Caspase recruitment domain-containing protein 8 (CARD8)
The protein contains 431 amino acids for an estimated molecular weight of 48933 Da.
Inflammasome sensor, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis of CD4(+) T-cells and macrophages (PubMed:11821383, PubMed:11408476, PubMed:15030775, PubMed:32840892, PubMed:32051255, PubMed:33542150). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:11821383, PubMed:11408476, PubMed:15030775). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as HIV-1 protease activity or Val-boroPro inhibitor, and mediates CARD8 inflammasome activation (PubMed:32840892, PubMed:33542150). In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the CARD8 inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:33053349, PubMed:32840892, PubMed:32051255, PubMed:33542150). Ability to sense HIV-1 protease activity leads to the clearance of latent HIV-1 in patient CD4(+) T-cel (updated: June 2, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs11881179 | |
| dbSNP:rs59878320 | |
| IBD30; unknown pathological significance | |
| IBD30 |
Biological Process
Activation of cysteine-type endopeptidase activity involved in apoptotic process
Inhibition of cysteine-type endopeptidase activity
Negative regulation of I-kappaB kinase/NF-kappaB signaling
Negative regulation of interleukin-1 beta production
Negative regulation of interleukin-1 beta secretion
Negative regulation of lipopolysaccharide-mediated signaling pathway
Negative regulation of NF-kappaB transcription factor activity
Negative regulation of tumor necrosis factor-mediated signaling pathway
Positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
Positive regulation of interleukin-1 beta production
Positive regulation of interleukin-1 beta secretion
Regulation of apoptotic process
Regulation of I-kappaB kinase/NF-kappaB signaling
The reference OMIM entry for this protein is 609051
Caspase recruitment domain-containing protein 8; card8
Tumor-upregulated card-containing antagonist of casp9; tucan
Card inhibitor of nfkb-activating ligands; cardinal
Ndpp1
Kiaa0955
DESCRIPTION
Caspase recruitment domain (CARD)-containing proteins, such as CARD8, are involved in pathways leading to activation of caspases or nuclear factor kappa-B (NFKB; see 164011) in the context of apoptosis or inflammation, respectively (Bouchier-Hayes et al., 2001).CLONING
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1999) cloned CARD8, which they designated KIAA0955. The transcript contains several repetitive elements in the 3-prime UTR, and the deduced protein contains 431 amino acids. RT-PCR ELISA detected highest expression of CARD8 in kidney and corpus callosum and lowest expression in pancreas. All other tissues and specific brain regions examined showed intermediate expression. By searching databases for sequences similar to the CARD domain of APAF1 (602233), followed by PCR, Pathan et al. (2001) cloned CARD8, which they designated TUCAN. CARD8 contains an N-terminal segment that shares 50% amino acid identity with a region of the proapoptotic protein DEFCAP (NALP1; 606636), as well as a C-terminal CARD domain. By Western blot analysis of several tissues, Bouchier-Hayes et al. (2001) found CARD8 expressed at an apparent molecular mass of 50 kD, close to the predicted molecular mass of 49 kD. Highest expression was in lung, ovary, testis, and placenta, with low or absent expression in brain, skeletal muscle, and spleen. By RT-PCR, Razmara et al. (2002) found highest CARD8 expression in placenta, spleen, lymph node, and bone marrow. By EST analysis, Zhang and Fu (2002) identified 5 splice variants of CARD8, which they called NDPP1. The variants all have different translation start sites. Yamamoto et al. (2005) cloned a splice variant of CARD8 that they named TUCAN54 after the calculated molecular mass of the encoded protein. The deduced 487-amino acid TUCAN54 protein has a unique 80-amino acid N terminus compared with the 48-kD isoform, TUCAN48, but both proteins contain a NALP homology domain, a candidate caspase cleavage site (DEED), a C-terminal CARD domain, and several putative phosphorylation sites. The N terminus of TUCAN54 provides phosphorylation sites not found in TUCAN48. RT-PCR detected high TUCAN54 expression in leukocytes and spleen. Expression was lower in heart, lung, thymus, liver, pancreas, and testis, and little to no expression was detected in other tissues examined. TUCAN54 was widely expressed in a variety of tumor cell lines. By EST database and RT-PCR analyses, Bagnall et al. (2008) characterized 5 isoforms of CARD8 that differ in their N termini and have predicted molecular masses of 47.5, 48, 51, 54, and 60 kD. The major 48-kD isoform has 432 amino acids and starts in exon 5, and the 54-kD isoform has 487 amino acids and starts in exon 4. The 47.5-kD isoform differs in the first 20 amino acids from the 48-kD isoform and results from a putative initiation codon 20 bp upstream of exon 6. Western blot analysis of lymphoblastoid cell lines from 6 Crohn disease (see IBD1; 266600) patients showed a 48- or 47.5-kD band in all cell lines and an additional band of 54 kD in only 1 cell line.GENE STRUCTURE
Zhang and Fu (2002) determined that the CARD8 gene contains 14 exons and spans more than 50 kb. The first 3 exons are noncoding.MAPPING
By genomic sequence analysis, Zhang and Fu (2002) mapped the CARD8 gene to chromosome 19q13.3.GENE FUNCTION
By overexpression in Jurkat human T cells, Pathan et al. ... More on the omim web site
July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for CARD8
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 609051 was added.
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed