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
• GTEx eGene: eQTL in 14 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.53 (unconstrained)
• 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: 7 — 6 protein_coding, 1 retained_intron

MANE Select: ENST00000247470

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 3: 1

ENST00000247470, ENST00000350605, ENST00000561508, ENST00000565022, ENST00001096474, ENST00001096475, ENST00001136391

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.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, granulocyte, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PYCARD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

17 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	1.0e-14	-0.70	16:31160302:A:G
Cells Cultured fibroblasts	eqtl	1.8e-09	-0.47	16:31174133:A:G
Skin Sun Exposed Lower leg	eqtl	3.2e-06	-0.34	16:31167642:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.4e-05	-0.30	16:31172620:G:C
Nerve Tibial	eqtl	1.6e-03	-0.30	16:31201285:T:C
Lung	eqtl	1.7e-03	-0.28	16:31201285:T:C
Thyroid	eqtl	2.0e-03	-0.38	16:31201285:T:C
Cells EBV-transformed lymphocytes	eqtl	6.8e-03	-0.15	16:31249101:A:G
Adipose Subcutaneous	eqtl	1.0e-02	-0.26	16:31179567:G:A
Brain Putamen basal ganglia	eqtl	1.5e-02	-0.81	16:31172196:C:CT
Spleen	eqtl	1.6e-02	-0.63	16:31671559:T:C
Adipose Visceral Omentum	sqtl	1.6e-02	+0.26	16:31006233:T:C
Prostate	eqtl	1.8e-02	-0.34	16:31207480:T:C
Pancreas	sqtl	2.4e-02	-0.89	16:31594069:A:G
Esophagus Muscularis	eqtl	3.1e-02	+0.09	16:31653541:C:T
Colon Transverse	eqtl	3.8e-02	+0.06	16:31393146:T:G
Adipose Subcutaneous	sqtl	4.7e-02	+1.08	16:31511822:C:T

FANTOM5 promoters

2 alternative TSS:

