pathway leading to death receptor-mediated apoptosis. The prodomains of these caspases are known to form fibrous structures in the perinuclear region when overexpressed, though the meaning of the structures remains unclear. In a previous study we showed that the overexpressed caspase-8 or -10 prodomain (PDCasp8 or PDCasp10) did not induce cell death, and we hypothesized that these prodomains interfere with the receptor-mediated cell death signaling pathway. Indeed, in 293, HeLa and Jurkat cells, cell death mediated by agonistic anti-Fas antibody, TRAIL or overexpression of full-length caspase-8 was significantly inhibited by overexpression of PDCasp8 or PDCasp10 which colocalized with the Golgi complex and with overexpressed FADD. However, when about 20 amino acid residues were deleted from either terminus of the caspase-10 prodomain (amino acid residue 1 to 219), the ability to inhibit Fas-mediated cell death was lost. Interestingly, these deletion mutants also lost the ability to make fibrous structures and to bind FADD, suggesting that FADD binding is important for their function, and that PDCasp8 and PDCasp10 act as dominant-negative inhibitors.
authors.affiliation: Department of Genetics, National Children's Medical Research Center, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shikama
authors.forename: Lisong
authors.initials: L
authors.lastname: Shen
authors.forename: Motokuni
authors.initials: M
authors.lastname: Yonetani
authors.forename: Jun
authors.initials: J
authors.lastname: Miyauchi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyashita
authors.forename: Masao
authors.initials: M
authors.lastname: Yamada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000032:analysis; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D053200:Fas-Associated Death Domain Protein; D006056:Golgi Apparatus / Q000737:chemistry / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D019014:fas Receptor / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D010455:Peptides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human