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PYCARD (PYD and CARD domain containing)

Written2014-07Jeffrey H Dunn, Mayumi Fujita
Department of Dermatology, University of Colorado Denver, SOM, Aurora, CO, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)TMS-1
CARD5
ASC
Other aliasTMS
TMS1
HGNC (Hugo) PYCARD
LocusID (NCBI) 29108
Atlas_Id 712
Location 16p11.2  [Link to chromosome band 16p11]
Location_base_pair Starts at 31201486 and ends at 31202776 bp from pter ( according to hg19-Feb_2009)  [Mapping PYCARD.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Description 3 exons spanning 1.4 kb, with a CpG island surrounding exon 1 (Conway et al., 2000; Gerhard et al., 2004; Ota et al., 2004). Exon 1 encodes a pyrin domain (PYD), exon 2 encodes a proline and glycine-rich (PGR) domain, and exon 3 encodes a caspase recruitment domain (CARD) (Masumoto et al., 1999; Matsushita et al., 2009).

Protein

Description PYCARD is composed of two protein-protein interaction domains: an N-terminal pyrin domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are structurally independent six-helix bundle motifs connected by a 23-residue proline and glycine-rich (PGR) linker domain (Martinon et al., 2000; Bertin et al., 2001; de Alba, 2009; Matsushita et al., 2009).
There are 4 transcripts (splice variants) including the canonical PYCARD (PYCARD1) (Matsushita et al., 2009; Bryan et al., 2010). Correlating to four transcript splice variants are four protein isoforms. In addition to the canonical PYCARD protein (also known as isoform 1, fASC), three additional isoforms display unique capabilities with respect to their function as part of the inflammasome, with one of the isoforms even showing an inhibitory effect. Isoforms 1 and 2 are the activating isoforms of ASC and co-localize with intracellular nucleotide oligomerization domain-like receptors (NLRs) and caspase-1. Isoform 2 (also known as ASC-b, vASC) lacks a PGR domain and may not be needed for caspase activation but is involved in direct regulation of IL-1β processing. The inhibitory isoform (isoform 3, ASC-c) co-localizes only with caspase-1, but not with NLRP3. Isoform 4 (ASC-d) does not co-localize with NLRP3 or with caspase-1 and lacks the ability to function as an inflammasome adaptor. It may not be a functional protein product and its precise function and relation to PYCARD is unknown (Matsushita et al., 2009; Bryan et al., 2010).
PYD is also known as the domain in apoptosis and interferon response (DAPIN) or the pyrin, AIM, ASC death-domain-like (PAAD) domain. It is an 80-100 residue domain with alpha-helical secondary structure located on the N-terminus of the protein. Like CARD, it is a member of the death domain-fold superfamily of proteins. Strong dipole moments in PYD suggest that electrostatic interactions play an important role for the binding between PYDs. The function of PYD is to bind other PYD-containing proteins and is also associated with domains such as CARD, leucine-rich repeat (LRR), dual specificity spore lysis A (splA) protein kinase and ryanodine receptor (SPRY), caspase, or zinc-finger B-box (Martinon et al., 2001; Pawlowski et al., 2001; Liepinsh et al., 2003).
CARD is 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. The CARD structure of PYCARD reveals two distinctive characteristics; helix 1 is not fragmented as in all other known CARDs; and it demonstrates a uniform distribution of positive and negative charges, whereas these are commonly separated into two areas in other death domains (de Alba, 2009).
CARD mediates the interaction between adaptor proteins participating in apoptosis by regulating caspases. CARD-containing proteins are also involved in inflammation through their regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The mechanisms by which CARDs activate caspases and NF-κB involve the assembly of multi-protein complexes, which can facilitate dimerization or serve as scaffolds on which proteases and kinases are assembled and activated. Domains associated with CARD include: PYD, Apoptotic protease activating factor-1 (Apaf-1) domains [including LRR, Tryptophan-Aspartic acid (WD or beta-transducin) repeats, nucleotide binding and oligomerization (NB-ARC or NOD) domains and ATPase domains], sarcoma (Src) tyrosine kinase proto-oncogene homology domains, death domain (DD) and the proform of caspases (e.g., CASP-9) (Hofmann et al., 1997; Bouchier-Hayes and Martin, 2002; Reed et al., 2004).
The PGR linker adopts a residual structure in order to maintain a back-to-back orientation of the PYD and CARD domains, which avoids steric interference of one domain with the binding site of the other. NMR relaxation experiments show that the linker is flexible despite the residual structure (de Alba, 2009).
Expression Silencing of PYCARD correlates with hypermethylation of the CpG island surrounding exon 1. Breast cancer cell lines exhibit complete methylation of PYCARD and do not express PYCARD mRNA, whereas overexpression of PYCARD inhibits the growth of breast cancer cells (Conway et al., 2000).
In normal fibroblasts, the CpG island of the PYCARD gene is composed of an unmethylated domain with distinct 5-prime and 3-prime boundaries. De novo or aberrant methylation of the PYCARD CpG island in cells is accompanied by localized hypoacetylation of histone H3 and H4 and gene silencing (Stimson and Vertino, 2002).
Localisation Cytoplasm, endoplasmic reticulum, mitochondrion, nucleus.
PYCARD forms hollow spherical aggregates near the perinuclear space of apoptotic cells (McConnell and Vertino, 2000). PYCARD also tends to self-aggregate during in vitro apoptosis induced by retinoids, etoposide and other anti-tumor drugs (Masumoto et al., 1999).
PYCARD is localized primarily in the nucleus in resting monocytes/macrophages but rapidly redistributes to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria upon pathogen infection and subsequent inflammasome activation (Bryan et al., 2009; Zhou et al., 2011).
Function PYCARD is known to interact with a variety of inflammatory and cell death-related genes including NLRs (NLRP1-14, NLRC4 [IL-1β converting enzyme protease-activating factor (IPAF)], Absent in Melanoma 2 (AIM2); caspase-1, caspase-2, caspase-3, caspase-5, caspase-8, caspase-9, caspase-12; pyrin; pyrin-only protein (POP) 1 and pyrin-only protein (POP) 2; cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A); AP-1; serum response factor. There are 75 genes known to be induced by PYCARD. A large proportion of them are related to transcription (23%), inflammation (21%), or cell death (16%) (Hasegawa et al., 2009).

Inflammation
PYCARD is an adaptor protein involved in the structure and function of inflammasomes. Inflammasomes are pattern recognition receptors characteristically composed of an NLR, ASC and caspase-1 and are responsible for production of pro-inflammatory cytokines, in particular IL-1β and IL-18. There are several subtypes of inflammasomes that recognize a diverse array of microbial, endogenous, and environmental danger signals (Agostini et al., 2004; Mariathasan et al., 2004; Muruve et al., 2008; Fernandes-Alnemri et al., 2009; Hornung et al., 2009; Zhou et al., 2011; Dunn et al., 2012).
Mounting evidence indicates that inflammasomes and PYCARD also elicit non-overlapping inflammatory functions. PYCARD interaction with NLRC4 regulates both apoptosis via caspase-8 and NF-κB activation via PYD. PYCARD can inhibit or activate NF-κB through PYD interactions with the NF-κB IKK complex (Stehlik et al., 2002; Masumoto et al., 2003; Sarkar et al., 2006; Fernandes-Alnemri et al., 2007; Hasegawa et al., 2009; Hornung et al., 2009; Taxman et al., 2011).
PYCARD is also associated with inflammasome-independent transcriptional activation of cytokines and chemokines via activator protein-1 (AP-1), NF-κB, mitogen activated protein kinase (MAPK) and caspase-8 (Taxman et al., 2006). In pathogen-infected cells, PYCARD regulates MAPK phosphorylation by pathogens and Toll-like receptor (TLR) agonists via suppression of the dual-specificity phosphatase (DUSP10/MKP5), and independent of caspase-1 and IL-1β; thus demonstrating a function for ASC that is distinct from the inflammasome in modulating MAPK activity and chemokine expression (Taxman et al., 2011).

Adaptive immunity
PYCARD may play an inflammasome-independent role in driving dendritic cells to stimulate T-cell priming for the induction of antigen-specific cellular and humoral immunity. Dendritic cell maturation stimuli activate caspase-1 in human dendritic cells. Inhibition of PYCARD and cathepsin B markedly diminishes the capacity of mature dendritic cells to stimulate antigen-specific T cells. The defective ability of PYCARD or cathepsin B-deficient dendritic cells to stimulate T cells is independent of inflammasome-mediated processing of inflammatory cytokines or priming of dendritic cells with pre-processed lipopolysaccharide (Guo and Dhodapkar, 2012).
On the other hand, PYCARD may also play an inflammasome-independent role in antigen-specific inflammatory disease. Mice genetically modified to lack both PYCARD alleles [ASC (-/-)] are protected from collagen-induced arthritis, whereas mice lacking Nlrp3 and caspase-1 are susceptible to collagen-induced arthritis. This may result from an inability of dendritic cells to facilitate antigen-specific activation of lymphocytes in mice lacking PYCARD. Furthermore, antigen-induced proliferation of purified T cells lacking PYCARD [ASC (-/-)] is restored upon incubation with wild type dendritic cells, but not when cultured with ASC (-/-) dendritic cells (Ippagunta et al., 2010).

Cell death (apoptosis, pyroptosis, necrosis)
PYCARD promotes caspase-mediated inhibition of cellular proliferation, DNA fragmentation and apoptosis via caspases including caspase-2/3/8 and 9 to activate the mitochondrial apoptotic pathway. The mechanism likely involves mitochondrial translocation of BAX, proteolytic maturation of BID and upregulation of the p53 response to cell stress or genotoxic insult (McConnell and Vertino, 2000; Ohtsuka et al., 2004; Hasegawa et al., 2007). PYCARD may also increase the susceptibility of leukemia cell lines to apoptotic stimuli by anticancer drugs (Masumoto et al., 1999).
PYCARD is involved in macrophage pyropoptosis (inflammatory cell death) which is characterized by potassium efflux and/or decreased intracellular potassium. The interaction of AIM2 with PYCARD leads to the formation of the pyroptosome, which induces pyroptotic cell death in response to cytoplasmic DNA in cells containing caspase-1 (Fernandes-Alnemri et al., 2007; Fernandes-Alnemri et al., 2009).
PYCARD also mediates cellular necrosis (pyronecrosis) in concert with NLRP3 and cathespin to cause programmed necrotic cell death that is independent from pyroptosis and does not require caspase-1 (Willingham et al., 2007; Satoh et al., 2013).

Implicated in

Note
  
Entity Cancer
  
  
Entity Anti-cancer immunity
Note ATP released by dying tumor cells activates P2RX7 receptors on dendritic cells, which triggers NLRP3/ASC (PYCARD)/ caspase-1 inflammasome-dependent IL-1β production and subsequent dendritic cell-mediated priming of tumor antigen-specific CD8+ T-cell production of IFN-γ (Aymeric et al., 2010).
  
