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CARD domain
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Caspase recruitment domains, or Caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s, typically those involved in processes relating to inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

Basic features

CARD domains are a subclass of protein motif known as the death fold
Death fold
The death fold is a tertiary structure motif commonly found in proteins involved in apoptosis or inflammation-related processes. This motif is commonly found in domains that participate in protein-protein interactions leading to the formation of large functional complexes...

, which features an arrangement of six to seven antiparallel alpha helices with a hydrophobic core and an outer face composed of charged residues. Other motifs in this class include the pyrin domain
Pyrin domain
A pyrin domain is a protein domain and a subclass of protein motif known as the death fold; it allows a pyrin domain containing protein to interact with other proteins that contain a pyrin domain...

 (PYD), death domain
Death domain
The death domain is a protein interaction module composed of a bundle of six alpha-helices. DD is a subclass of protein motif known as the death fold and is related in sequence and structure to the death effector domain and the caspase recruitment domain , which work in similar pathways and show...

 (DD), and death effector domain
Death effector domain
The death-effector domain is a protein interaction domain found to regulate a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein...

 (DED), all of which also function primarily in regulation of apoptosis and inflammatory responses.

CARD domains in apoptosis

CARD domains were originally characterized based on their involvement in the regulation of caspase activation and apoptosis. The basic six-helix structure of the domain appears to be conserved as far back as the ced-3 and ced-4 genes in C. elegans, the organism in which several components of the apoptotic machinery were first characterized. CARD motifs are present on a number of proteins that promote apoptosis, primarily caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....

s 1,2,4,5,9, and 15 in mammals.

IL-1 and IL-18 processing

A number of CARD proteins have been shown to play a role in regulating inflammation in response to bacterial and viral pathogens as well as to a variety of endogenous stress signals. Recently, studies on the NLR protein Ipaf-1 have provided insight into how CARD proteins participate in the immune response. Ipaf-1 features an N-terminal CARD domain, a nucleotide-binding domain, and C-terminal leucine-rich repeats (LRRs), thought to function in a similar fashion to those found in Toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...

s. The primary role of this molecule appears to be regulation of the proteolytic processing of pro-IL-1β and pro-IL-18 into their mature forms via association in a large complex known as the inflammasome. Upon activation of Ipaf-1 by the intracellular bacterium S. typhimurium or other stress signals, Ipaf-1 recruits a CARD-containing adapter termed ASC and caspase-1 in unknown stoichiometry via CARD-CARD association. This complex in turn leads to autoproteolytic activation of caspase-1 and subsequent IL-1β and IL-18 maturation.

Antiviral signaling

Recently, a subset of CARD proteins has been shown to participate in recognition of intracellular double-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

, a common constituent of a number of viral genomes, including the para- and orthomyxoviridae and rhabdoviridae. Unlike NLRs, these proteins, termed RIG-I and MDA5, contain twin N-terminal CARD domains and C-terminal RNA helicase domains that directly interact with and process the double-stranded viral RNA. This processing makes the CARD domains available for interaction with the CARD motif of IPS-1/MAVS/VISA/Cardif, a downstream adapter anchored in the mitochondria. Although the interactions between IPS-1 and RIG-I/MDA-5 have been shown in vitro, the nature of the complex formed upon viral detection has not been characterized.
The adaptor protein VISA further activates the IKK-protein-kinase family members. Although the
canonical IKK family members IKKa and IKKb are essential for virus-triggered NF-κB activation, the noncanonical IKK family members TBK1 and IKK3 are responsible for phosphorylating
and activating IRF3 and IRF7 (Fitzgerald et al., 2003; Hemmi et al., 2004; Matsui et al., 2006). Various studies have also demonstrated the involvement of several other signaling components in virus-induced activation of NF-κB and/or IRF3, including TRAF3, TRAF6, TANK, NEMO(IKKg), TRADD, FADD, and RIP (Kawai et al., 2005; Michallet et al., 2008; Oganesyan et al.,
2006; Saha et al., 2006; Xu et al., 2005; Zhao et al., 2007).

Autoimmunity

Because of their role as regulators of inflammation, constitutive activation of certain CARD proteins, either conferred by mutation or by constant presence of stress signals, has been suggested to play a causative role in a number of inflammatory syndromes. Gain-of-function mutations in the intracellular NOD2 protein has been linked to increased risk for Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...

. Activating mutations in at least two related PYD-containing proteins, cryopyrin/CIAS-1
CIAS1
NACHT, LRR and PYD domains-containing protein 3 or cryopyrin is a protein that in humans is encoded by the NLRP3 gene. The gene is also called cold induced autoinflammatory syndrome 1 and is located on the long arm of chromosome 1...

 and pyrin/MEFV, have been linked to Muckle-Wells Syndrome
Muckle-Wells syndrome
Muckle–Wells syndrome , also known as , is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and painful joints. As a result, MWS is considered a type of periodic fever syndrome...

 and familial Mediterranean fever
Familial Mediterranean fever
Familial Mediterranean fever is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin....

, respectively.

List of CARD containing proteins

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