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
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
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
Card or The Card may refer to:
Common uses
* Plastic cards of various types:
**Bank card
**Credit card
**Debit card
**Payment card
* Playing card, used in games
* Printed circuit board, or card
* Greeting card, given on special occasions
Arts an ...
). This protein was identified by its selective association with the CARD domain of
BCL10, a positive regulator and
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
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
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
and by this activates pro-inflammatory cytokines (
TNF,
IL-23,
IL-6,
IL-2
The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...
) 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
Candidiasis is a fungal infection due to any species of the genus '' Candida'' (a yeast). When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the ...
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
Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...
and
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...
(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.
References
External links
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Further reading
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Proteins