  
Entity Melanoma
Note ASC has a dual role in melanoma progression via differential regulation of NF-κB activity and IL-1β processing. In primary melanoma, relatively high levels of ASC expression inhibit NF-κB activity and IL-1β transcription, with net inhibition of tumorigenesis. In metastatic melanoma, however, aberrant methylation results in decreased levels of ASC. The relative paucity of ASC protein in these cells, as well as assembly of a constitutionally active ASC-dependent inflammasome, may result competition among various pathways for a limited supply of ASC, with a net result of decreased inhibition of NF-κB, a positive feedback loop of IL-1 signalling and a pro-tumorigenic effect (Guan et al., 2003; Okamoto et al., 2010; Liu et al., 2013).
  
  
Entity Skin squamous cell carcinoma
Note ASC expression is reduced in squamous cell carcinoma. Tissue-specific analysis of a murine model of squamous cell carcinoma reveals that ASC has opposing functions: ASC acts as an inflammasome-independent p53-dependent tumor suppressor in keratinocytes while functioning as an inflammasome-dependent tumor promoter in dendritic cells (Drexler et al., 2012).
  
  
Entity Colorectal cancer
Note ASC expression sensitizes colorectal cancer cells to chemotherapeutic agents, resulting in inflammasome-independent cell death via mitochondrial reactive oxygen species and janus-kinase signalling. Methylation and silencing of ASC in colorectal cancer cells confers resistence to cell death by DNA-damaging chermotherapeutics (Riojas et al., 2007; Hong et al., 2013). NLRP3/ASC-dependent caspase-1 activity is critical for IL-18-mediated IFN-γ-dependent STAT1 tumor suppression of colorectal cancer triggered by chronic inflammation (Allen et al., 2010; Dupaul-Chicoine et al., 2010; Zaki et al., 2010). On the other hand ASC-dependent caspase-1 activity has a tumorigenic effect via IL-6 and STAT3 in response to microbial induction of aryl hydrocarbon receptors in the cecum (Ikuta et al., 2013).
  
  
Entity Breast cancer
Note Epigenetic silencing of TMS1 (PYCARD, ASC) results in failure of breast cancer cells to undergo BIM- and caspase-8-dependent apoptosis (anoikis) after detachment from the extra-cellular matrix (Parsons and Vertino, 2006; Parsons et al., 2009).
  
  
Entity Prostate cancer
Note Interferons induce expression of the cytosolic DNA-sensing AIM2/ASC inflammasome in normal human prostate cells. AIM2 mRNA levels are higher in benign prostate hyperplasia (BPH) cells than in normal prostate tissue. AIM2 mRNA levels are lower, however, in prostate cancer cells relative to BPH cells (Ponomareva et al., 2013).
Aberrant methylation and reduced expression of ASC occurs in prostate cancer cell lines and is associated with more aggressive disease (Collard et al., 2006; Das et al., 2006).
  
  
Entity Glioblastoma
Note Glioblastoma astrocytes aberrantly methylate ASC resulting in decreased ASC expression relative to normal human brain tissue. Decreased ASC expression may be associated with decreased patient survival and progression from grade III to grade IV glioma (Stone et al., 2004).
  
  
Entity Lung cancer
Note Hypermethylation of the ASC promoter with reduced ASC expression occurs in primary lung cancer and is correlated with progression and metastasis of human lung adenocarcinoma. ASC hypermethylation in sputum DNA correlates with a high risk of lung cancer (Machida et al., 2006).
  
  
Entity Promyelocytic leukemia
Note Promyelocytic leukemia protein (PML) limits ASC function and relegates ASC to the nucleus, limiting inflammasome activation and IL-1β production in bone marrow macrophages (Dowling et al., 2014). Another study, using a genetically distinct murine model, found that PML enhances NLRP3 inflammasome assembly and production of IL-1β, but did not specifically examine interactions between PML and ASC (Lo et al., 2013).
  
  
Entity Inflammatory diseases
  
  
Entity Atopic dermatitis
Note Downregulation of NLRP3/ASC inflammasome function in atopic dermatitis may predispose patients to Staphylococcus aureus superinfection (Niebuhr et al., 2014).
  
  
Entity Psoriasis
Note AIM2, ASC, caspase-1, and caspase-5 expression is upregulated in psoriatic skin lesions (Dombrowski et al., 2011; Kopfnagel et al., 2011; Salskov-Iversen et al., 2011).
  
  
Entity Contact dermatitis
Note Ultraviolet (UV) light triggers cutaneous production of uric acid with demonstrated effects on the NLRP3/ASC/caspase-1 inflammasome and varying impact on immunity and carcinogenesis. The NLRP3/ASC inflammasome contributes to a caspase-dependent IL-1β hypersensitivity response (Watanabe et al., 2007). Allopurinol (a xanthine oxidase inhibitor of uric acid production) prevents UV-induced NLRP3 upregulation but not UV-induced ASC downregulation (Leighton et al., 2013).
  
  
Entity Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome
Note Alterations in ASC as well as upstream and downstream components of the inflammasome pathway are involved in a variety of inflammatory skin diseases. Hereditary mutations in proline serine threonine phosphatase-interacting protein [PSTPIP1, or CD2-binding protein 1 (CD2BP1)], which regulates pyrin and is involved in filament organization, may activate NLRP3-independent ASC/caspase-1 activity, resulting in the persistent IL-1β secretion implicated in PAPA syndrome (Shoham et al., 2003; Waite et al., 2009).
  
