CARD9 explained

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.

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]

Further reading

Notes and 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 . 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 . 11053425 . 10.1074/jbc.C000726200 . free .
  2. Web site: Entrez Gene: CARD9 caspase recruitment domain family, member 9.
  3. Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, Merriam S, Du MQ, Dyer MJ, Robison KE, DiStefano PS, Alnemri ES . 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 . 11053425 . 10.1074/jbc.C000726200 . free .
  4. Gross O, Gewies A, Finger K, Schäfer M, Sparwasser T, Peschel C, Förster I, Ruland J . Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity . Nature . 442 . 7103 . 651–6 . Aug 2006 . 16862125 . 10.1038/nature04926 . 2006Natur.442..651G . 4405404 .
  5. 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 . A homozygous CARD9 mutation in a family with susceptibility to fungal infections . N. Engl. J. Med. . 361 . 18 . 1727–35 . Oct 2009 . 19864672 . 2793117 . 10.1056/NEJMoa0810719 .
  6. 24131138 . 10.1056/NEJMoa1208487 . 369 . 18 . Deep dermatophytosis and inherited CARD9 deficiency . 4084693 . 2013 . N Engl J Med . 1704–14 . Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, Prando C, Migaud M, Taibi L, Ammar-Khodja A, Boudghene Stambouli O, Guellil B, Jacobs F, Goffard JC, Schepers K, del Marmol V, Boussofara L, Denguezli M, Larif M, Bachelez H, Michel L, Lefranc G, Hay R, Jouvion G, Chretien F, Fraitag S, Bougnoux ME, Boudia M, Abel L, Lortholary O, Casanova JL, Picard C, Grimbacher B, Puel A.
  7. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, Oppermann U, Opperman U, Dilthey A, Pirinen M, Stone MA, Appleton L, Moutsianas L, Moutsianis L, Leslie S, Wordsworth T, Kenna TJ, Karaderi T, Thomas GP, Ward MM, Weisman MH, Farrar C, Bradbury LA, Danoy P, Inman RD, Maksymowych W, Gladman D, Rahman P, Morgan A, Marzo-Ortega H, Bowness P, Gaffney K, Gaston JS, Smith M, Bruges-Armas J, Couto AR, Sorrentino R, Paladini F, Ferreira MA, Xu H, Liu Y, Jiang L, Lopez-Larrea C, Díaz-Peña R, López-Vázquez A, Zayats T, Band G, Bellenguez C, Blackburn H, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Freeman C, Gillman M, Gray E, Gwilliam R, Hammond N, Hunt SE, Jankowski J, Jayakumar A, Langford C, Liddle J, Markus HS, Mathew CG, McCann OT, McCarthy MI, Palmer CN, Peltonen L, Plomin R, Potter SC, Rautanen A, Ravindrarajah R, Ricketts M, Samani N, Sawcer SJ, Strange A, Trembath RC, Viswanathan AC, Waller M, Weston P, Whittaker P, Widaa S, Wood NW, McVean G, Reveille JD, Wordsworth BP, Brown MA, Donnelly P . 6 . 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 . 21743469 . 10.1038/ng.873 . 3640413.
  8. 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 . 6 . Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease . Nature Genetics . 43 . 11 . 1066–73 . October 2011 . 21983784 . 3378381 . 10.1038/ng.952 .
  9. Cao Z, Conway KL, Heath RJ, Rush JS, Leshchiner ES, Ramirez-Ortiz ZG, Nedelsky NB, Huang H, Ng A, Gardet A, Cheng SC, Shamji AF, Rioux JD, Wijmenga C, Netea MG, Means TK, Daly MJ, Xavier RJ . 6 . Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation . Immunity . 43 . 4 . 715–26 . October 2015 . 26488816 . 4672733 . 10.1016/j.immuni.2015.10.005 .

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