PYCARD

Summary

PYCARD (PYD and CARD domain containing, HGNC:16608) is a protein-coding gene on chromosome 16p11.2, encoding Apoptosis-associated speck-like protein containing a CARD (Q9ULZ3). Functions as a key mediator in apoptosis and inflammation.

This gene encodes an adaptor protein that is composed of two protein-protein interaction domains: a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD). The PYD and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the inflammatory and apoptotic signaling pathways via the activation of caspase. In normal cells, this protein is localized to the cytoplasm; however, in cells undergoing apoptosis, it forms ball-like aggregates near the nuclear periphery. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 29108 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 14 total
• Druggable target: yes
• MANE Select transcript: NM_013258

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16608
Approved symbol	PYCARD
Name	PYD and CARD domain containing
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	TMS-1, CARD5, ASC
Ensembl gene	ENSG00000103490
Ensembl biotype	protein_coding
OMIM	606838
Entrez	29108

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000247470, ENST00000350605, ENST00000561508, ENST00000565022

RefSeq mRNA: 2 — MANE Select: NM_013258 NM_013258, NM_145182

CCDS: CCDS10708, CCDS10709

Canonical transcript exons

ENST00000247470 — 3 exons

Exon	Start	End
ENSE00000675723	31202147	31202203
ENSE00001420974	31202417	31202760
ENSE00003600161	31201486	31201841

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.0611 / max 996.6123, expressed in 1572 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157144	35.1217	1570
157143	2.9394	989

Top tissues by expression

274 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.81	gold quality
mononuclear cell	CL:0000842	98.65	gold quality
leukocyte	CL:0000738	98.61	gold quality
granulocyte	CL:0000094	98.45	gold quality
mucosa of transverse colon	UBERON:0004991	98.35	gold quality
blood	UBERON:0000178	97.15	gold quality
mammalian vulva	UBERON:0000997	96.46	gold quality
penis	UBERON:0000989	96.25	gold quality
skin of leg	UBERON:0001511	95.90	gold quality
skin of abdomen	UBERON:0001416	95.85	gold quality
spleen	UBERON:0002106	95.85	gold quality
zone of skin	UBERON:0000014	95.15	gold quality
gingival epithelium	UBERON:0001949	94.93	gold quality
upper leg skin	UBERON:0004262	94.72	gold quality
palpebral conjunctiva	UBERON:0001812	93.87	gold quality
duodenum	UBERON:0002114	93.87	gold quality
gingiva	UBERON:0001828	93.84	gold quality
esophagus mucosa	UBERON:0002469	93.50	gold quality
bone marrow	UBERON:0002371	93.07	gold quality
nipple	UBERON:0002030	92.94	gold quality
transverse colon	UBERON:0001157	92.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.70	gold quality
bone marrow cell	CL:0002092	92.56	gold quality
pharyngeal mucosa	UBERON:0000355	92.35	gold quality
epithelium of nasopharynx	UBERON:0001951	92.26	gold quality
periodontal ligament	UBERON:0008266	92.24	gold quality
ileal mucosa	UBERON:0000331	91.94	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.84	gold quality
small intestine	UBERON:0002108	91.51	gold quality
right lung	UBERON:0002167	91.36	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	205.01
E-CURD-122	yes	76.95
E-HCAD-1	yes	72.63
E-MTAB-6701	yes	61.58
E-HCAD-10	yes	43.96
E-MTAB-10553	yes	39.56
E-HCAD-6	yes	37.33
E-CURD-46	yes	34.36
E-MTAB-9467	yes	29.16
E-MTAB-9221	yes	27.91
E-GEOD-134144	yes	27.82
E-MTAB-10287	yes	27.06
E-HCAD-9	yes	26.88
E-CURD-112	yes	25.39
E-CURD-88	yes	20.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GABPA, MYOD1, PAX6, TP53

Literature-anchored findings (GeneRIF, showing 40)

