Alternative titles; symbols
HGNC Approved Gene Symbol: CARD18
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38): 11:105,137,714-105,139,769 (from NCBI)
CARD18, or ICEBERG, is a caspase recruitment domain (CARD) protein that regulates caspase-1 (CASP1; 147678) activation and interleukin-1-beta (IL1B; 147720) secretion (Druilhe et al., 2001).
By EST database searching for sequences with significant homology to the CARD-containing prodomain of caspase-1, Humke et al. (2000) identified a cDNA encoding a novel 90-amino acid protein, which they termed ICEBERG. The structure of ICEBERG revealed it to be a member of the death-domain-fold superfamily. Analysis of multiple tissue cDNA panels and Northern blots revealed that ICEBERG was primarily expressed in the heart and placenta.
Independently, Druilhe et al. (2001) cloned and characterized ICEBERG.
Humke et al. (2000) found that ICEBERG inhibited generation of IL1B by interacting with caspase-1 and preventing its association with RIP2 (RIPK2; 603455). ICEBERG was induced by proinflammatory stimuli, suggesting that it may be part of a negative-feedback loop. Consistent with this, enforced retroviral expression of ICEBERG inhibited lipopolysaccharide (LPS)-induced IL1B generation. The distribution of surface charge was complementary to the homologous prodomain of caspase-1, suggesting that charge-charge interactions mediate binding of ICEBERG to the prodomain of caspase-1.
By coimmunoprecipitation analysis, Druilhe et al. (2001) showed that ICEBERG and the related CARD protein pseudo-ICE (CARD16; 615680) both self-associated and interacted with each other. Both proteins inhibited binding of CASP1 to RICK (RIPK2), although pseudo-ICE was more potent, perhaps due to its binding to both CASP1 and RICK. Secretion of IL1B following stimulation of a monocyte line with LPS and IFNG (147570) could be significantly inhibited by expression of ICEBERG and completely blocked by pseudo-ICE. Although CASP1 induced apoptosis in a mammary carcinoma cell line, presumably through a nuclear localization signal-like sequence, pseudo-ICE and ICEBERG, which share this sequence, did not. Luciferase analysis showed that pseudo-ICE, but not ICEBERG, induced NFKB (see 164011) activation. Druilhe et al. (2001) proposed that pseudo-ICE and ICEBERG are intracellular regulators of CASP1 activation and IL1B, as well as of NFKB, during proinflammatory cytokine responses.
Scott (2000) mapped the ICEBERG gene to chromosome 11q21-q22 based on sequence similarity between the ICEBERG sequence (GenBank AF208005) and chromosome 11 clones (GenBank AC027011 and AC023068).
By genomic sequence analysis, Druilhe et al. (2001) mapped the CARD18 gene to chromosome 11q22, in the same region as CASP1, CASP4 (602664), CASP5 (602665), and pseudo-ICE.
Druilhe, A., Srinivasula, S. M., Razmara, M., Ahmad, M., Alnemri, E. S. Regulation of IL-1-beta generation by pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 8: 649-657, 2001. [PubMed: 11536016] [Full Text: https://doi.org/10.1038/sj.cdd.4400881]
Humke, E. W., Shriver, S. K., Starovasnik, M. A., Fairbrother, W. J., Dixit, V. M. ICEBERG: a novel inhibitor of interleukin-1-beta generation. Cell 103: 99-111, 2000. [PubMed: 11051551] [Full Text: https://doi.org/10.1016/s0092-8674(00)00108-2]
Scott, A. F. Personal Communication. Baltimore, Md. 10/18/2000.