  
Entity Familial mediterranean fever
Note Similar to the PAPA syndrome, gain of function mutations in the pyrin-encoding MEFV gene result in ASC-dependent, NLRP3-independent, caspase-1-mediated activation of IL-1β (Waite et al., 2009; Chae et al., 2011; Franchi and Núñez, 2011).
  
  
Entity Inflammatory bowel disease
Note ASC triggers caspase-driven enteric neuronal cell death in response to inflammatory driven ATP activation of P2X7R and pannexin channels (Gulbransen et al., 2012). Alterations in the NLRP6 inflammasome pathway including ASC, caspase-1 and IL-18 may contribute to the etiology of human inflammatory bowel disease (Elinav et al., 2011).
  
  
Entity Metabolic diseases including: gout, rheumatoid arthritis, diabetes mellitus and atherosclerosis
Note Macrophages, TLRs, NLRs and other components of the innate immune system play a role in the etiology of a variety of metabolic inflammatory diseases. Dysregulated ATP, lipid, urate and glucose metabolism disrupts microtubule polymerization, inflammasome assembly and proinflammatory cytokine production. Tubulin polymerization is critical for mitochondrial transport and inflammasome assembly by allowing for juxtaposition of ASC with NLRP3 in the cytosol (Martinon et al., 2006; Griffith et al., 2009; Ippagunta et al., 2010; Wen et al., 2011; Lu et al., 2012; Wen et al., 2012; Akira et al., 2013; Benetti et al., 2013; Grant and Dixit, 2013; Jourdan et al., 2013; Lee et al., 2013).
  
  
Entity Infectious diseases
  
  
Entity Anthrax
Note Anthrax lethal toxin triggers the formation of ASC-dependent NLRC4, NLRP3 and AIM2, but not NLRP1-dependent processing of caspase-1 with subsequent autoproteolysis and IL-1β secretion in murine macrophages (Nour et al., 2009; Lu et al., 2012; Van Opdenbosch et al., 2014). The 7-desacetoxy-6,7-dehydrogedunin (7DG) small molecule has been shown to protect macrophages from anthrax lethal toxin. 7DG inhibits protein kinase R, which is has a role in ASC assembly, caspase-1 activation and macrophage pyroptosis (Hett et al., 2013).
  
  
Entity Chlamydia trachomatis
Note Chlamydia trachomatis, an obligate intracellular bacteria, triggers secretion of IL-1β secretion in human trophoblasts via Nod1 but independent of Nalp3 (NLRP3) inflammasomes (Kavathas et al., 2013). Murine macrophages lacking ASC display prolonged courses of infection with Chlamydia muridarum, associated with reduced IL-18 production as well as T cell recruitment and proliferation but exhibit normal levels of IL-1β secretion and no change oviduct pathology, suggesting ASC has an IL-1-independent role in adaptive immunity during genital chlamydial infection (Nagarajan et al., 2012). Cervical epithelial cells, however, are the preferred host medium for Chlamydia trachomatis and these cells do not normally produce IL-1β. Infection by Chlamydia trachomatis activates NLRP3/ASC/caspase-1 which instead alters lipid metabolism by caspase mediated fragmentation of the Golgi apparatus diversion of Golgi lipids to the Chlamydia intracellular inclusion. This provides an optimal growth environment for intracellular chlamydia and blocking casapase-1 in these cells can inhibit chlamydial infection by ~60% (Abdul-Sater et al., 2009).
  
  
Entity Chlamydia pneumonia
Note Chlamydia pneumonia is a significant cause of atypical pneumonia and inflammatory diseases including asthma and COPD, infects alveolar macrophages. IL-1β secretion depends on Chlamydia pneumonia entry into murine macrophages with subsequent protein synthesis resulting in mitochondrial dysfunction, NLRP3/ASC/Caspase-1 activation, and IL-1β secretion. This suggests an important role for ASC in clearing Chlamydia pneumonia infection as well as chronic inflammatory diseases affecting the airway (He et al., 2010; Shimada et al., 2011).
  
  
Entity Escherichia coli
Note Enterohemorrhagic E. coli (EHEC) O157:H7 enterohemolysin (Ehx) triggers NLRP3/ASC/caspase-1-dependent production of IL-1 in THP-1 macrophages (Zhang et al., 2012). As with salmonella, double-stranded RNA-dependent protein kinase (PKR, EIF2AK2) interacts with ASC and other inflammasome components including NLRP3, NLRP1, NLRC4 and AIM2 to trigger caspase-1-dependent IL-1β production and pryopoptosis in E. coli-infected macrophages IL-1β (Lu et al., 2012). Extracellular infection, however, requires ATP co-stimulation of the P2X7 receptor and potassium efflux for NLRC4/ASC-driven caspase-1 activation in macrophages (Franchi et al., 2007a).
  
  
Entity HSV
Note The nuclear promyelocytic leukemia (PML) protein limits formation of cytosolic ASC dimers in HSV-infected bone marrow macrophages with subsequent decreases in IL-1β secretion (Dowling et al., 2014).
  
  
Entity Legionella
Note Legionella avoids caspase-1 activation through downregulation of NLRC4 and ASC expression through an unknown mechanism (Abdelaziz et al., 2011; Pereira et al., 2011).
  
  
Entity Listeria
Note The AIM2/ASC inflammasome senses cytosolic double strand DNA from intracellular viruses and bacteria including Listeria and triggers caspase-1-dependent maturation of IL-1β and IL-18 (Franchi et al., 2007a; Jin et al., 2013).
  
