WikiJournal Preprints/CARD-CC family

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The CARD-CC protein family is defined by an evolutionary conserved "caspase activation and recruitment domain" (CARD) and a coiled-coil (CC) domain.[1] Coiled-coils (CC) act as oligomerization domains for many proteins such as structural and motor proteins, and transcription factors. This means that monomers are converted to macromolecular complexes by polymerization.[2] In humans and other jawed vertebrates, the family consists of CARD9 and the three "CARD-containing MAGUK protein" (CARMA)[3] proteins CARD11 (CARMA1), CARD14 (CARMA2) and CARD10 (CARMA3).

Evolution and species distributionEdit

CARD-CC protein family structure

The protein family is ancient and can be found as far back as Cnidaria, but has almost exclusively been studied in humans and mice. Notably, the protein family is absent in insects and nematodes, which makes it impossible to study its function in the most popular invertebrate model organisms (Drosophila and C. elegans). Invertebrates only have a CARD9-like ancestral CARD-CC member, and the earliest occurrence of a CARD-CC member with the CARMA domain composition is in the jawless vertebrate hagfish. Already in sharks are all four CARD-CC family members present, indicating that the 3 distinct CARMA CARD-CC family members were formed by two duplication events just before or very early in the jawed vertebrate evolution. The four CARD-CC members in mice and humans differ in expression domains, where CARD9 is mostly expressed in myelocytes, CARD11 in lymphocytes, while CARD10 and CARD14 are mostly expressed in non-hemapoetic cells. This gene expression differentiation between the four CARD-CC family members conserved at least as far back as frogs (Xenopus tropicalis) and fish (Danio rerio),[4] indicating that the four CARD-CC family members have had distinct functions since early jawed vertebrate evolution.


Graphical overview of signaling pathways dependent on a CARD-CC family member

A common theme for all four CARD-CC family proteins in mice and humans is that they are activated by different protein kinase C isoforms,[5] and recruit BCL10 and the paracaspase MALT1 upon activation, forming a so-called CBM complex. There are four different CBM complexes, defined by which CARD-CC family member that is responsible for its assembly: CBM-9 (CARD9), CBM-1 (CARD11/CARMA1), CBM-2 (CARD14/CARMA2) and CBM-3 (CARD10/CARMA3). [6] CBM complex assembly results in recruitment of TRAF6 to MALT1 and downstream activation of NF-κB transcriptional activity and expression of pro-inflammatory cytokines. The different CARD-CC family members show different expression pattern and gain- or loss of function mutation in the different CARD-CC family proteins cause different phenotypes.


  1. "Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions". Frontiers in Immunology 9: 1136. 2018. doi:10.3389/fimmu.2018.01136. PMID 29881386. PMC 5978004. // 
  2. "CC Protein Domain | Coiled Coil | Cell Signaling Technology". Retrieved 2020-02-01.
  3. "The three CARMA sisters: so different, so similar: a portrait of the three CARMA proteins and their involvement in human disorders". Journal of Cellular Physiology 229 (8): 990–7. August 2014. doi:10.1002/jcp.24543. PMID 24375035. 
  4. "BioGPS". BioGPS. The Scripps Research Institute. Retrieved 2021-07-27.
  5. Staal, Jens; Driege, Yasmine; Haegman, Mira; Kreike, Marja; Iliaki, Styliani; Vanneste, Domien; Lork, Marie; Afonina, Inna S. et al. (2020-08-13). "Defining the combinatorial space of PKC::CARD-CC signal transduction nodes". The FEBS Journal 288 (5): 1630–1647. doi:10.1111/febs.15522. ISSN 1742-4658. PMID 32790937. 
  6. Gehring, Torben; Seeholzer, Thomas; Krappmann, Daniel (2018). "BCL10 – Bridging CARDs to Immune Activation". Frontiers in Immunology 9: 1539. doi:10.3389/fimmu.2018.01539. ISSN 1664-3224. PMID 30022982. PMC 6039553. // 
  7. "Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity". Nature 442 (7103): 651–6. August 2006. doi:10.1038/nature04926. PMID 16862125. 
  8. Online 'Mendelian Inheritance in Man' (OMIM) 607212
  9. "Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects". The Journal of Allergy and Clinical Immunology 131 (2): 477–85.e1. February 2013. doi:10.1016/j.jaci.2012.11.050. PMID 23374270. 
  10. "Germline hypomorphic CARD11 mutations in severe atopic disease". Nature Genetics 49 (8): 1192–1201. August 2017. doi:10.1038/ng.3898. PMID 28628108. PMC 5664152. // 
  11. "Germline CARD11 Mutation in a Patient with Severe Congenital B Cell Lymphocytosis". Journal of Clinical Immunology 35 (1): 32–46. January 2015. doi:10.1007/s10875-014-0106-4. PMID 25352053. PMC 4466218. // 
  12. "Oncogenic CARD11 mutations in human diffuse large B cell lymphoma". Science 319 (5870): 1676–9. March 2008. doi:10.1126/science.1153629. PMID 18323416. 
  13. "PSORS2 is due to mutations in CARD14". American Journal of Human Genetics 90 (5): 784–95. May 2012. doi:10.1016/j.ajhg.2012.03.012. PMID 22521418. PMC 3376640. // 
  14. Online 'Mendelian Inheritance in Man' (OMIM) 607211
  15. "Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis". The Journal of Allergy and Clinical Immunology 143 (1): 173–181.e10. January 2019. doi:10.1016/j.jaci.2018.09.002. PMID 30248356. 
  16. "CARMA3 Is a Critical Mediator of G Protein-Coupled Receptor and Receptor Tyrosine Kinase-Driven Solid Tumor Pathogenesis". Frontiers in Immunology 9: 1887. 2018. doi:10.3389/fimmu.2018.01887. PMID 30158935. PMC 6104486. // 
  17. "CARD10 enriched in primary open-angle glaucoma". Molecular Genetics & Genomic Medicine 4 (6): 624–633. November 2016. doi:10.1002/mgg3.248. PMID 27896285. PMC 5118207. //