• Same as TMS1(target of methylation-induced silencing-1). TMS1/ASC found to be inactivated in association with promoter region methylation in human breast cancer cell lines and tumors. (PMID:11103776)
• Proapoptotic CARD protein. Subcellular redistribution into perinuclear spherical structure appears to precede the downstream activation of a caspase-9-mediated apoptotic pathway. Does not activate NK-kB-dependent transcription. (PMID:11103777)
• there are sites of protein binding and/or structural transitions define the boundaries of the unmethylated CpG island in normal cells and aberrant methylation overcomes these boundaries to direct change in chromatin structure, resulting in gene silencing. (PMID:11733524)
• The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. (PMID:11967258)
• ASC, which is composed of a PYD and a CARD, is up-regulated by inflammation and apoptosis in human neutrophils (PMID:12054656)
• inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1; a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta (PMID:12191486)
• findings suggest that ASC modulates diverse NF-kappaB induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses (PMID:12486103)
• Results suggest a direct role for aberrant methylation of the TMS1 gene in the progression of breast and gastric cancer involving down-regulation of the proapoptotic TMS1 gene. (PMID:12553049)
• there is a cryopyrin signaling pathway activated through the induced proximity of ASC, which is negatively regulated by pyrin (PMID:12615073)
• ASC is a mediator of NF-kappa B activation and Caspase-8-dependent apoptosis in an Ipaf signaling pathway (PMID:12646168)
• gene silencing and dense methylation are tightly coupled events that affect individual chromosomal copies of TMS1 in an all-or-none manner (PMID:12776200)
• Aberrant methylation of TMS1 is associated with pathogenesis of small cell, non small cell lung cancer and breast cancer (PMID:12800194)
• Downregulated by aberrant methylation of Tms1 is associated with melanoma (PMID:12949795)
• electrostatic interactions play an important role for the binding between PYRIN domains in ASC protein (PMID:14499617)
• ASC binds by its caspase recruitment domain (CARD) to procaspase-1 and to adapter proteins involved in caspase-1 activation, thereby regulating cytokine pro-IL-1 beta activation by this protease in monocytic leukemia THP-1 cells. (PMID:14634131)
• Methylation of ASC protein is associated with colorectal cancer (PMID:14643031)
• Results suggest that apoptosis-associated speck-like protein (ASC) can function as an adaptor molecule for Bax and regulate a p53-Bax mitochondrial pathway of apoptosis. (PMID:14730312)
• cellular location of pyrin mutant isoforms, in the presence or absence of ASC protein (PMID:14985395)
• ASC has a role in cryopyrin-induced interleukin 1beta secretion in monocytic cells (PMID:15020601)
• Methylation-mediated silencing of TMS1/ASC confers a survival advantage to ovarian tumor cells. (PMID:15041718)
• A coherent interaction surface is identified in apoptosis-associated speck-like protein containing a caspase recruitment domain, establishing a molecular model of PYRIN domain (PYD)-PYD complexes with an important role for charge-charge interactions. (PMID:15641782)
• caspase-8 plays an important role in the ASC-mediated NF-kappaB activation and IL-8 production, which actually induces physiologically relevant gene expression (PMID:15701651)
• data suggest that both pyrin and cryopyrin are capable of assembling independent inflammasome complexes with ASC and procaspase-1, and activating caspase-1 via ASC oligomerization (PMID:16037825)
• methylation of adjacent normal tissue occurs significantly more often in prostate cancer patients who later undergo biochemical recurrence, suggesting a role for inactivation of the ASC gene in the initial stages of aggressive disease (PMID:16425203)
• Epigenetic silencing of TMS1 may contribute to carcinogenesis (PMID:16715133)
• ASC expression correlates with IL-8 secretion and may play an important role in maintaining mucosal homeostasis (PMID:16777061)
• Study demonstrates that methylation-mediated silencing of TMS1/ASC is a frequent event in prostate cancer. (PMID:16848908)
• ASC, like death receptors, mediates two types of apoptosis depending on the cell type, in a manner involving caspase-8 (PMID:16964285)
• Hypermethylation of the proapoptotic gene TMS1 is associated with glioblastoma multiforme (PMID:17048097)
• Correlation was observed between promoter methylation and loss of protein expression confirming our hypothesis that promoter methylation is an important mechanism for transcriptional silencing of these genes in breast cancer (PMID:17599361)
• PSTPIP1 mutants require pyrin to induce formation of ASC pyroptosome, a molecular platform that recruits and activates caspase-1. (PMID:17964261)
• The ASC/TMS1 gene is frequently silenced in colorectal cancer due to promoter hypermethylation. (PMID:17986858)
• Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. (PMID:18263805)
• The pyrin domain of the ASC and NALP1 proteins were simulated at two different pH values, 3.7 and 6.5, with two different force-field parameter sets, and the molecular dynamics simulation trajectories were compared to NMR experimental data (PMID:18348116)
• Epigenetic silencing of TMS1 is associated with cancer (PMID:18701507)
• ASC is expressed in renal glomeruli of patients with familial mediterranean fever. High local ASC expression results in speck formation and the specks from dying cells may persist in the extracellular space where they may nucleate amyloid. (PMID:18791131)
• PYCARD appeared to play a central role in a stromal/hematopoietic cell coculture-dependent induction of genes relevant to the activation of caspase signaling and apoptosis (PMID:18945969)
• P. gingivalis causes ASC- and NLRP3-dependent necrosis (PMID:19201894)
• TMS1 is selectively down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary Ductal carcinoma in situ lesions. (PMID:19223547)
• Prevention of ASC cytosolic redistribution completely abolishes pathogen-induced inflammasome activity, which affirms that cytosolic localization of ASC is essential for inflammasome function. (PMID:19234215)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pycard	ENSMUSG00000030793
rattus_norvegicus	Pycard	ENSRNOG00000019675
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000819
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Apoptosis-associated speck-like protein containing a CARD — Q9ULZ3 (reviewed: Q9ULZ3)