  
Entity Malaria
Note Malaria is characterized by cyclical fevers and associated with high levels of IL-1β and other cytokines. Mice infected with plasmodium demonstrate caspase-1 activation dependent on ASC, NLRP3 and other inflammasome components. Pro-IL-1β production depends on secondary stimulation with LPS, IFN-γ or TNF-R1. Uric acid release during malaria infection may further augment host response via NLRP3 inflammasome activation. As a result of caspase-1 activation in plasmodium-infected mice, microbial stimulus results in extremely high levels of IL-1β and sensitivity to septic shock. IL-1R antagonist prevents bacterial-induced lethality in rodents. Peripheral blood monocytes in febrile malaria patients display activated caspase-1 and produce large amounts of IL-1β after stimulation with LPS, suggesting that NLRP3/ASC-dependent activation of caspase-1 is crucial to production of systemic IL-1β and hypersensitivity to sepsis during malaria infection (Ataide et al., 2014).
  
  
Entity Pseudomonas
Note Pseudomonas aeruginosa increases expression of human pattern recognition receptors including TLR2 and TLR4, proinflammatory cytokines including IL-1 and IFN-γ, and inflammasome components NLRP3, NLRC4 and ASC compared with control donor corneas. Putative molecules triggering this response are the bacterial pilus protein type IV pilin, as well as several type III secretion apparatus proteins (Franchi et al., 2007b; Arlehamn and Evans, 2011; Karthikeyan et al., 2013).
  
  
Entity Salmonella
Note ASC forms a complex with NLRP3, NLRC4, caspase-1, caspase-8 and pro-IL-1 in S. typhimurium-infected THP-1 macrophages (Broz et al., 2010; Man et al., 2013; Man et al., 2014). The nuclear promyelocytic leukemia (PML) protein limits formation of cytosolic ASC dimers in S. typhimurium-infected bone marrow macrophages with subsequent decreases in IL-1β and IL-18 secretion but no effect on pyroptotic cell death (Dowling et al., 2014). Double-stranded RNA-dependent protein kinase (PKR, EIF2AK2) interacts with ASC and other inflammasome components including NLRP3, NLRP1, NLRC4 and AIM2 to trigger caspase-1-dependent IL-1β production and pryopoptosis in S. typhimurium-infected macrophages (Lu et al., 2012). Salmonella flagellin and type III secretion proteins promotes potassium-efflux independent ASC oligomerization and NLRC4 inflammasome-dependent caspase-1 activation (Franchi et al., 2007a; Hwang et al., 2012).
  
  
Entity Schistosoma mansoni
Note Schistosoma infection activates the Dectin-2 receptor, which triggers NLRP3/ASC-dependent IL-1β secretion as well with subsequent alteration of the adaptive immune reponse, increased granuloma formation and liver disease (Ritter et al., 2010).
  
  
Entity Shigella
Note Shigella type III secretion proteins induce NLRC4/ASC/caspase-1-dependent processing of IL-1β and pyroptosome formation in macrophages (Suzuki et al., 2007; Willingham et al., 2007; Suzuki et al., 2014).
  
  
Entity Streptococcus pneumonia
Note ASC is involved in controlling pneumococcus infection via several putative downstream intermediates including IL-17, GM-CSF and adaptive immune regulatory genes (van Lieshout et al., 2014). ASC regulates systemic inflammatory responses to pneumococcal meningitis infection via caspase-1, IL-1, IL-18 and IFN-γ (Fang et al., 2011; Geldhoff et al., 2013). Bacterial keratitis caused by S. pneumonia pneumolysin triggers increased expression of inflammasome components NLRP3, NLRC4 and ASC compared with control donor corneas (Karthikeyan et al., 2013).
  
  
Entity Streptococcus pyogenes
Note ASC and NLP3 is necessary for caspase-1-dependent IL-1β secretion (but not pro-IL-1β expression) in response to S. Pyogenes infection. Caspase-1 activation activation in response to streptolysin O pore-forming toxin also depdends on NF-κB but not on P2X7R or TLR signaling (Harder et al., 2009).
  
  
Entity Tuberculosis
Note Mycobacterium tuberculosis infection induces NLRP3/ASC-dependent IL-1β secretion and apoptosis in bone marrow derived dendritic cells (Abdalla et al., 2012).
  
  
Entity West Nile virus
Note ASC is critical for clearance of west nile virus infection via secretion of IL-1β, IL-6, IFN-γ, and IFN-α as well as increased levels of IgM, suggesting a role for ASC in coordinating innate as well as adaptive immune reponses to west nile virus infection (Kumar et al., 2013).
  
  
Entity Vaccine adjuvent
Note ASC has an NLRP3/caspase-1-independent role in mediating antigen-specific immunity to oil-in-water adjuvent H5N1 influenza vaccine via B-cell antigen-specific antibody production and dendritic cell inflammatory cytokine release (Ellebedy et al., 2011).
  

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Cell Death Dis. 2013 May 23;4:e644. doi: 10.1038/cddis.2013.169.
PMID 23703389
 
Caspase-1 dependent IL-1b secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection.
Shimada K, Crother TR, Karlin J, Chen S, Chiba N, Ramanujan VK, Vergnes L, Ojcius DM, Arditi M.
PLoS One. 2011;6(6):e21477. doi: 10.1371/journal.pone.0021477. Epub 2011 Jun 23.
PMID 21731762
 
Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.
Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL.
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13501-6. Epub 2003 Oct 31.
PMID 14595024
 
The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways.
Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM, Sagara J, Reed JC.
J Exp Med. 2002 Dec 16;196(12):1605-15.
PMID 12486103
 
Methylation-mediated silencing of TMS1/ASC is accompanied by histone hypoacetylation and CpG island-localized changes in chromatin architecture.
Stimson KM, Vertino PM.
J Biol Chem. 2002 Feb 15;277(7):4951-8. Epub 2001 Dec 3.
PMID 11733524
 
