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MGP004997

UniProt Annotations

Entry Information
Gene NamePYD and CARD domain containing
Protein EntryASC_HUMAN
UniProt IDQ9ULZ3
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=3; Name=1; Synonyms=fASC; IsoId=Q9ULZ3-1; Sequence=Displayed; Name=2; Synonyms=Asc-b, vASC; IsoId=Q9ULZ3-2; Sequence=VSP_004119; Name=3; Synonyms=Asc-c; IsoId=Q9ULZ3-3; Sequence=VSP_004118; Note=No experimental confirmation available.;
DomainThe CARD domain mediates interaction with CASP1 and NLRC4 (PubMed:14634131 and PubMed:11967258). {ECO:0000269|PubMed:11786556}.
DomainThe DAPIN domain mediates homotypic interactions with DAPIN domains of proteins such as of NLRP3, PYDC1 and AIM2 (PubMed:11786556, PubMed:12656673, PubMed:19158676 and PubMed:19158675). {ECO:0000269|PubMed:11786556}.
FunctionFunctions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the DAPIN and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. Isoform 2 may have a regulating effect on the function as inflammasome adapter. Isoform 3 seems to inhibit inflammasome- mediated maturation of interleukin-1 beta. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing. {ECO:0000269|PubMed:11103777, ECO:0000269|PubMed:12486103, ECO:0000269|PubMed:12646168, ECO:0000269|PubMed:14499617, ECO:0000269|PubMed:14730312, ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:16585594, ECO:0000269|PubMed:16964285, ECO:0000269|PubMed:16982856, ECO:0000269|PubMed:17349957, ECO:0000269|PubMed:17599095, ECO:0000269|PubMed:19158675, ECO:0000269|PubMed:19158676, ECO:0000269|PubMed:19234215, ECO:0000269|PubMed:19494289, ECO:0000269|PubMed:21487011, ECO:0000269|PubMed:22732093}.
InteractionO14862:AIM2; NbExp=5; IntAct=EBI-751215, EBI-6253193; Q07812:BAX; NbExp=7; IntAct=EBI-751215, EBI-516580; Q9C000:NLRP1; NbExp=5; IntAct=EBI-751215, EBI-1220518; Q96P20:NLRP3; NbExp=4; IntAct=EBI-751215, EBI-6253230; Q56P42:PYDC2; NbExp=4; IntAct=EBI-751215, EBI-6374418;
MiscellaneousIn breast tumorigenesis, methylation-mediated silencing may affect genes and proteins that act as positive mediators of cell death.
PtmPhosphorylated. {ECO:0000269|PubMed:12656673}.
Sequence CautionSequence=BAA91012.1; Type=Frameshift; Positions=4; Evidence={ECO:0000305};
SimilarityContains 1 CARD domain. {ECO:0000255|PROSITE- ProRule:PRU00046}.
SimilarityContains 1 DAPIN domain. {ECO:0000255|PROSITE- ProRule:PRU00061}.
Subcellular LocationCytoplasm. Endoplasmic reticulum. Mitochondrion. Nucleus. Note=Upstream of caspase activation, a redistribution from the cytoplasm to the aggregates occurs. These appear as hollow, perinuclear spherical, ball-like structures. Upon NLRP3 inflammasome activation redistributes to the perinuclear space localizing to endoplasmic reticulum and mitochondria. Localized primarily to the nucleus in resting monocytes/macrophages and rapidly redistributed to the cytoplasm upon pathogen infection. Localized to large cytoplasmic aggregate appearing as a speck containing AIM2, PYCARD, CASP8 and bacterial DNA after infection with Francisella tularensis (By similarity). {ECO:0000250}.
SubunitSelf-associates; enforced oligomerization induces apoptosis, NF-kappa-B regulation and interleukin-1 beta seceretion. Homooligomers can form disk-like particles of approximately 12 nm diameter and approximately 1 nm height. Next to isorm 1 also isoform 2 and isoform 3 may be involved in oligomerization leading to functional regulation. Component of several inflammasomes containing one pattern recognition receptor/sensor, such as NLRP1, NLRP2, NLRP3, AIM2, MEFV or NOD2, and probably NLRC4, NLRP12 or IFI16. Major component of the ASC pyroptosome, a 1-2 um supramolecular assembly (one per macrophage cell) which consists of oligomerized PYCARD dimers and CASP1. Interacts with CASP1 (precursor form); the interaction induces activation of CASP1 leading to the processing of interleukin-1 beta; PYCARD competes with RIPK2 for binding to CASP1. Interacts with NLRP3; the interaction requires the homooligomerization of NLRP3. Interacts with NLRP2, NLRC4, MEFV, CARD16, AIM2, IFI16, NOD2, DDX58, RIPK2, PYDC1, PYDC2, NLRP10, CASP8, CHUK, IKBKB and BAX. {ECO:0000269|PubMed:11374873, ECO:0000269|PubMed:11498534, ECO:0000269|PubMed:11786556, ECO:0000269|PubMed:11967258, ECO:0000269|PubMed:12191486, ECO:0000269|PubMed:12486103, ECO:0000269|PubMed:12646168, ECO:0000269|PubMed:12656673, ECO:0000269|PubMed:14634131, ECO:0000269|PubMed:14730312, ECO:0000269|PubMed:15020601, ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:15096476, ECO:0000269|PubMed:15456791, ECO:0000269|PubMed:16585594, ECO:0000269|PubMed:17178784, ECO:0000269|PubMed:17339483, ECO:0000269|PubMed:17599095, ECO:0000269|PubMed:18362139, ECO:0000269|PubMed:19158675, ECO:0000269|PubMed:19158676, ECO:0000269|PubMed:19915568, ECO:0000269|PubMed:21575908}.
Tissue SpecificityWidely expressed at low levels. Detected in peripheral blood leukocytes, lung, small intestine, spleen, thymus, colon and at lower levels in placenta, liver and kidney. Very low expression in skeletal muscle, heart and brain. Detected in the leukemia cell lines HL-60 and U-937, but not in Jurkat T- cell lymphoma and Daudi Burkitt's lymphoma. Detected in the melanoma cell line WM35, but not in WM793. Not detected in HeLa cervical carcinoma cells and MOLT-4 lymphocytic leukemia cells.
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