Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins.
We report here the identification and functional characterization of two new human caspase recruitment domain (CARD) molecules, termed Pseudo-interleukin-1beta converting enzyme (ICE) and ICEBERG. Both proteins share a high degree of homology, reaching 92% and 53% identity, respectively, to the prodomain of caspase-1/ICE. Interestingly, both Pseudo-ICE and ICEBERG are mapped to chromosome 11q22 that bears caspases-1, -4- and -5 genes, all involved in cytokine production rather than in apoptosis. We demonstrate that Pseudo-ICE and ICEBERG interact physically with caspase-1 and block, in a monocytic cell line, the interferon-gamma and lipopolysaccharide-induced secretion of interleukin-1beta which is a well-known consequence of caspase-1 activation. Moreover, Pseudo-ICE, but not ICEBERG, interacts with the CARD-containing kinase RICK/RIP2/CARDIAK and activates NF-kappaB. Our data suggest that Pseudo-ICE and ICEBERG are intracellular regulators of caspase-1 activation and could play a role in the regulation of IL-1beta secretion and NF-kappaB activation during the pro-inflammatory cytokine response.
Druilhe
A
A
Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Srinivasula
S M
SM
Razmara
M
M
Ahmad
M
M
Alnemri
E S
ES
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D004789:Enzyme Activation; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D016415:Sequence Alignment; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C415523:CARD18 protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; C436144:LLID-114769 protein, human; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011494:Protein Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020169:Caspases; D020170:Caspase 1