| CARD14 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | CARD14 , BIMP2, CARMA2, PRP, PSORS2, PSS1, caspase recruitment domain family member 14 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 607211; MGI: 2386258; HomoloGene: 11469; GeneCards: CARD14; OMA:CARD14 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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]
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]
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]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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