Granzyme A is an interleukin 1 beta-converting enzyme.
Martin Irmler,Sylvie Hertig,H R MacDonald,R. Sadoul,J. D. Becherer,A Proudfoot,Roberto Solari,Juerg Tschopp +7 more
TL;DR: It is concluded that the apoptosis-inducing granzyme A and ICE share at least one downstream target substrate, i.e., pIL-1 beta, which suggests that lymphocytes, by means of their own converting enzyme, could initiate a local inflammatory response independent of the presence of ICE.
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Abstract: Apoptosis is critically dependent on the presence of the ced-3 gene in Caenorhabditis elegans, which encodes a protein homologous to the mammalian interleukin (IL)-1 beta-converting enzyme (ICE). Overexpression of ICE or ced-3 promotes apoptosis. Cytotoxic T lymphocyte-mediated rapid apoptosis is induced by the proteases granzyme A and B. ICE and granzyme B share the rare substrate site of aspartic acid, after which amino acid cleavage of precursor IL-1 beta (pIL-1 beta) occurs. Here we show that granzyme A, but not granzyme B, converts pIL-1 beta to its 17-kD mature form. Major cleavage occurs at Arg120, four amino acids downstream of the authentic processing site, Asp116. IL-1 beta generated by granzyme A is biologically active. When pIL-1 beta processing is monitored in lipopolysaccharide-activated macrophage target cells attacked by cytotoxic T lymphocytes, intracellular conversion precedes lysis. Prior granzyme inactivation blocks this processing. We conclude that the apoptosis-inducing granzyme A and ICE share at least one downstream target substrate, i.e., pIL-1 beta. This suggests that lymphocytes, by means of their own converting enzyme, could initiate a local inflammatory response independent of the presence of ICE.
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The Human Cytotoxic T Cell Granule Serine Protease Granzyme H Has Chymotrypsin-like (Chymase) Activity and Is Taken Up into Cytoplasmic Vesicles Reminiscent of Granzyme B-containing Endosomes
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References
A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.
Nancy A. Thornberry,Herbert G. Bull,Jimmy R. Calaycay,Kevin T. Chapman,Andrew D. Howard,Matthew J. Kostura,Douglas K. Miller,Susan M. Molineaux,Jeffrey R. Weidner,John G. Aunins,Keith O. Elliston,Julia M. Ayala,Francesca J. Casano,Jayne Chin,Gloria J.-F. Ding,Linda A. Egger,Erin P. Gaffney,Guadalupe A. Limjuco,Oksana C. Palyha,S.M. Raju,Anna M. Rolando,J. Paul Salley,Ting-Ting Yamin,Terry D. Lee,John E. Shively,Malcolm MacCross,Richard A. Mumford,John A. Schmidt,Michael J. Tocci +28 more
TL;DR: Purification and cloning of the complementary DNA indicates that IL-lβ-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis.
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Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factor family
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The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme
TL;DR: It is proposed that the CED-3 protein acts as a cysteine protease in the initiation of programmed cell death in C. elegans and that cysteINE proteases also function in programmed cell deaths in mammals.
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Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3
TL;DR: The results suggest that ICE may function during mammalian development to cause programmed cell death.
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Molecular cloning of the interleukin-1 beta converting enzyme
Douglas P. Cerretti,Carl J. Kozlosky,Bruce Mosley,Nicole Nelson,Kirk P. Van Ness,Teresa A. Greenstreet,Carl J. March,Shirley R. Kronheim,Teresa Druck,Linda A. Cannizzaro,Kay Huebner,Roy A. Black +11 more
TL;DR: A complementary DNA encoding a protease that carries out this cleavage has been cloned in this paper, and the gene encoding the protease was mapped to chromosomal band 11q23, a site frequently involved in rearrangement in human cancers.
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