CARD9

Caspase recruitment domain family, member 9
Identifiers
Symbols	CARD9 ; CANDF2; hCARD9
External IDs	OMIM: 607212 MGI: 2685628 HomoloGene: 14150 GeneCards: CARD9 Gene
Gene ontology Molecular function • protein binding • protein homodimerization activity • CARD domain binding Cellular component • cytoplasm • cytosol • plasma membrane Biological process • stimulatory C-type lectin receptor signaling pathway • I-kappaB kinase/NF-kappaB signaling • response to fungus • response to peptidoglycan • response to muramyl dipeptide • positive regulation of interleukin-6 production • positive regulation of tumor necrosis factor production • positive regulation of stress-activated MAPK cascade • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • response to drug • regulation of tumor necrosis factor biosynthetic process • regulation of apoptotic process • positive regulation of I-kappaB kinase/NF-kappaB signaling • response to exogenous dsRNA • regulation of interleukin-2 biosynthetic process • innate immune response • regulation of interleukin-6 biosynthetic process • positive regulation of JNK cascade • defense response to Gram-positive bacterium • defense response to virus • nucleotide-binding oligomerization domain containing signaling pathway Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	64170	332579
Ensembl	ENSG00000187796	ENSMUSG00000026928
UniProt	Q9H257	A2AIV8
RefSeq (mRNA)	NM_052813	NM_001037747
RefSeq (protein)	NP_434700	NP_001032836
Location (UCSC)	Chr 9: 136.36 – 136.37 Mb	Chr 2: 26.35 – 26.36 Mb
PubMed search

Caspase recruitment domain-containing protein 9 is an adaptor protein that in humans is encoded by the CARD9 gene.^[1][2]

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 is a protein interaction domain known to participate in activation or suppression of CARD containing members of the caspase family, and thus plays an important regulatory role in cell apoptosis. This protein was identified by its selective association with the CARD domain of BCL10, a positive regulator of apoptosis and NF-κB activation, and 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

It recently became clear that Card9 plays important roles as part of the innate immune response for the defense against pathogens such as 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 for the efficient clearance of the infection.^[3] Importantly, it was reported that an autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9.^[4] Mutations in this gene have been associated to inflammatory diseases such as Ankylosing spondylitis and inflammatory bowel disease (Crohn's Disease and Ulcerative Colitis).^[5][6]

Interactions

CARD9 has been shown to interact with BCL10.^[7]

Model organisms

Model organisms have been used in the study of CARD9 function. A conditional knockout mouse line called Card9^{tm1a(EUCOMM)Hmgu} was generated at the Wellcome Trust Sanger Institute.^[8] Male and female animals underwent a standardized phenotypic screen^[9] to determine the effects of deletion.^{[10][11][12][13]} Additional screens performed: - In-depth immunological phenotyping^[14] - in-depth bone and cartilage phenotyping^[15]

Card9 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[9][14]
Insulin	Normal
Homozygous viability at P14	Normal
Homozygous Fertility	Normal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Bone Marrow Immunophenotyping	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal

References

1. Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES (Jan 2001). "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. doi:10.1074/jbc.C000726200. PMID 11053425.
2. "Entrez Gene: CARD9 caspase recruitment domain family, member 9".
3. Gross O, Gewies A, Finger K, Schäfer M, Sparwasser T, Peschel C, Förster I, Ruland J (Aug 2006). "Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity". Nature 442 (7103): 651–6. doi:10.1038/nature04926. PMID 16862125.
4. Glocker EO, Hennigs A, Nabavi M, Schäffer AA, Woellner C, Salzer U, Pfeifer D, Veelken H, Warnatz K, Tahami F, Jamal S, Manguiat A, Rezaei N, Amirzargar AA, Plebani A, Hannesschläger N, Gross O, Ruland J, Grimbacher B (Oct 2009). "A homozygous CARD9 mutation in a family with susceptibility to fungal infections". N. Engl. J. Med. 361 (18): 1727–35. doi:10.1056/NEJMoa0810719. PMC 2793117. PMID 19864672.
5. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, et al. (August 2011). "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. doi:10.1038/ng.873. PMID 21743469.
6. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, Boucher G, Ripke S, Ellinghaus D, Burtt N, Fennell T, Kirby A, Latiano A, Goyette P, Green T, Halfvarson J, Haritunians T, Korn JM, Kuruvilla F, Lagacé C, Neale B, Lo KS, Schumm P, Törkvist L, Dubinsky MC, Brant SR, Silverberg MS, Duerr RH, Altshuler D, Gabriel S, Lettre G, Franke A, D'Amato M, McGovern DP, Cho JH, Rioux JD, Xavier RJ, Daly MJ (November 2011). "Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease". Nat. Genet. 43 (11): 1066–73. doi:10.1038/ng.952. PMC 3378381. PMID 21983784.
7. Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES (December 2000). "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. doi:10.1074/jbc.C000726200. PMID 11053425.
8. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
9. "International Mouse Phenotyping Consortium".
10. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
11. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
12. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
13. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
14. "Infection and Immunity Immunophenotyping (3i) Consortium".
15. "OBCD Consortium".

Further reading

• Yang H, Minamishima YA, Yan Q, Schlisio S, Ebert BL, Zhang X, Zhang L, Kim WY, Olumi AF, Kaelin WG (2007). "pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2". Mol. Cell 28 (1): 15–27. doi:10.1016/j.molcel.2007.09.010. PMC 2128776. PMID 17936701.
• Hsu YM, Zhang Y, You Y, Wang D, Li H, Duramad O, Qin XF, Dong C, Lin X (2007). "The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens". Nat. Immunol. 8 (2): 198–205. doi:10.1038/ni1426. PMID 17187069.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
• Wang L, Guo Y, Huang WJ, Ke X, Poyet JL, Manji GA, Merriam S, Glucksmann MA, DiStefano PS, Alnemri ES, Bertin J (2001). "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. doi:10.1074/jbc.M102488200. PMID 11259443.