title: Granzyme A is an interleukin 1 beta-converting enzyme.
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.
authors.affiliation: Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Irmler
authors.forename: S
authors.initials: S
authors.lastname: Hertig
authors.forename: H R
authors.initials: HR
authors.lastname: MacDonald
authors.forename: R
authors.initials: R
authors.lastname: Sadoul
authors.forename: J D
authors.initials: JD
authors.lastname: Becherer
authors.forename: A
authors.initials: A
authors.lastname: Proudfoot
authors.forename: R
authors.initials: R
authors.lastname: Solari
authors.forename: J
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D053804:Granzymes; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D011498:Protein Precursors; C043830:interleukin 1 precursor; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; D003546:Cysteine Endopeptidases; D020170:Caspase 1