Biology:CARD9
 Generic protein structure example |
Caspase recruitment domain-containing protein 9 is an adaptor protein of the CARD-CC protein family, which in humans is encoded by the CARD9 gene.[1][2] It mediates signals from pattern recognition receptors to activate pro-inflammatory and anti-inflammatory cytokines, regulating inflammation. Homozygous mutations in CARD9 are associated with defective innate immunity against yeasts, like Candida and dermatophytes.
Function
CARD9 is a member of the CARD protein family, which is defined by the presence of a characteristic caspase-associated recruitment domain (CARD). This protein was identified by its selective association with the CARD domain of BCL10, a positive regulator and NF-κB activation.[3] It is thought to function as a molecular scaffold for the assembly of a BCL10 signaling complex that activates NF-κB. Several alternatively spliced transcript variants have been observed, but their full-length nature is not clearly defined.[2]
Clinical significance
In 2006, it became clear that Card9 plays important roles within the innate immune response against yeasts. Card9 mediates signals from so called pattern recognition receptors (Dectin-1) to downstream signalling pathways such as NF-κB and by this activates pro-inflammatory cytokines (TNF, IL-23, IL-6, IL-2) and an anti-inflammatory cytokine (IL-10) and subsequently an appropriate innate and adaptive immune response to clear an infection.[4] An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis was found in 2009 to be associated with homozygous mutations in CARD9.[5] Deep dermatophytosis and Card9 deficiency reported in an Iranian family led to its discovery in 17 people from Tunisian, Algerian, and Moroccan families with deep dermatophytosis.[6]
CARD9 mutations have been associated with inflammatory diseases such as ankylosing spondylitis and inflammatory bowel disease (Crohn's Disease and Ulcerative Colitis).[7] A genetic variant, c.IVS11+1G>C was found to be protective against crohn's disease, ulcerative colitis, and ankylosing spondilitis by Manuel Rivas, Mark Daly and colleagues.[8] CARD9 S12NΔ11, is a rare splice variant in which exon 11 of CARD9 is deleted. This allele, identified by deep sequencing of GWAS loci, results in a protein with a C-terminal truncation. In a functional follow-up study, using re-expressed human CARD9 isoforms in murine Card9−/− bone marrow-derived dendritic cells (BMDCs) were assessed for cytokine production. BMDCs expressing the predisposing variant CARD9 S12N showed increased TNFα and IL-6 production compared to BMDCs expressing wild-type CARD9. In contrast, CARD9 Δ11 and CARD9 S12NΔ11, as well as the C-terminal truncated variant CARD9 V6, showed significant impairment in TNFα and IL-6 production. CARD9 Δ11 was found to have a dominant negative effect on CARD9 function when co-expressed with wild-type CARD9 in human and mouse dendritic cells.[9]
References
- ↑ "CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B". J. Biol. Chem. 275 (52): 41082–6. Jan 2001. doi:10.1074/jbc.C000726200. PMID 11053425.
- ↑ 2.0 2.1 "Entrez Gene: CARD9 caspase recruitment domain family, member 9". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=64170.
- ↑ "CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B". J. Biol. Chem. 275 (52): 41082–6. December 2000. doi:10.1074/jbc.C000726200. PMID 11053425.
- ↑ "Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity". Nature 442 (7103): 651–6. Aug 2006. doi:10.1038/nature04926. PMID 16862125. Bibcode: 2006Natur.442..651G.
- ↑ "A homozygous CARD9 mutation in a family with susceptibility to fungal infections". N. Engl. J. Med. 361 (18): 1727–35. Oct 2009. doi:10.1056/NEJMoa0810719. PMID 19864672.
- ↑ "Deep dermatophytosis and inherited CARD9 deficiency". N Engl J Med 369 (18): 1704–14. 2013. doi:10.1056/NEJMoa1208487. PMID 24131138.
- ↑ "Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility". Nat. Genet. 43 (8): 761–7. August 2011. doi:10.1038/ng.873. PMID 21743469.
- ↑ "Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease". Nature Genetics 43 (11): 1066–73. October 2011. doi:10.1038/ng.952. PMID 21983784.
- ↑ "Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation". Immunity 43 (4): 715–26. October 2015. doi:10.1016/j.immuni.2015.10.005. PMID 26488816.
External links
- Human CARD9 genome location and CARD9 gene details page in the UCSC Genome Browser.
Further reading
- "pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2". Mol. Cell 28 (1): 15–27. 2007. doi:10.1016/j.molcel.2007.09.010. PMID 17936701.
- "The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens". Nat. Immunol. 8 (2): 198–205. 2007. doi:10.1038/ni1426. PMID 17187069.
- "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R.
- "Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-kappa B". J. Biol. Chem. 276 (24): 21405–9. 2001. doi:10.1074/jbc.M102488200. PMID 11259443.
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