Caspase recruitment domain | |||||||||||
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![]() Structure of the RAIDD CARD. [1] | |||||||||||
Identifiers | |||||||||||
Symbol | CARD | ||||||||||
Pfam | PF00619 | ||||||||||
InterPro | IPR001315 | ||||||||||
SMART | SM00114 | ||||||||||
PROSITE | PS50209 | ||||||||||
SCOP2 | 3crd / SCOPe / SUPFAM | ||||||||||
CDD | cd01671 | ||||||||||
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Caspase recruitment domain, IPS1/RIG-I | |||||||||
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Identifiers | |||||||||
Symbol | CARD_2 | ||||||||
Pfam | PF00619 | ||||||||
InterPro | IPR031964 | ||||||||
SCOP2 | 2lwd / SCOPe / SUPFAM | ||||||||
CDD | cd08789 | ||||||||
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Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARDs are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.
CARDs are a subclass of protein motif known as the death fold, 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 (PYD), death domain (DD), and death effector domain (DED), all of which also function primarily in regulation of apoptosis and inflammatory responses.
CARDs were originally characterized based on their involvement in the regulation of caspase activation and apoptosis. [2] 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. CARDs are present on a number of proteins that promote apoptosis, primarily caspases 1,2,4,5,9, and 15 in mammals.
A number of CARDs 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 CARDs participate in the immune response. Ipaf-1 features an N-terminal CARD, a nucleotide-binding domain, and C-terminal leucine-rich repeats (LRRs), thought to function in a similar fashion to those found in Toll-like receptors. 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.
Recently, a subset of CARD-containing proteins has been shown to participate in recognition of intracellular double-stranded RNA, 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 CARDs and C-terminal RNA helicase domains that directly interact with and process the double-stranded viral RNA. This processing makes the CARDs available for interaction with the CARD 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 inhibitor of nuclear factor kappa-B kinase (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 IKBKE 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).
Because of their role as regulators of inflammation, constitutive activation of certain CARD-containing 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. Activating mutations in at least two related PYD-containing proteins, cryopyrin/CIAS-1 and pyrin/MEFV, have been linked to Muckle–Wells syndrome and familial Mediterranean fever, respectively.
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Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.
The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates 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 (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis. Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.
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. Examples of death fold domains include the death domain (DD), death effector domain (DED), caspase recruitment domain (CARD), and pyrin domain (PYD).
NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.
Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.
Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.
Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.
PYCARD, often referred to as ASC, is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome.
NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. NLRP1 is expressed by a variety of cell types, which are predominantly epithelial or hematopoietic. The expression is also seen within glandular epithelial structures including the lining of the small intestine, stomach, airway epithelia and in hairless or glabrous skin. NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD. Its highest expression was detected in human skin, in psoriasis and in vitiligo. Polymorphisms of NLRP1 were found in lupus erythematosus and diabetes type 1. Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the protease in anthrax lethal factor.
NACHT, LRR and PYD domains-containing protein 2 is a protein that in humans is encoded by the NLRP2 gene.
Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 is a protein that in humans is encoded by the NLRP12 gene.
The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.
Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.
The death domain (DD) 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 (DED) and the caspase recruitment domain (CARD), which work in similar pathways and show similar interaction properties. DD bind each other forming oligomers. Mammals have numerous and diverse DD-containing proteins. Within these proteins, the DD domains can be found in combination with other domains, including: CARDs, DEDs, ankyrin repeats, caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR), TIR domains, and ZU5 domains.
A pyrin domain is a protein domain and a subclass of protein motif known as the death fold, the 4th and most recently discovered member of the death domain superfamily (DDF). It was originally discovered in the pyrin protein, or marenostrin, encoded by MEFV. The mutation of the MEFV gene is the cause of the disease known as Familial Mediterranean Fever. The domain is encoded in 23 human proteins and at least 31 mouse genes.
NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6
Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.
Death regulator Nedd2-like caspase was firstly identified and characterised in Drosophila in 1999 as a cysteine protease containing an amino-terminal caspase recruitment domain. At first, it was thought of as an effector caspase involved in apoptosis, but subsequent findings have proved that it is, in fact, an initiator caspase with a crucial role in said type of programmed cell death.
Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.