Alternative names: Caspase recruitment domain-containing protein 5, PYD and CARD domain-containing protein, Target of methylation-induced silencing 1

All UniProt accessions (2): Q9ULZ3, H3BP42

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a 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 innate immune response by acting as an integral adapter in the assembly of various inflammasomes (NLRP1, NLRP2, NLRP3, NLRP6, AIM2 and probably IFI16) which recruit and activate caspase-1 leading to processing and secretion of pro-inflammatory cytokines. Caspase-1-dependent inflammation leads to macrophage pyroptosis, a form of cell death. The function as activating adapter in different types of inflammasomes is mediated by the pyrin and CARD domains and their homotypic interactions. Clustered PYCARD nucleates the formation of caspase-1 filaments through the interaction of their respective CARD domains, acting as a platform for of caspase-1 polymerization. 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 RIGI-triggered pro-inflammatory responses and inflammasome activation. 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. Modulates host resistance to DNA virus infection, probably by inducing the cleavage of and inactivating CGAS in presence of cytoplasmic double-stranded DNA. May have a regulating effect on the function as inflammasome adapter. Seems to inhibit inflammasome-mediated maturation of interleukin-1 beta.

Subunit / interactions. Self-associates; enforced oligomerization induces apoptosis, NF-kappa-B regulation and interleukin-1 beta secretion. Homooligomers can form disk-like particles of approximately 12 nm diameter and approximately 1 nm height. Next to isoform 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, NLRP6, NLRC4, 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, RIGI, RIPK2, PYDC1, PYDC2, NLRP10, CASP8, CHUK, IKBKB and BAX. Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis).

Subcellular location. Cytoplasm. Inflammasome. Endoplasmic reticulum. Mitochondrion. Nucleus Golgi apparatus membrane.

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. Expressed in lung epithelial cells (at protein level). 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.

Post-translational modifications. Phosphorylated. ‘Lys-63’-linked polyubiquitination by TRAF3 is critical for speck formation and inflammasome activation. ‘Lys-63’-linked deubiquitinated by USP50; a crucial step for NLRP3-mediated inflammasome activation. ‘Lys-63’-linked polyubiquitination by PELI1 is also critical for speck formation and inflammasome activation. Deubiquitinated by USP3 that cleaves ‘Lys-48’-linked ubiquitin chains and strengthens its stability by blocking proteasomal degradation.