Aberrant methylation and down-regulation of TMS1/ASC in human glioblastoma.
Stone AR, Bobo W, Brat DJ, Devi NS, Van Meir EG, Vertino PM.
Am J Pathol. 2004 Oct;165(4):1151-61.
PMID 15466382
 
Shigella type III secretion protein MxiI is recognized by Naip2 to induce Nlrc4 inflammasome activation independently of Pkcd.
Suzuki S, Franchi L, He Y, Munoz-Planillo R, Mimuro H, Suzuki T, Sasakawa C, Nunez G.
PLoS Pathog. 2014 Feb 6;10(2):e1003926. doi: 10.1371/journal.ppat.1003926. eCollection 2014.
PMID 24516390
 
Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages.
Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nuez G.
PLoS Pathog. 2007 Aug 10;3(8):e111.
PMID 17696608
 
The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome.
Taxman DJ, Holley-Guthrie EA, Huang MT, Moore CB, Bergstralh DT, Allen IC, Lei Y, Gris D, Ting JP.
J Biol Chem. 2011 Jun 3;286(22):19605-16. doi: 10.1074/jbc.M111.221077. Epub 2011 Apr 12.
PMID 21487011
 
Cutting edge: ASC mediates the induction of multiple cytokines by Porphyromonas gingivalis via caspase-1-dependent and -independent pathways.
Taxman DJ, Zhang J, Champagne C, Bergstralh DT, Iocca HA, Lich JD, Ting JP.
J Immunol. 2006 Oct 1;177(7):4252-6.
PMID 16982856
 
Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation.
Van Opdenbosch N, Gurung P, Vande Walle L, Fossoul A, Kanneganti TD, Lamkanfi M.
Nat Commun. 2014;5:3209. doi: 10.1038/ncomms4209.
PMID 24492532
 
Pyrin Modulates the Intracellular Distribution of PSTPIP1.
Waite AL, Schaner P, Richards N, Balci-Peynircioglu B, Masters SL, Brydges SD, Fox M, Hong A, Yilmaz E, Kastner DL, Reinherz EL, Gumucio DL.
PLoS One. 2009 Jul 7;4(7):e6147. doi: 10.1371/journal.pone.0006147.
PMID 19584923
 
Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity.
Watanabe H, Gaide O, Petrilli V, Martinon F, Contassot E, Roques S, Kummer JA, Tschopp J, French LE.
J Invest Dermatol. 2007 Aug;127(8):1956-63. Epub 2007 Apr 12.
PMID 17429439
 
Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP.
Nat Immunol. 2011 May;12(5):408-15. doi: 10.1038/ni.2022. Epub 2011 Apr 10.
PMID 21478880
 
A role for the NLRP3 inflammasome in metabolic diseases--did Warburg miss inflammation?
Wen H, Ting JP, O'Neill LA.
Nat Immunol. 2012 Mar 19;13(4):352-7. doi: 10.1038/ni.2228. (REVIEW)
PMID 22430788
 
Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC.
Willingham SB, Bergstralh DT, O'Connor W, Morrison AC, Taxman DJ, Duncan JA, Barnoy S, Venkatesan MM, Flavell RA, Deshmukh M, Hoffman HM, Ting JP.
Cell Host Microbe. 2007 Sep 13;2(3):147-59.
PMID 18005730
 
IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation.
Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD.
J Immunol. 2010 Oct 15;185(8):4912-20. doi: 10.4049/jimmunol.1002046. Epub 2010 Sep 20.
PMID 20855874
 
Enterohemorrhagic Escherichia coli specific enterohemolysin induced IL-1? in human macrophages and EHEC-induced IL-1b required activation of NLRP3 inflammasome.
Zhang X, Cheng Y, Xiong Y, Ye C, Zheng H, Sun H, Zhao H, Ren Z, Xu J.
PLoS One. 2012;7(11):e50288. doi: 10.1371/journal.pone.0050288. Epub 2012 Nov 27.
PMID 23209696
 
A role for mitochondria in NLRP3 inflammasome activation.
Zhou R, Yazdi AS, Menu P, Tschopp J.
Nature. 2011 Jan 13;469(7329):221-5. doi: 10.1038/nature09663. Epub 2010 Dec 1.
PMID 21124315
 
Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC).
de Alba E.
J Biol Chem. 2009 Nov 20;284(47):32932-41. doi: 10.1074/jbc.M109.024273. Epub 2009 Sep 15.
PMID 19759015
 
NLRP3 and ASC differentially affect the lung transcriptome during pneumococcal pneumonia.
van Lieshout MH, Scicluna BP, Florquin S, van der Poll T.
Am J Respir Cell Mol Biol. 2014 Apr;50(4):699-712. doi: 10.1165/rcmb.2013-0015OC.
PMID 24164497
 

Citation

This paper should be referenced as such :
JH Dunn, M Fujita
PYCARD (PYD, CARD domain containing)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(4):291-301.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PYCARDID712ch16p12.html

