CARD14

CARD14
Identifiers
AliasesCARD14, BIMP2, CARMA2, PRP, PSORS2, PSS1, caspase recruitment domain family member 14
External IDsOMIM: 607211; MGI: 2386258; HomoloGene: 11469; GeneCards: CARD14; OMA:CARD14 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

79092

170720

Ensembl

ENSG00000141527

ENSMUSG00000013483

UniProt

Q9BXL6

Q99KF0

RefSeq (mRNA)

NM_001257970
NM_024110
NM_052819
NM_001366385

NM_130886

RefSeq (protein)

NP_001244899
NP_077015
NP_438170
NP_001353314

NP_570956

Location (UCSC)Chr 17: 80.17 – 80.21 MbChr 11: 119.2 – 119.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Caspase recruitment domain-containing protein 14, also known as D-containing MAGUK protein 2 (Carma 2), is a protein in the CARD-CC protein family that in humans is encoded by the CARD14 gene.[5][6][7]

Structure

CARD14 is a multidomain scaffold protein belonging to the CARMA (CARD-CC) family, sharing structural similarities with CARD10 and CARD11. It comprises five major domains arranged from the N- to C-terminus: an N-terminal caspase recruitment domain (CARD), a LATCH linker region, a coiled-coil (CC) domain, an inhibitory domain, and a C-terminal membrane-associated guanylate kinase (MAGUK) module. The MAGUK module includes PDZ, SH3, and guanylate kinase-like subdomains.[8][9]

The CARD domain, composed of six alpha-helices, mediates protein-protein interactions critical for signalosome assembly. The coiled-coil and LATCH linker domains (residues ~200–600) are common sites of pathogenic mutations linked to psoriasis and other autoinflammatory conditions.[10] The inhibitory domain regulates autoinhibition; for example, the R547S mutation may destabilize this region, promoting constitutive activation.[9] The PDZ domain facilitates interactions with C-terminal motifs of partner proteins, while the guanylate kinase-like domain may participate in ATP-dependent phosphorylation.[9]

Overall, the modular architecture of CARD14 supports its role as a scaffold for multi-protein complex assembly at specialized membrane subdomains, enabling downstream signaling.[8][9]

Function

CARD14 functions as a scaffold in the assembly of signaling complexes that activate inflammatory pathways. It interacts with BCL10, a key regulator of NF-κB, through its CARD domain. In its inactive state, the LATCH linker region suppresses this interaction via autoinhibition.[11]

Upon activation or overexpression, CARD14 forms a CBM signalosome complex with BCL10, MALT1, and LUBAC, leading to downstream activation of NF-κB and the mTOR pathway.[8][11][5] Signaling is associated with post-translational modifications of BCL10, including phosphorylation and linear ubiquitination.[8] Gain-of-function CARD14 variants can localize to endosomal compartments, where they nucleate constitutively active signalosomes in keratinocyte cultures.[8]

The CARD14 gene was recently identified as the first gene directly linked to the most common form of psoriasis. It has been suggested that a mutation in the gene plus an environmental trigger were enough to elicit plaque psoriasis.[12][13] These rare, but highly penetrant, mutations were found to disrupt an auto-inhibited state of CARD14, which leads to the independent activation of NF-κB and mTOR pathways.[11][14] Pharmacological inhibition of NF-κB transcriptional targets or mTOR function in specific mouse models of CARD14-driven psoriasis have both proven to be beneficial, indicating the need of combination therapies for inflammation and proliferation phenotypes.[8][15]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000141527 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000013483 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: caspase recruitment domain family".
  6. ^ Bertin J, Wang L, Guo Y, Jacobson MD, Poyet JL, Srinivasula SM, et al. (April 2001). "CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B". Journal of Biological Chemistry. 276 (15): 11877–11882. doi:10.1074/jbc.M010512200. PMID 11278692. S2CID 35815019.
  7. ^ Gaide O, Martinon F, Micheau O, Bonnet D, Thome M, Tschopp J (May 2001). "Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation". FEBS Letters. 496 (2–3): 121–127. doi:10.1016/S0014-5793(01)02414-0. PMID 11356195. S2CID 22024213.
  8. ^ a b c d e f O'Sullivan PA, Aidarova A, Afonina IS, Manils J, Thurston TL, Instrell R, et al. (September 2024). "CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation". The Biochemical Journal. 481 (18): 1143–1171. doi:10.1042/BCJ20240058. PMC 11555713. PMID 39145956.
  9. ^ a b c d Suleman S, Chhabra G, Raza R, Hamid A, Qureshi JA, Ahmad N (August 2022). "Association of CARD14 Single-Nucleotide Polymorphisms with Psoriasis". International Journal of Molecular Sciences. 23 (16): 9336. doi:10.3390/ijms23169336. PMC 9409305. PMID 36012602.
  10. ^ Bespalov D, Pino D, Vidal-Guirao S, Franquesa J, Lopez-Ramajo D, Filgaira I, et al. (October 2024). "Bioinformatic analysis of molecular characteristics and oncogenic features of CARD14 in human cancer". Scientific Reports. 14 (1): 22972. Bibcode:2024NatSR..1422972B. doi:10.1038/s41598-024-74565-4. PMC 11452207. PMID 39362963.
  11. ^ a b c Howes A, O'Sullivan P, Breyer F, Ghose A, Cao L, Krappmann D, et al. (12 April 2016). "Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation". The Biochemical Journal. 473 (12): 1759–1768. doi:10.1042/BCJ20160270. PMC 5810350. PMID 27071417.
  12. ^ Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al. (May 2012). "Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis". American Journal of Human Genetics. 90 (5): 796–808. doi:10.1016/j.ajhg.2012.03.013. PMC 3376540. PMID 22521419.
  13. ^ Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. (May 2012). "PSORS2 is due to mutations in CARD14". American Journal of Human Genetics. 90 (5): 784–795. doi:10.1016/j.ajhg.2012.03.012. PMC 3376640. PMID 22521418.
  14. ^ Aidarova A, Afonina IS, Manils J, Thurston TL, Instrell R, Howell M, et al. (2024-09-06). "CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation". The Biochemical Journal. 481 (18): 1143–1171. doi:10.1042/bcj20240058. ISSN 0264-6021. PMC 11555713. PMID 39145956.
  15. ^ Webb LV, Howes A, Janzen J, Boeing S, Bowcock AM, Ley SC, et al. (2020-06-29). van der Meer JW, Rothlin CV, Rothlin CV, Vandenbogaard E (eds.). "CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation". eLife. 9 e56720. doi:10.7554/elife.56720. PMC 7351492. PMID 32597759.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


This article is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.