Domain organisation. The CARD domain mediates interaction with CASP1 and NLRC4. The pyrin domain mediates homotypic interactions with pyrin domains of proteins such as of NLRP3, PYDC1, PYDC2 and AIM2.

Induction. In macrophages, up-regulated by endocannabinoid anandamide/AEA.

Miscellaneous. In breast tumorigenesis, methylation-mediated silencing may affect genes and proteins that act as positive mediators of cell death.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9ULZ3-1	1, fASC	yes
Q9ULZ3-2	2, Asc-b, vASC
Q9ULZ3-3	3, Asc-c

RefSeq proteins (2): NP_037390, NP_660183 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001315	CARD	Domain
IPR004020	DAPIN	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR033516	CARD8/ASC/NALP1_CARD	Domain
IPR051249	NLRP_Inflammasome	Family

Pfam: PF00619, PF02758

UniProt features (54 total): mutagenesis site 29, helix 14, domain 2, strand 2, cross-link 2, splice variant 2, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
6KI0	X-RAY DIFFRACTION	2
7E5B	X-RAY DIFFRACTION	2.29
9WZC	ELECTRON MICROSCOPY	2.45
9WZ7	ELECTRON MICROSCOPY	2.66
9WZB	ELECTRON MICROSCOPY	2.67
9WZD	ELECTRON MICROSCOPY	2.86
9WZ5	ELECTRON MICROSCOPY	2.91
9WZ8	ELECTRON MICROSCOPY	3.14
6N1H	ELECTRON MICROSCOPY	3.17
9WZ4	ELECTRON MICROSCOPY	3.21
3J63	ELECTRON MICROSCOPY	3.8
7KEU	ELECTRON MICROSCOPY	3.9
9WZH	ELECTRON MICROSCOPY	4.02
6K99	ELECTRON MICROSCOPY	4.1
5H8O	X-RAY DIFFRACTION	4.21
9WZG	ELECTRON MICROSCOPY	4.41
1UCP	SOLUTION NMR
2KN6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULZ3-F1	73.06	0.00

Antibody-complex structures (SAbDab): 1 — 5H8O

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 195, 55, 174

Mutagenesis-validated functional residues (29):

Position	Phenotype
12	abolishes promotion of apoptosis and nf-kappa-b activation.
13	abolishes interaction with pydc1.
13	abolishes interaction with nlrp2.
15	abolishes homooligomerization.
19	abolishes homooligomerization.
20	abolishes homooligomerization.
21	abolishes homooligomerization.
23	abolishes homooligomerization.
25	abolishes homooligomerization.
26	abolishes homooligomerization.
27	abolishes homooligomerization.
36	abolishes interaction with pydc1.
40	abolishes homooligomerization.
41	abolishes homooligomerization.
45	abolishes homooligomerization.
47	abolishes homooligomerization.
48	abolishes homooligomerization.
48	abolishes interaction with pydc1.
52	abolishes homooligomerization.
55	strongly reduced peli1-mediated ubiquitination.
56	abolishes homooligomerization.
62	abolishes homooligomerization.
67	abolishes homooligomerization.
68	abolishes homooligomerization.
72	abolishes homooligomerization.

