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CARD9
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CARD9

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CARD9
Identifiers
Aliases CARD9, CANDF2, hcaspase recruitment domain family member 9
External IDs OMIM: 607212 MGI: 2685628 HomoloGene: 14150 GeneCards: CARD9
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_052814
NM_052813
NM_022352

NM_001037747

RefSeq (protein)

NP_434700
NP_434701

NP_001032836

Location (UCSC) Chr 9: 136.36 – 136.37 Mb Chr 2: 26.24 – 26.25 Mb
PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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. 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. 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.

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. An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis was found in 2009 to be associated with homozygous mutations in CARD9. 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.

CARD9 mutations have been associated with inflammatory diseases such as ankylosing spondylitis and inflammatory bowel disease (Crohn's Disease and Ulcerative Colitis). 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. 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.

Model organisms

Model organisms have been used in the study of CARD9 function. A conditional knockout mouse line called Card9tm1a(EUCOMM)Hmgu was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping

External links

Further reading


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