The prodomain of caspase-1 enhances Fas-mediated apoptosis through facilitation of caspase-8 activation.
Caspase-1 (interleukin-1beta converting enzyme) is produced in the form of a latent precursor, which is cleaved to yield a prodomain in addition to the p20 and p10 subunits. It has been established that the (p20/p10)(2) heterotetramer processes the latent precursor of interleukin-1beta into an active form during apoptosis, but the function of the residual prodomain of caspase-1 (Pro-C1) has not been established. To evaluate the involvement of Pro-C1 in apoptosis, a Pro-C1 expression vector was transfected into the HeLa cell line, which is susceptible to Fas-mediated apoptosis. Expression of recombinant Pro-C1 in HeLa cells enhanced apoptosis mediated by Fas, but not etoposide-induced apoptosis. This enhancement of Fas-mediated apoptosis was abolished by inhibitors of caspase-8 (Ile-Glu-Thr-Asp-fluoromethyl ketone) and caspase-3 (Asp-Glu-Val-Asp-aldehyde) but was only slightly diminished by an inhibitor of caspase-1 (acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone). During apoptosis induced by an agonistic anti-Fas antibody, the activation of caspase-8 and caspase-3 was more pronounced and occurred more rapidly in HeLa/Pro-C1 cells than in the empty vector transfectant (HeLa/vec) cells; in contrast, caspase-1 was not activated in either HeLa/Pro-C1 or HeLa/vec cells. These results demonstrate an additional and novel function for caspase-1 in which Pro-C1 acts to enhance Fas-mediated apoptosis, most probably through facilitation of the activation of caspase-8.
Tatsuta
T
T
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan. tatuta@shina.sankyo.co.jp
Shiraishi
A
A
Mountz
J D
JD
D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D017931:DNA Primers; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
D015853:Cysteine Proteinase Inhibitors; D017931:DNA Primers; D004792:Enzyme Precursors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D005047:Etoposide; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1