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-5660668	CLEC7A/inflammasome pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-844456	The NLRP3 inflammasome
R-HSA-844615	The AIM2 inflammasome
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5621481	C-type lectin receptors (CLRs)
R-HSA-5663205	Infectious disease
R-HSA-622312	Inflammasomes
R-HSA-9658195	Leishmania infection
R-HSA-9664424	Cell recruitment (pro-inflammatory response)
R-HSA-9678108	SARS-CoV-1 Infection
R-HSA-9679506	SARS-CoV Infections
R-HSA-9692914	SARS-CoV-1-host interactions
R-HSA-9824443	Parasitic Infection Pathways
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 562 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_PINOCYTOSIS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (67): myeloid dendritic cell activation (GO:0001773), activation of innate immune response (GO:0002218), pattern recognition receptor signaling pathway (GO:0002221), positive regulation of defense response to virus by host (GO:0002230), myeloid dendritic cell activation involved in immune response (GO:0002277), positive regulation of antigen processing and presentation of peptide antigen via MHC class II (GO:0002588), positive regulation of adaptive immune response (GO:0002821), apoptotic process (GO:0006915), inflammatory response (GO:0006954), signal transduction (GO:0007165), osmosensory signaling pathway (GO:0007231), regulation of autophagy (GO:0010506), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), positive regulation of actin filament polymerization (GO:0030838), regulation of protein stability (GO:0031647), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), negative regulation of interferon-beta production (GO:0032688), positive regulation of chemokine production (GO:0032722), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), tumor necrosis factor-mediated signaling pathway (GO:0033209), positive regulation of activated T cell proliferation (GO:0042104), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), macropinocytosis (GO:0044351), NLRP3 inflammasome complex assembly (GO:0044546), innate immune response (GO:0045087), positive regulation of JNK cascade (GO:0046330), icosanoid biosynthetic process (GO:0046456), regulation of inflammatory response (GO:0050727), positive regulation of inflammatory response (GO:0050729), positive regulation of phagocytosis (GO:0050766), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830)

GO Molecular Function (15): protease binding (GO:0002020), interleukin-6 receptor binding (GO:0005138), tropomyosin binding (GO:0005523), myosin I binding (GO:0017024), enzyme binding (GO:0019899), protein-macromolecule adaptor activity (GO:0030674), Pyrin domain binding (GO:0032090), pattern recognition receptor activity (GO:0038187), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), transmembrane transporter binding (GO:0044325), protein dimerization activity (GO:0046983), BMP receptor binding (GO:0070700), cysteine-type endopeptidase activator activity (GO:0140608), protein binding (GO:0005515)

GO Cellular Component (22): Golgi membrane (GO:0000139), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), microtubule (GO:0005874), IkappaB kinase complex (GO:0008385), protein-containing complex (GO:0032991), secretory granule lumen (GO:0034774), azurophil granule lumen (GO:0035578), neuronal cell body (GO:0043025), canonical inflammasome complex (GO:0061702), NLRP1 inflammasome complex (GO:0072558), NLRP3 inflammasome complex (GO:0072559), AIM2 inflammasome complex (GO:0097169), NLRP6 inflammasome complex (GO:0140738), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Innate Immune System	3
Inflammasomes	2
CLEC7A (Dectin-1) signaling	1
Cell recruitment (pro-inflammatory response)	1
SARS-CoV-1-host interactions	1
Immune System	1
C-type lectin receptors (CLRs)	1
Disease	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Parasitic Infection Pathways	1
Leishmania infection	1
SARS-CoV Infections	1
Viral Infection Pathways	1
SARS-CoV-1 Infection	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	5
cellular anatomical structure	4
canonical inflammasome complex	4
intracellular membrane-bounded organelle	3
cytoplasm	3
positive regulation of cytokine production	2
nuclear lumen	2
cytosol	2
myeloid leukocyte activation	1
activation of immune response	1
positive regulation of innate immune response	1
innate immune response-activating signaling pathway	1
regulation of defense response to virus by host	1
myeloid dendritic cell activation	1
myeloid cell activation involved in immune response	1
immune response	1
antigen processing and presentation of peptide antigen via MHC class II	1
positive regulation of antigen processing and presentation of peptide or polysaccharide antigen via MHC class II	1
positive regulation of antigen processing and presentation of peptide antigen	1
regulation of antigen processing and presentation of peptide antigen via MHC class II	1
adaptive immune response	1
regulation of adaptive immune response	1
positive regulation of immune response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signal transduction	1
cellular response to osmotic stress	1
autophagy	1
regulation of catabolic process	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
actin filament polymerization	1
regulation of actin filament polymerization	1