External links

Nomenclature
HGNC (Hugo)PYCARD   16608
Cards
AtlasPYCARDID712ch16p12
Entrez_Gene (NCBI)PYCARD  29108  PYD and CARD domain containing
AliasesASC; CARD5; TMS; TMS-1; 
TMS1
GeneCards (Weizmann)PYCARD
Ensembl hg19 (Hinxton)ENSG00000103490 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000103490 [Gene_View]  ENSG00000103490 [Sequence]  chr16:31201486-31202776 [Contig_View]  PYCARD [Vega]
ICGC DataPortalENSG00000103490
TCGA cBioPortalPYCARD
AceView (NCBI)PYCARD
Genatlas (Paris)PYCARD
WikiGenes29108
SOURCE (Princeton)PYCARD
Genetics Home Reference (NIH)PYCARD
Genomic and cartography
GoldenPath hg38 (UCSC)PYCARD  -     chr16:31201486-31202776 -  16p11.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PYCARD  -     16p11.2   [Description]    (hg19-Feb_2009)
EnsemblPYCARD - 16p11.2 [CytoView hg19]  PYCARD - 16p11.2 [CytoView hg38]
Mapping of homologs : NCBIPYCARD [Mapview hg19]  PYCARD [Mapview hg38]
OMIM606838   
Gene and transcription
Genbank (Entrez)AB023416 AF184073 AF255794 AF310103 AF384665
RefSeq transcript (Entrez)NM_013258 NM_145182 NM_145183
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PYCARD
Cluster EST : UnigeneHs.499094 [ NCBI ]
CGAP (NCI)Hs.499094
Alternative Splicing GalleryENSG00000103490
Gene ExpressionPYCARD [ NCBI-GEO ]   PYCARD [ EBI - ARRAY_EXPRESS ]   PYCARD [ SEEK ]   PYCARD [ MEM ]
Gene Expression Viewer (FireBrowse)PYCARD [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)29108
GTEX Portal (Tissue expression)PYCARD
Human Protein AtlasENSG00000103490-PYCARD [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9ULZ3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9ULZ3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9ULZ3
Splice isoforms : SwissVarQ9ULZ3
PhosPhoSitePlusQ9ULZ3
Domaine pattern : Prosite (Expaxy)CARD (PS50209)    DAPIN (PS50824)   
Domains : Interpro (EBI)CARD    CARD8/ASC/NALP1_CARD    DAPIN    DEATH-like_dom   
Domain families : Pfam (Sanger)CARD (PF00619)    PYRIN (PF02758)   
Domain families : Pfam (NCBI)pfam00619    pfam02758   
Domain families : Smart (EMBL)PYRIN (SM01289)  
Conserved Domain (NCBI)PYCARD
DMDM Disease mutations29108
Blocks (Seattle)PYCARD
PDB (SRS)1UCP    2KN6    3J63    5H8O   
PDB (PDBSum)1UCP    2KN6    3J63    5H8O   
PDB (IMB)1UCP    2KN6    3J63    5H8O   
PDB (RSDB)1UCP    2KN6    3J63    5H8O   
Structural Biology KnowledgeBase1UCP    2KN6    3J63    5H8O   
SCOP (Structural Classification of Proteins)1UCP    2KN6    3J63    5H8O   
CATH (Classification of proteins structures)1UCP    2KN6    3J63    5H8O   
SuperfamilyQ9ULZ3
Human Protein Atlas [tissue]ENSG00000103490-PYCARD [tissue]
Peptide AtlasQ9ULZ3
HPRD06020
IPIIPI00001699   IPI00221360   IPI00221362   
Protein Interaction databases
DIP (DOE-UCLA)Q9ULZ3
IntAct (EBI)Q9ULZ3
FunCoupENSG00000103490
BioGRIDPYCARD
STRING (EMBL)PYCARD
ZODIACPYCARD
Ontologies - Pathways
QuickGOQ9ULZ3
Ontology : AmiGOmyeloid dendritic cell activation  protease binding  activation of innate immune response  positive regulation of defense response to virus by host  myeloid dendritic cell activation involved in immune response  positive regulation of antigen processing and presentation of peptide antigen via MHC class II  positive regulation of adaptive immune response  interleukin-6 receptor binding  protein binding  tropomyosin binding  extracellular region  nucleus  nucleus  nucleolus  cytoplasm  cytoplasm  mitochondrion  endoplasmic reticulum  cytosol  cytosol  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  signal transduction  IkappaB kinase complex  IkappaB kinase complex  cysteine-type endopeptidase activator activity involved in apoptotic process  regulation of autophagy  regulation of tumor necrosis factor-mediated signaling pathway  myosin I binding  enzyme binding  positive regulation of actin filament polymerization  regulation of protein stability  negative regulation of NF-kappaB transcription factor activity  Pyrin domain binding  interleukin-1 beta production  negative regulation of interferon-beta production  positive regulation of interferon-gamma production  positive regulation of interleukin-6 production  positive regulation of tumor necrosis factor production  tumor necrosis factor-mediated signaling pathway  secretory granule lumen  azurophil granule lumen  positive regulation of activated T cell proliferation  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  identical protein binding  protein homodimerization activity  neuronal cell body  positive regulation of apoptotic process  regulation of GTPase activity  negative regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  neutrophil degranulation  ion channel binding  macropinocytosis  innate immune response  positive regulation of JNK cascade  positive regulation of interleukin-1 beta secretion  regulation of inflammatory response  positive regulation of phagocytosis  defense response to Gram-negative bacterium  positive regulation of T cell activation  positive regulation of DNA binding transcription factor activity  positive regulation of NF-kappaB transcription factor activity  positive regulation of NF-kappaB transcription factor activity  defense response to virus  positive regulation of ERK1 and ERK2 cascade  BMP receptor binding  cellular response to lipopolysaccharide  cellular response to interleukin-1  cellular response to tumor necrosis factor  negative regulation of protein serine/threonine kinase activity  intrinsic apoptotic signaling pathway by p53 class mediator  NLRP1 inflammasome complex  NLRP3 inflammasome complex  positive regulation of chemokine secretion  positive regulation of release of cytochrome c from mitochondria  cysteine-type endopeptidase activity involved in apoptotic process  AIM2 inflammasome complex  activation of cysteine-type endopeptidase activity  positive regulation of T cell migration  positive regulation of interleukin-8 secretion  positive regulation of interleukin-6 secretion  positive regulation of cysteine-type endopeptidase activity  positive regulation of interleukin-10 secretion  positive regulation of extrinsic apoptotic signaling pathway  regulation of intrinsic apoptotic signaling pathway  