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

Top tissues by expression

showing 100 of 274 tissues 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
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.22	gold quality
jejunal mucosa	UBERON:0000399	90.63	gold quality
oral cavity	UBERON:0000167	90.51	gold quality
vermiform appendix	UBERON:0001154	90.50	gold quality
colonic mucosa	UBERON:0000317	90.27	gold quality
nasal cavity mucosa	UBERON:0001826	89.72	gold quality
lower esophagus mucosa	UBERON:0035834	89.70	gold quality
skin of hip	UBERON:0001554	89.65	gold quality
upper arm skin	UBERON:0004263	89.61	gold quality
caecum	UBERON:0001153	89.54	gold quality
nasal cavity epithelium	UBERON:0005384	89.41	gold quality
upper lobe of left lung	UBERON:0008952	89.29	gold quality
stromal cell of endometrium	CL:0002255	89.15	gold quality
trabecular bone tissue	UBERON:0002483	89.13	gold quality
omental fat pad	UBERON:0010414	89.13	gold quality
peritoneum	UBERON:0002358	89.07	gold quality
mouth mucosa	UBERON:0003729	89.02	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.79	gold quality
upper lobe of lung	UBERON:0008948	88.79	gold quality
minor salivary gland	UBERON:0001830	88.63	gold quality
intestine	UBERON:0000160	88.50	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.43	gold quality
squamous epithelium	UBERON:0006914	88.39	gold quality
ectocervix	UBERON:0012249	88.29	gold quality
hair follicle	UBERON:0002073	88.22	gold quality
large intestine	UBERON:0000059	88.09	gold quality
colon	UBERON:0001155	88.05	gold quality
right coronary artery	UBERON:0001625	87.94	gold quality
vagina	UBERON:0000996	87.67	gold quality
esophagus	UBERON:0001043	87.35	gold quality
lymph node	UBERON:0000029	87.06	gold quality
epithelium of esophagus	UBERON:0001976	87.01	gold quality
right uterine tube	UBERON:0001302	86.96	gold quality
left uterine tube	UBERON:0001303	86.75	gold quality
esophagus squamous epithelium	UBERON:0006920	86.68	gold quality
parietal pleura	UBERON:0002400	86.65	gold quality
right ovary	UBERON:0002118	86.27	gold quality
saliva-secreting gland	UBERON:0001044	86.21	gold quality
endocervix	UBERON:0000458	86.19	gold quality
thymus	UBERON:0002370	86.09	gold quality
rectum	UBERON:0001052	86.05	gold quality
tongue squamous epithelium	UBERON:0006919	85.84	gold quality
amniotic fluid	UBERON:0000173	85.69	gold quality
tendon of biceps brachii	UBERON:0008188	85.56	gold quality
left coronary artery	UBERON:0001626	85.47	gold quality
descending thoracic aorta	UBERON:0002345	85.37	gold quality
cervix squamous epithelium	UBERON:0006922	85.36	gold quality
pleura	UBERON:0000977	85.33	gold quality
coronary artery	UBERON:0001621	85.19	gold quality
visceral pleura	UBERON:0002401	84.96	gold quality
tonsil	UBERON:0002372	84.83	gold quality
lung	UBERON:0002048	84.78	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.49	gold quality
left ovary	UBERON:0002119	84.47	gold quality
body of stomach	UBERON:0001161	84.44	gold quality
layer of synovial tissue	UBERON:0007616	84.41	gold quality
uterine cervix	UBERON:0000002	84.38	gold quality
thoracic aorta	UBERON:0001515	83.99	gold quality
synovial joint	UBERON:0002217	83.98	gold quality
ascending aorta	UBERON:0001496	83.78	gold quality
mucosa of stomach	UBERON:0001199	83.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.72	gold quality
lower lobe of lung	UBERON:0008949	83.62	gold quality
adipose tissue	UBERON:0001013	83.45	gold quality
connective tissue	UBERON:0002384	83.32	gold quality
cervix epithelium	UBERON:0004801	83.24	gold quality
right adrenal gland cortex	UBERON:0035827	83.00	gold quality
germinal epithelium of ovary	UBERON:0001304	82.79	gold quality
left adrenal gland	UBERON:0001234	82.77	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Duodenum	tissue	60.0	medium
Skin 1	tissue	48.1	medium
Spleen	tissue	43.5	high
Small intestine	tissue	41.7	medium
Bone marrow	tissue	40.9	high
Vagina	tissue	40.3	medium
Colon	tissue	31.5	low
Appendix	tissue	31.0	medium
Hypothalamus	tissue	21.0
Stomach 1	tissue	20.8	medium
Pons	tissue	20.3
Lung	tissue	20.1	high
Periaqueductal gray	tissue	19.9
Spinal cord	tissue	18.7
Corpus callosum	tissue	18.7
Substantia nigra	tissue	18.2
Medulla oblongata	tissue	18.1
Lymph node	tissue	17.9	high
Septum	tissue	16.7
Midbrain	tissue	16.0
Salivary gland	tissue	14.7	low
Thalamus	tissue	14.5
Putamen	tissue	13.5
Superior colliculi	tissue	13.4
Ventral forebrain	tissue	13.2
Tonsil	tissue	11.9	high
Amygdala	tissue	11.1
Adipose tissue	tissue	11.0	not detected
Hippocampal formation	tissue	11.0
Basal ganglia	tissue	10.5	medium
Pituitary gland	tissue	9.7
Breast	tissue	9.5	medium
Rectum	tissue	9.0	medium
Thymus	tissue	8.8
Choroid plexus	tissue	8.6
Ovary	tissue	8.3	not detected
Seminal vesicle	tissue	8.2	low
Urinary bladder	tissue	7.5	medium
Cervix	tissue	7.4	medium
Cerebral cortex	tissue	7.0	medium
Motor cortex	tissue	7.0
Fallopian tube	tissue	7.0	medium
Insular cortex	tissue	7.0
Esophagus	tissue	6.9	medium
Temporal cortex	tissue	6.9
Olfactory bulb	tissue	6.8
Locus coeruleus	tissue	6.7
Entorhinal cortex	tissue	6.5
Retrosplenial cortex	tissue	6.3
Prostate	tissue	6.0	medium
Caudate putamen	tissue	6.0
Prefrontal cortex	tissue	5.8
Placenta	tissue	5.8	low
Frontal cortex	tissue	5.7
Hippocampus	tissue	5.6	medium
Retrosplenial and cingulate cortex	tissue	5.6
Occipital cortex	tissue	5.6
Smooth muscle	tissue	5.4	not detected
Liver	tissue	5.4	medium
Adrenal gland	tissue	5.4	not detected

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Blood vessel (22.3), Lateral funiculus (white matter) (22.2), Dorsal spinal cord (18.7), White matter (18.7), Ventral spinal cord (17.3).

