Regulation of IL-1β generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins

Abstract

We report here the identification and functional characterization of two new human caspase recruitment domain (CARD) molecules, termed Pseudo-interleukin-1b 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-g and lipopolysaccharide-induced secretion of interleukin-1b 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-kB. 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-1b secretion and NF-kB activation during the pro-inflammatory cytokine response. Cell Death and Differentiation (2001) 8, 649 ± 657.

Differential gene expression profiles of radioresistant oesophageal cancer cell lines established by continuous fractionated irradiation

“…ICEBERG proteins are intracellular regulators of caspase-1 activation and could play a role in the regulation of IL-1b secretion and NF-kB activation during the proinflammatory cytokine response (Humke et al, 2000;Druilhe et al, 2001), NFkB is a well-defined radiation-responsive transcription factor (Thanos and Maniatis, 1995). Furthermore, NF-kB is associated with the cell cycle, and we found that cyclin A2 (CCNA2) was downregulated.…”

Caspase-12: an overview

“…27 Therefore, this type of human caspase-12 may be comparable with two other human CARD-only proteins, ICEBERG and COP/Pseudo-ICE, residing on the same chromosome (Figure 1b). [29][30][31] Similar to the human pseudocaspase-12 gene, ICEBERG and COP/Pseudo-ICE are encoded by caspase-like genes that have acquired premature nonsense mutations leading to the production of truncated molecules. Both ICEBERG and COP/Pseudo-ICE closely resemble the prodomain of caspase-1.…”

“…Furthermore, both proteins interact with the CARD present in the prodomain of caspase-1, preventing the activation of this caspase and the subsequent generation of IL-1b. [29][30][31] Interestingly, COP/ Pseudo-ICE is also capable of activating NF-kB and binding to the CARD of RIP2, a known inducer of NF-kB activation. 29,31 ICEBERG does not bind to RIP2 nor does it signal to NF-kB activation.…”

“…[29][30][31] Interestingly, COP/ Pseudo-ICE is also capable of activating NF-kB and binding to the CARD of RIP2, a known inducer of NF-kB activation. 29,31 ICEBERG does not bind to RIP2 nor does it signal to NF-kB activation. 29,30 Since human pseudo-caspase-12 is structurally comparable to ICEBERG and COP/Pseudo-ICE, it would be interesting to study its involvement in similar pathways.…”

“…29,31 ICEBERG does not bind to RIP2 nor does it signal to NF-kB activation. 29,30 Since human pseudo-caspase-12 is structurally comparable to ICEBERG and COP/Pseudo-ICE, it would be interesting to study its involvement in similar pathways.…”