Protein interactions and networks

STRING

1708 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PYCARD	CASP1	P29466	999
PYCARD	NLRP3	Q96P20	999
PYCARD	AIM2	O14862	998
PYCARD	CASP5	P51878	998
PYCARD	NLRC4	Q9NPP4	998
PYCARD	NLRP1	Q9C000	985
PYCARD	MEFV	O15553	978
PYCARD	CARD8	Q9Y2G2	967
PYCARD	NLRP6	P59044	940
PYCARD	IL18	Q14116	940
PYCARD	NAIP	Q13075	908
PYCARD	NLRP12	P59046	895
PYCARD	IL1B	P01584	894
PYCARD	IFI16	Q16666	888
PYCARD	NLRP7	Q8WX94	876

IntAct

147 interactions, top by confidence:

A	B	Type	Score
CHUK	IKBKB	psi-mi:“MI:0914”(association)	0.960
IKBKB	CHUK	psi-mi:“MI:0914”(association)	0.960
NLRP3	PYCARD	psi-mi:“MI:0407”(direct interaction)	0.950
PYCARD	NLRP3	psi-mi:“MI:0915”(physical association)	0.950
NLRP3	PYCARD	psi-mi:“MI:0915”(physical association)	0.950
NLRP3	PYCARD	psi-mi:“MI:0403”(colocalization)	0.950
MALT1	BCL10	psi-mi:“MI:0914”(association)	0.950
PYCARD	NLRP3	psi-mi:“MI:0403”(colocalization)	0.950
PYCARD	NLRP3	psi-mi:“MI:0407”(direct interaction)	0.950
AIM2	PYCARD	psi-mi:“MI:0915”(physical association)	0.890
PYCARD	AIM2	psi-mi:“MI:0915”(physical association)	0.890
PYCARD	AIM2	psi-mi:“MI:0407”(direct interaction)	0.890
AIM2	PYCARD	psi-mi:“MI:0407”(direct interaction)	0.890

BioGRID (151): PYCARD (Two-hybrid), PYCARD (Two-hybrid), DNAJC28 (Affinity Capture-MS), PSTPIP1 (Affinity Capture-MS), FAM184A (Affinity Capture-MS), PML (Affinity Capture-MS), INPP4B (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), CEP131 (Affinity Capture-MS), ARMC2 (Affinity Capture-MS), MYO1C (Affinity Capture-MS), IL6ST (Affinity Capture-MS), MCM4 (Affinity Capture-MS), TSHZ2 (Affinity Capture-MS), NUP107 (Affinity Capture-MS)

ESM2 similar proteins: A6QLE5, B0FPE9, D4A523, O08736, O14862, O35732, O62640, O77736, O89110, O95786, P25445, P29452, P43527, P55865, P55867, P57730, P70343, Q13158, Q14790, Q15121, Q153Z0, Q504J1, Q5R529, Q5RAV7, Q5U318, Q61160, Q62048, Q63199, Q645M6, Q6GZR1, Q6Q899, Q7RTR0, Q8HXK9, Q8IXQ6, Q8R4B8, Q8WXC3, Q91VJ1, Q920D5, Q92851, Q96P20

Diamond homologs: A1Z198, A6QLE5, A8Y3R9, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, P10775, P13489, P29315, P59044, P59046, P59047, Q0GKD5, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q5RAV7, Q63035, Q6B966, Q86W24, Q86W25, Q86W26, Q8CCN1, Q8HXK9, Q8HZP9, Q8R4B8, Q91VI7, Q91WS2, Q96P20, Q9C000, Q9EPB4, Q9I9N6, Q9ULZ3, Q9Y2G2

