InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: PYCARD

Summary

InnateDB Protein

IDBP-28014.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

PYCARD

Protein Name

PYD and CARD domain containing

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000247470

InnateDB Gene

IDBG-28012 (PYCARD)

Protein Structure

UniProt Annotation

Function

Functions 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:0000269PubMed:11103777, ECO:0000269PubMed:12486103, ECO:0000269PubMed:12646168, ECO:0000269PubMed:14499617, ECO:0000269PubMed:14730312, ECO:0000269PubMed:15030775, ECO:0000269PubMed:16585594, ECO:0000269PubMed:16964285, ECO:0000269PubMed:16982856, ECO:0000269PubMed:17349957, ECO:0000269PubMed:17599095, ECO:0000269PubMed:19158675, ECO:0000269PubMed:19158676, ECO:0000269PubMed:19234215, ECO:0000269PubMed:19494289, ECO:0000269PubMed:21487011, ECO:0000269PubMed:22732093}.

Subcellular Localization

Cytoplasm. 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}.

Disease Associations

Tissue Specificity

Widely 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.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 48 experimentally validated interaction(s) in this database.
They are also associated with 5 interaction(s) predicted by orthology.

Experimentally validated
Total	48 [view]
Protein-Protein	45 [view]
Protein-DNA	3 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	5 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0005515	protein binding
GO:0008656	cysteine-type endopeptidase activator activity involved in apoptotic process
GO:0032090	Pyrin domain binding
GO:0042803	protein homodimerization activity

Biological Process

GO:0001773	myeloid dendritic cell activation
GO:0002218	activation of innate immune response
GO:0002277	myeloid dendritic cell activation involved in immune response
GO:0002588	positive regulation of antigen processing and presentation of peptide antigen via MHC class II
GO:0002821	positive regulation of adaptive immune response
GO:0006915	apoptotic process
GO:0006919	activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0007165	signal transduction
GO:0010803	regulation of tumor necrosis factor-mediated signaling pathway
GO:0030838	positive regulation of actin filament polymerization
GO:0031647	regulation of protein stability
GO:0032088	negative regulation of NF-kappaB transcription factor activity
GO:0032688	negative regulation of interferon-beta production
GO:0032729	positive regulation of interferon-gamma production
GO:0032755	positive regulation of interleukin-6 production
GO:0032760	positive regulation of tumor necrosis factor production
GO:0033209	tumor necrosis factor-mediated signaling pathway
GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0042104	positive regulation of activated T cell proliferation
GO:0042771	intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:0042981	regulation of apoptotic process
GO:0043065	positive regulation of apoptotic process
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043280	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0044351	macropinocytosis
GO:0045087	innate immune response (InnateDB)
GO:0046330	positive regulation of JNK cascade
GO:0050718	positive regulation of interleukin-1 beta secretion
GO:0050766	positive regulation of phagocytosis
GO:0050829	defense response to Gram-negative bacterium
GO:0050870	positive regulation of T cell activation
GO:0051091	positive regulation of sequence-specific DNA binding transcription factor activity
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0051607	defense response to virus
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0071222	cellular response to lipopolysaccharide
GO:0071347	cellular response to interleukin-1
GO:0071356	cellular response to tumor necrosis factor
GO:0071901	negative regulation of protein serine/threonine kinase activity
GO:0072332	intrinsic apoptotic signaling pathway by p53 class mediator
GO:0090197	positive regulation of chemokine secretion
GO:0090200	positive regulation of release of cytochrome c from mitochondria
GO:2000406	positive regulation of T cell migration
GO:2000484	positive regulation of interleukin-8 secretion
GO:2000778	positive regulation of interleukin-6 secretion
GO:2001056	positive regulation of cysteine-type endopeptidase activity
GO:2001181	positive regulation of interleukin-10 secretion
GO:2001238	positive regulation of extrinsic apoptotic signaling pathway
GO:2001242	regulation of intrinsic apoptotic signaling pathway

Cellular Component

GO:0005634	nucleus
GO:0005730	nucleolus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005783	endoplasmic reticulum
GO:0005829	cytosol
GO:0008385	IkappaB kinase complex
GO:0072558	NLRP1 inflammasome complex
GO:0072559	NLRP3 inflammasome complex
GO:0097169	AIM2 inflammasome complex