Identification and characterization of a novel mammalian caspase with proapoptotic activity.
Caspases are essential proteases in programmed cell death and inflammation. Studies in murine and human cells have led to the characterization of 14 members of this enzyme family. Here we report the identification of caspase-15, a novel caspase that is expressed in various mammalian species including pig, dog, and cattle. The caspase-15 protein contains a catalytic domain with all amino acid residues critical for caspase activity and a prodomain that is predicted to fold into a pyrin domain structure, which is a unique feature among mammalian caspases. Recombinant porcine caspase-15 underwent autocatalytic processing into its subunits and cleaved both tetrapeptide caspase substrates and the apoptosis regulator protein Bid in vitro. Overexpression of caspase-15 in mammalian cells induced proenzyme maturation, cleavage of Bid, activation of caspase-3, and eventually cell death. Both the proteolytic and the pro-apoptotic activity of caspase-15 were abolished by mutation of the active site cysteine. Since a homolog of caspase-15 is absent in the human and the mouse genome, our results reveal an unexpected variability in the molecular apoptotic machinery of mammals.
Eckhart
Leopold
L
Department of Dermatology, Medical University of Vienna, Vienna A-1090, Austria.
Ballaun
Claudia
C
Uthman
Aumaid
A
Kittel
Christian
C
Stichenwirth
Martin
M
Buchberger
Maria
M
Fischer
Heinz
H
Sipos
Wolfgang
W
Tschachler
Erwin
E
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry; D001665:Binding Sites; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002384:Catalysis; D020134:Catalytic Domain; D016923:Cell Death; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D016678:Genome; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D000071198:Pyrin; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D014162:Transfection
D051023:BH3 Interacting Domain Death Agonist Protein; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C000604192:MEFV protein, human; C000604193:Mefv protein, mouse; D010455:Peptides; D011506:Proteins; D000071198:Pyrin; D011994:Recombinant Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases