CARD14

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.

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.

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. 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.

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.

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.

Link to psoriasis

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. 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. 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.

External links

• Human CARD14 genome location and CARD14 gene details page in the UCSC Genome Browser.

Further reading

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