Ontology : EGO-EBImyeloid dendritic cell activation  protease binding  activation of innate immune response  positive regulation of defense response to virus by host  myeloid dendritic cell activation involved in immune response  positive regulation of antigen processing and presentation of peptide antigen via MHC class II  positive regulation of adaptive immune response  interleukin-6 receptor binding  protein binding  tropomyosin binding  extracellular region  nucleus  nucleus  nucleolus  cytoplasm  cytoplasm  mitochondrion  endoplasmic reticulum  cytosol  cytosol  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  signal transduction  IkappaB kinase complex  IkappaB kinase complex  cysteine-type endopeptidase activator activity involved in apoptotic process  regulation of autophagy  regulation of tumor necrosis factor-mediated signaling pathway  myosin I binding  enzyme binding  positive regulation of actin filament polymerization  regulation of protein stability  negative regulation of NF-kappaB transcription factor activity  Pyrin domain binding  interleukin-1 beta production  negative regulation of interferon-beta production  positive regulation of interferon-gamma production  positive regulation of interleukin-6 production  positive regulation of tumor necrosis factor production  tumor necrosis factor-mediated signaling pathway  secretory granule lumen  azurophil granule lumen  positive regulation of activated T cell proliferation  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  identical protein binding  protein homodimerization activity  neuronal cell body  positive regulation of apoptotic process  regulation of GTPase activity  negative regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  neutrophil degranulation  ion channel binding  macropinocytosis  innate immune response  positive regulation of JNK cascade  positive regulation of interleukin-1 beta secretion  regulation of inflammatory response  positive regulation of phagocytosis  defense response to Gram-negative bacterium  positive regulation of T cell activation  positive regulation of DNA binding transcription factor activity  positive regulation of NF-kappaB transcription factor activity  positive regulation of NF-kappaB transcription factor activity  defense response to virus  positive regulation of ERK1 and ERK2 cascade  BMP receptor binding  cellular response to lipopolysaccharide  cellular response to interleukin-1  cellular response to tumor necrosis factor  negative regulation of protein serine/threonine kinase activity  intrinsic apoptotic signaling pathway by p53 class mediator  NLRP1 inflammasome complex  NLRP3 inflammasome complex  positive regulation of chemokine secretion  positive regulation of release of cytochrome c from mitochondria  cysteine-type endopeptidase activity involved in apoptotic process  AIM2 inflammasome complex  activation of cysteine-type endopeptidase activity  positive regulation of T cell migration  positive regulation of interleukin-8 secretion  positive regulation of interleukin-6 secretion  positive regulation of cysteine-type endopeptidase activity  positive regulation of interleukin-10 secretion  positive regulation of extrinsic apoptotic signaling pathway  regulation of intrinsic apoptotic signaling pathway  
REACTOMEQ9ULZ3 [protein]
REACTOME PathwaysR-HSA-844615 [pathway]   
NDEx NetworkPYCARD
Atlas of Cancer Signalling NetworkPYCARD
Wikipedia pathwaysPYCARD
Orthology - Evolution
OrthoDB29108
GeneTree (enSembl)ENSG00000103490
Phylogenetic Trees/Animal Genes : TreeFamPYCARD
HOVERGENQ9ULZ3
HOGENOMQ9ULZ3
Homologs : HomoloGenePYCARD
Homology/Alignments : Family Browser (UCSC)PYCARD
Gene fusions - Rearrangements
Fusion : QuiverPYCARD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPYCARD [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PYCARD
dbVarPYCARD
ClinVarPYCARD
1000_GenomesPYCARD 
Exome Variant ServerPYCARD
ExAC (Exome Aggregation Consortium)ENSG00000103490
GNOMAD BrowserENSG00000103490
Genetic variants : HAPMAP29108
Genomic Variants (DGV)PYCARD [DGVbeta]
DECIPHERPYCARD [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPYCARD 
Mutations
ICGC Data PortalPYCARD 
TCGA Data PortalPYCARD 
Broad Tumor PortalPYCARD
OASIS PortalPYCARD [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPYCARD  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPYCARD
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PYCARD
DgiDB (Drug Gene Interaction Database)PYCARD
DoCM (Curated mutations)PYCARD (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PYCARD (select a term)
intoGenPYCARD
NCG5 (London)PYCARD
Cancer3DPYCARD(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606838   
Orphanet
DisGeNETPYCARD
MedgenPYCARD
Genetic Testing Registry PYCARD
NextProtQ9ULZ3 [Medical]
TSGene29108
GENETestsPYCARD
Target ValidationPYCARD
Huge Navigator PYCARD [HugePedia]
snp3D : Map Gene to Disease29108
BioCentury BCIQPYCARD
ClinGenPYCARD
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD29108
Chemical/Pharm GKB GenePA134950175
Clinical trialPYCARD
Miscellaneous
canSAR (ICR)PYCARD (select the gene name)
Probes
Litterature
PubMed135 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePYCARD
EVEXPYCARD
GoPubMedPYCARD
iHOPPYCARD
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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