CARD14

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.{{cite journal | vauthors = O'Sullivan PA, Aidarova A, Afonina IS, Manils J, Thurston TL, Instrell R, Howell M, Boeing S, Ranawana S, Herpels MB, Chetian R, Bassa M, Flynn H, Frith D, Snijders AP, Howes A, Beyaert R, Bowcock AM, Ley SC | title = CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation | journal = The Biochemical Journal | volume = 481 | issue = 18 | pages = 1143–1171 | date = September 2024 | pmid = 39145956 | pmc = 11555713 | doi = 10.1042/BCJ20240058 | url = }}{{cite journal | vauthors = Suleman S, Chhabra G, Raza R, Hamid A, Qureshi JA, Ahmad N | title = Association of CARD14 Single-Nucleotide Polymorphisms with Psoriasis | journal = International Journal of Molecular Sciences | volume = 23 | issue = 16 | date = August 2022 | page = 9336 | pmid = 36012602 | pmc = 9409305 | doi = 10.3390/ijms23169336 | doi-access = free | url = }}

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.{{cite journal | vauthors = Bespalov D, Pino D, Vidal-Guirao S, Franquesa J, Lopez-Ramajo D, Filgaira I, Wan L, O'Sullivan PA, Ley SC, Forcales SV, Rojas JJ, Izquierdo-Serra M, Soler C, Manils J | title = Bioinformatic analysis of molecular characteristics and oncogenic features of CARD14 in human cancer | journal = Scientific Reports | volume = 14 | issue = 1 | pages = 22972 | date = October 2024 | pmid = 39362963 | pmc = 11452207 | doi = 10.1038/s41598-024-74565-4 | bibcode = 2024NatSR..1422972B | url = }} The inhibitory domain regulates autoinhibition; for example, the R547S mutation may destabilize this region, promoting constitutive activation. The PDZ domain facilitates interactions with C-terminal motifs of partner proteins, while the guanylate kinase-like domain may participate in ATP-dependent phosphorylation.

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

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.{{cite journal | vauthors = Howes A, O'Sullivan P, Breyer F, Ghose A, Cao L, Krappmann D, Bowcock A, Ley S | title = Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation | journal = The Biochemical Journal | volume = 473 | issue = 12 | pages = 1759–1768 | date = 12 April 2016 | pmid = 27071417 | pmc = 5810350 | doi = 10.1042/BCJ20160270 }}

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. Signaling is associated with post-translational modifications of BCL10, including phosphorylation and linear ubiquitination. Gain-of-function CARD14 variants can localize to endosomal compartments, where they nucleate constitutively active signalosomes in keratinocyte cultures.

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.{{cite journal | vauthors = Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, Duffin KC, Stuart PE, Goldgar D, Hayashi G, Olfson EH, Feng BJ, Pullinger CR, Kane JP, Wise CA, Goldbach-Mansky R, Lowes MA, Peddle L, Chandran V, Liao W, Rahman P, Krueger GG, Gladman D, Elder JT, Menter A, Bowcock AM | title = Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis | journal = American Journal of Human Genetics | volume = 90 | issue = 5 | pages = 796–808 | date = May 2012 | pmid = 22521419 | pmc = 3376540 | doi = 10.1016/j.ajhg.2012.03.013 }}{{cite journal | vauthors = Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, Ryan C, Duan S, Helms CA, Liu Y, Chen Y, McBride AA, Hwu WL, Wu JY, Chen YT, Menter A, Goldbach-Mansky R, Lowes MA, Bowcock AM | title = PSORS2 is due to mutations in CARD14 | journal = American Journal of Human Genetics | volume = 90 | issue = 5 | pages = 784–795 | date = May 2012 | pmid = 22521418 | pmc = 3376640 | doi = 10.1016/j.ajhg.2012.03.012 }} 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.{{Cite journal |vauthors=Aidarova A, Afonina IS, Manils J, Thurston TL, Instrell R, Howell M, Boeing S, Ranawana S, Herpels MB, Chetian R, Bassa M, Flynn H, Frith D, Snijders AP, O'Sullivan PA |date=2024-09-06 |title=CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation |journal=The Biochemical Journal |volume=481 |issue=18 |pages=1143–1171 |doi=10.1042/bcj20240058 |issn=0264-6021 |pmc=11555713 |pmid=39145956}} 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.{{Cite journal | vauthors = Webb LV, Howes A, Janzen J, Boeing S, Bowcock AM, Ley SC, Manils J | title = CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation | journal = eLife | volume = 9 | pages = e56720 | date = 2020-06-29 | pmid = 32597759 | pmc = 7351492 | doi = 10.7554/elife.56720 | doi-access = free | veditors = van der Meer JW, Rothlin CV, Rothlin CV, Vandenbogaard E }}

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• {{UCSC gene info|CARD14}}

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• {{cite journal | vauthors = Wang L, Guo Y, Huang WJ, Ke X, Poyet JL, Manji GA, Merriam S, Glucksmann MA, DiStefano PS, Alnemri ES, Bertin J | title = Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-kappa B. | journal = Journal of Biological Chemistry | volume = 276 | issue = 24 | pages = 21405–21409 | date = Jun 2001 | pmid = 11259443 | doi = 10.1074/jbc.M102488200 | doi-access = free }}

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