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PYCARD	up-regulates	BAX	relocalization
PYCARD	“form complex”	“AIM2 inflammasome”	binding
PYCARD	“form complex”	“NLRC4 inflammasome”	binding
PYCARD	“form complex”	“NLRP1 inflammasome”	binding
PYCARD	“form complex”	“NLRP3 inflammasome”	binding
PYCARD	“form complex”	“Pyrin inflammasome”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 62 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	6	51.0×	3e-07
CLEC7A (Dectin-1) signaling	6	20.4×	2e-05
Leishmania infection	5	19.4×	2e-04
Parasitic Infection Pathways	5	19.4×	2e-04
Programmed Cell Death	5	17.4×	3e-04
Signaling by Interleukins	8	12.2×	2e-05
Cytokine Signaling in Immune system	8	7.8×	2e-04
Innate Immune System	11	6.7×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
pattern recognition receptor signaling pathway	6	106.2×	3e-09
pyroptotic inflammatory response	7	63.8×	3e-09
positive regulation of interleukin-1 beta production	9	41.7×	5e-10
obsolete negative regulation of NF-kappaB transcription factor activity	5	32.0×	3e-05
tumor necrosis factor-mediated signaling pathway	5	29.5×	5e-05
obsolete positive regulation of NF-kappaB transcription factor activity	8	29.4×	5e-08
extrinsic apoptotic signaling pathway	5	27.4×	6e-05
positive regulation of inflammatory response	8	20.8×	6e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

14 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

196 predictions. Top by Δscore:

Variant	Effect	Δscore
16:31202411:GCTCA:G	donor_loss	1.0000
16:31202412:CTCAC:C	donor_loss	1.0000
16:31202413:TCAC:T	donor_loss	1.0000
16:31202414:CA:C	donor_loss	1.0000
16:31202415:AC:A	donor_gain	1.0000
16:31202416:C:CT	donor_loss	1.0000
16:31202416:CC:C	donor_gain	1.0000
16:31201837:CAGGC:C	acceptor_gain	0.9900
16:31201841:CCT:C	acceptor_loss	0.9900
16:31201842:C:CC	acceptor_gain	0.9900
16:31202415:A:AC	donor_gain	0.9900
16:31202416:C:CC	donor_gain	0.9900
16:31201838:AGGC:A	acceptor_gain	0.9800
16:31201839:GGC:G	acceptor_gain	0.9800
16:31201840:GCCT:G	acceptor_gain	0.9800
16:31201838:AGGCC:A	acceptor_gain	0.9700
16:31201839:GGCCT:G	acceptor_gain	0.9700
16:31201840:GC:G	acceptor_gain	0.9700
16:31201841:CC:C	acceptor_gain	0.9700
16:31201841:CCTG:C	acceptor_gain	0.9700
16:31201842:C:A	acceptor_gain	0.9700
16:31202415:ACC:A	donor_gain	0.9700
16:31202416:CCC:C	donor_gain	0.9700
16:31202416:CCCTG:C	donor_gain	0.9700
16:31201848:G:GC	acceptor_gain	0.9600
16:31202416:CCCT:C	donor_gain	0.9600
16:31201843:T:A	acceptor_gain	0.9500
16:31202141:CCTCA:C	donor_loss	0.9500
16:31202142:CTCA:C	donor_loss	0.9500
16:31202143:TCACC:T	donor_loss	0.9500

AlphaMissense

1247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:31202623:A:G	F23S	0.988
16:31202536:A:G	L52P	0.985
16:31201668:A:G	W169R	0.983
16:31201668:A:T	W169R	0.983
16:31202575:A:G	I39T	0.983
16:31202622:G:C	F23L	0.982
16:31202622:G:T	F23L	0.982
16:31202624:A:G	F23L	0.982
16:31202619:C:A	K24N	0.981
16:31202619:C:G	K24N	0.981
16:31201651:C:A	K174N	0.979
16:31201651:C:G	K174N	0.979
16:31201831:A:C	F114L	0.978
16:31201831:A:T	F114L	0.978
16:31201833:A:G	F114L	0.978
16:31202611:A:G	L27P	0.974
16:31201808:A:T	L122H	0.973
16:31202647:A:G	L15P	0.973
16:31201694:C:G	R160P	0.968
16:31202473:A:G	L73P	0.966
16:31202524:A:G	L56P	0.966
16:31201699:C:A	K158N	0.962
16:31201699:C:G	K158N	0.962
16:31202536:A:T	L52H	0.960
16:31201631:A:G	L181P	0.959
16:31201808:A:G	L122P	0.959
16:31201666:C:A	W169C	0.958
16:31201666:C:G	W169C	0.958
16:31201688:A:T	L162H	0.958
16:31201697:A:C	M159R	0.956

