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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Citations
Secretion of bioactive interleukin-1β by dendritic cells is modulated by interaction with antigen specific T cells
Stefania Gardella,Cristina Andrei,Sara Costigliolo,Lucia Olcese,M. Raffaella Zocchi,Anna Rubartelli +5 more
TL;DR: It is suggested that CD4(+) and CD8(+) T-lymphocyte subsets have distinct roles in the induction of IL-1beta secretion by DCs and support the hypothesis that IL- 1beta plays a role in cell-mediated immune responses.
42
Human keratinocytes maintain reversible anti-apoptotic defenses in vivo and in vitro.
David A. Norris,Marjorie H. Middleton,K. Whang,Mary S. Schleicher,T. McGovern,Scott D. Bennion,Kathleen M. David-Bajar,D. Davis,Richard C. Duke +8 more
TL;DR: The experiments show that the strong keratinocyte defences against apoptosis are stratified within the epidermis, and can be altered by differentiation and growth factor withdrawal.
41
Purification and identification of a binding protein for pancreatic secretory trypsin inhibitor: a novel role of the inhibitor as an anti-granzyme A.
Satoshi Tsuzuki,Yoshimasa Kokado,Shigeki Satomi,Yoshie Yamasaki,Hirofumi Hirayasu,Toshihiko Iwanaga,Tohru Fushiki +6 more
TL;DR: It is concluded that the PSTI-binding protein isolated from the dispersed cells is GzmA that is produced in the lymphocytes of the tissue, a trypsin inhibitor produced in cytotoxic lymphocytes.
Cell death-independent functions of granzymes: hit viruses where it hurts.
TL;DR: Evidence is emerging that granzymes also use noncytotoxic strategies to inhibit viral replication and potential viral reactivation from latency, and the potential therapeutic applications that could emerge from this intriguing mechanism are addressed.
39
Granzyme M: behind enemy lines.
S A H de Poot,Niels Bovenschen +1 more
TL;DR: The granule-exocytosis pathway is the major mechanism via which cytotoxic lymphocytes eliminate virus-infected and tumor cells and a role for GrM in lipopolysaccharide-induced inflammatory responses has been proposed.
39
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A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.
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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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