Caspase recruitment domain-containing protein 14, also known as D-containing MAGUK protein 2 (Carma 2), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

in the CARD-CC protein family that in humans is encoded by the ''CARD14''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Structure

CARD14 is a multidomain scaffold protein belonging to the CARMA (CARD-CC) family, sharing structural similarities with

CARD10 Caspase recruitment domain-containing protein 10 is a protein in the CARD-CC protein family that in humans is encoded by the ''CARD10'' gene. Function The caspase recruitment domain (CARD) is a protein module that consists of 6 or 7 antipara ...

and

CARD11 Caspase recruitment domain-containing protein 11 also known as CARD-containing MAGUK protein 1 (Carma 1) is a protein in the CARD-CC protein family that in humans is encoded by the ''CARD11'' gene. CARD 11 is a membrane associated protein that i ...

. 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 A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a v ...

(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 B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by the ''BCL10'' gene. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma. Function Bcl10 was identified by its translocation in a case o ...

, a key regulator of

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

, 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

, MALT1, and LUBAC, leading to downstream activation of

and the

mTOR The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...

pathway. Signaling is associated with post-translational modifications of BCL10, including

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

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 Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

. It has been suggested that a mutation in the gene plus an environmental trigger were enough to elicit

plaque psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

. 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

pathways. Pharmacological inhibition of

transcriptional targets or

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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological properti ...

Structure

Function

Link to psoriasis

References

External links

Further reading