Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.
Although the mechanism of mammalian apoptosis has not been elucidated, a protease of the CED-3/ICE family is anticipated to be a component of the death machinery. Several lines of evidence predict that this protease cleaves the death substrate poly(ADP-ribose) polymerase (PARP) to a specific 85 kDa form observed during apoptosis, is inhibitable by the CrmA protein, and is distinct from ICE. We cloned a ced-3/ICE-related gene, designated Yama, that encodes a protein identical to CPP32 beta. Purified Yama was a zymogen that, when activated, cleaved PARP to generate the 85 kDa apoptotic fragment. Cleavage of PARP by Yama was inhibited by CrmA but not by an inactive point mutant of CrmA. Furthermore, CrmA blocked cleavage of PARP in cells undergoing apoptosis. We propose that Yama may represent an effector component of the mammalian cell death pathway and suggest that CrmA blocks apoptosis by inhibiting Yama.
Tewari
M
M
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Quan
L T
LT
O'Rourke
K
K
Desnoyers
S
S
Zeng
Z
Z
Beidler
D R
DR
Poirier
G G
GG
Salvesen
G S
GS
Dixit
V M
VM
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D020170:Caspase 1; D053148:Caspase 3; D020169:Caspases; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015801:Helminth Proteins / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D017354:Point Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins
D029742:Caenorhabditis elegans Proteins; D018076:DNA, Complementary; D004792:Enzyme Precursors; D015801:Helminth Proteins; D011993:Recombinant Fusion Proteins; D015843:Serpins; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans; D020170:Caspase 1