Involvement of caspase-4(-like) protease in Fas-mediated apoptotic pathway.
Proteases of the caspase family, especially caspase-1 (ICE)(-like), caspase-3 (CPP32/Yama/apopain)(-like) and caspase-8 (MACH/FLICE/Mch5) proteases, are implicated in Fas (APO-1/CD95)-mediated apoptosis. Here, we show that the caspase-4 (TX/ICH-2/ICE(rel)II)(-like) protease, another member of the caspase family, is also involved in Fas-mediated apoptosis, based upon the observations: (i) caspase-4 is processed in response to an agonistic anti-Fas antibody treatment, (ii) overexpression of a mutant caspase-4 with active site mutations in both p20 and p10 subunits delays Fas-mediated apoptosis, (iii) microinjected anti-caspase-4 antibodies inhibit Fas-mediated apoptosis. Together with our observations that the mutant caspase-4 inhibits the Fas-mediated activation of caspase-3(-like) proteases and purified caspase-4 cleaves pro-caspase-3 to generate a subunit of active form, these results suggest that Fas-mediated apoptosis is driven by a caspase cascade in which the caspase-4(-like) protease transmits a death signal from caspase-8 to caspase-3(-like) proteases probably through directly cleaving pro-caspase-3(-like) proteases.
Kamada
S
S
Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Washida
M
M
Hasegawa
J
J
Kusano
H
H
Funahashi
Y
Y
Tsujimoto
Y
Y
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D001120:Arginine; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D018698:Glutamic Acid; D006367:HeLa Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011994:Recombinant Proteins / Q000378:metabolism; D016324:Sequence Tagged Sites; D012694:Serine; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
D000906:Antibodies; D004792:Enzyme Precursors; D011994:Recombinant Proteins; D019014:fas Receptor; D018698:Glutamic Acid; D012694:Serine; D001120:Arginine; D003546:Cysteine Endopeptidases; D020170:Caspase 1