dbSNP variants (sampled 300 via entrez): RS1000722745 (16:31203915 G>A), RS1001049534 (16:31204109 A>G), RS1001661265 (16:31201367 T>C,G), RS1002321311 (16:31202869 C>G), RS1002787067 (16:31202511 G>C), RS1002986144 (16:31204549 G>A,T), RS1004785565 (16:31204467 C>T), RS1004859066 (16:31204225 C>T), RS1005527098 (16:31201452 A>C,G), RS1006459511 (16:31203214 T>G), RS1006751184 (16:31202283 G>A), RS1007889660 (16:31203815 T>C,G), RS1008004303 (16:31203594 G>C), RS1008185913 (16:31203882 A>G), RS1009682335 (16:31202146 C>G)

Disease associations

OMIM: gene MIM:606838 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003262_298	Post bronchodilator FEV1	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067324 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	58	nM	CHEMBL6170794
6.07	Kd	850	nM	CHEMBL6145386

CTD chemical–gene interactions

132 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, affects cotreatment, decreases reaction, increases abundance, increases expression	8
Acetylcysteine	decreases reaction, increases expression, increases reaction	7
Lipopolysaccharides	increases reaction, affects cotreatment, decreases expression, affects response to substance, decreases reaction (+1 more)	6
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression	6
Air Pollutants	decreases expression, increases abundance	5
Cadmium Chloride	increases abundance, increases expression, decreases reaction, affects reaction	5
bisphenol A	affects expression, decreases expression, increases methylation, decreases reaction	4
lipopolysaccharide, Escherichia coli O111 B4	affects reaction, decreases reaction, affects cotreatment, increases expression	4
Adenosine Triphosphate	decreases reaction, affects reaction, affects cotreatment, increases expression, decreases expression	4
Benzo(a)pyrene	decreases expression, increases expression	4
N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide	affects cotreatment, affects reaction, increases expression, decreases reaction	3
sodium arsenite	decreases expression, affects splicing, increases expression	3
Decitabine	affects methylation, affects expression, increases expression, increases reaction	3
Ethanol	decreases reaction, increases expression, affects cotreatment, increases abundance	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Uric Acid	affects reaction, increases secretion, affects binding, decreases reaction, increases reaction (+1 more)	3
ruscogenin	decreases reaction, increases expression	2
puerarin	decreases reaction, increases expression, increases reaction	2
entinostat	affects cotreatment, increases expression	2
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases reaction, increases expression, increases abundance	2
Arsenic Trioxide	decreases methylation, increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Cadmium	increases abundance, increases expression, affects reaction	2
Cisplatin	increases expression, affects cotreatment, decreases reaction	2
Glucose	affects cotreatment, decreases reaction, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	decreases reaction, increases expression, increases reaction	2
Smoke	decreases expression, increases abundance	2
Sodium Chloride	decreases reaction, increases expression, increases reaction, affects cotreatment, affects localization (+1 more)	2
Tetrachlorodibenzodioxin	increases expression	2

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652199	Binding	Binding affinity to human PYCARD incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0406	MAIL8-3	Transformed cell line	Female
CVCL_A8AN	THP1-KO-ASC	Cancer cell line	Male
CVCL_A8AT	THP1-ASC-GFP	Cancer cell line	Male
CVCL_A8GJ	MAIL8-19	Transformed cell line	Female
CVCL_F1UD	HyCyte THP-1 KO-hPYCARD	Cancer cell line	Male
CVCL_TH82	HAP1 PYCARD (-) 1	Cancer cell line	Male
CVCL_TH83	HAP1 PYCARD (-) 2	Cancer cell line	Male
CVCL_X598	THP1-defASC	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.