Regulation

Is transcription factor: no

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

Functional genomics

gnomAD constraint: pLI 0.000431, LOEUF 1.53, missense Z 0.276 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000247470 — one region, missense o/e 0.92.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1931465) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 24 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased interleukin-1 beta secretion	9
decreased interleukin-18 secretion	4
decreased circulating interleukin-18 level	3
decreased interleukin-1 alpha secretion	3
decreased susceptibility to endotoxin shock	3
abnormal macrophage physiology	2
decreased circulating interleukin-1 beta level	2
decreased inflammatory response	1
increased IgA level	1
decreased incidence of tumors by chemical induction	1
abnormal large intestine crypts of Lieberkuhn morphology	1
abnormal response to infection	1
decreased susceptibility to type IV hypersensitivity reaction	1
decreased NK cell number	1
enlarged Peyer’s patches	1
increased susceptibility to induced colitis	1
increased tumor necrosis factor secretion	1
decreased tumor necrosis factor secretion	1
increased interferon-beta secretion	1
decreased interferon-gamma secretion	1
decreased interleukin-6 secretion	1
increased IgG2c level	1
abnormal gut flora balance	1
increased susceptibility to Herpesvirales infection	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q8HXK9	75.4%	Diamond
Danio rerio	Q9I9N6	73.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
FUS	protein-coding	2521
PYDC1	protein-coding	260434
ITGAM	protein-coding	3684
TRIM72	protein-coding	493829
PYCARD-AS1	ncRNA	100652740
PRSS36	protein-coding	146547
PRSS8	protein-coding	5652
ITGAD	protein-coding	3681
ITGAX	protein-coding	3687

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). Interacts with FAM120A; this interaction inhibits inflammasome activation.

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 (56 total): mutagenesis site 29, helix 16, domain 2, cross-link 2, strand 2, splice variant 2, chain 1, modified residue 1, turn 1

Structure

Experimental structures (PDB)

18 structures by resolution:

PDB	Title	Method	Resolution (Å)
6KI0	Crystal Structure of Human ASC-CARD	X-RAY DIFFRACTION	2
7E5B	Crystal structure of ASC PYD Domain and Rb-B7	X-RAY DIFFRACTION	2.29
9WZC	R41E-ASC CARD filament	ELECTRON MICROSCOPY	2.45
9WZ7	Full-length ASCb filament	ELECTRON MICROSCOPY	2.66
9WZB	K21E/K22E-ASC CARD filament	ELECTRON MICROSCOPY	2.67
9WZD	R125E-ASC PYD filament	ELECTRON MICROSCOPY	2.86
9WZ5	Full-length ASC-CARD filament	ELECTRON MICROSCOPY	2.91
9WZ8	Full-length ASC-GFP PYD-filament	ELECTRON MICROSCOPY	3.14
6N1H	Cryo-EM structure of ASC-CARD filament	ELECTRON MICROSCOPY	3.17
9WZ4	Full-length ASC-PYD filament	ELECTRON MICROSCOPY	3.21
3J63	Unified assembly mechanism of ASC-dependent inflammasomes	ELECTRON MICROSCOPY	3.8
7KEU	Cryo-EM structure of the Caspase-1-CARD:ASC-CARD octamer	ELECTRON MICROSCOPY	3.9
9WZH	Full-length ASC-CARD filament	ELECTRON MICROSCOPY	4.02
6K99	Structure of ASC CARD filament	ELECTRON MICROSCOPY	4.1
5H8O	Crystal structure of an ASC-binding nanobody in complex with the CARD domain of ASC	X-RAY DIFFRACTION	4.21
9WZG	Full-length ASC-PYD filament	ELECTRON MICROSCOPY	4.41
1UCP	NMR structure of the PYRIN domain of human ASC	SOLUTION NMR
2KN6	Structure of full-length human ASC (Apoptosis-associated speck-like protein containing a …	SOLUTION NMR

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 5H8O

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol; nucleoli

Antibody reliability (HPA): IH enhanced · IF supported

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)

Type	Positions
Phosphoserine	195
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	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

5 curated (TAS) of 21; 11 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

21 pathways:

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

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 (61): 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 tumor necrosis factor-mediated signaling pathway (GO:0010803), positive regulation of actin filament polymerization (GO:0030838), regulation of protein stability (GO:0031647), 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), positive regulation of T cell activation (GO:0050870), protein homooligomerization (GO:0051260), defense response to virus (GO:0051607), pyroptotic inflammatory response (GO:0070269), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to lipopolysaccharide (GO:0071222), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), negative regulation of protein serine/threonine kinase activity (GO:0071901), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), positive regulation of release of cytochrome c from mitochondria (GO:0090200), apoptotic signaling pathway (GO:0097190), intrinsic apoptotic signaling pathway (GO:0097193), negative regulation of cytokine production involved in inflammatory response (GO:1900016), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), positive regulation of T cell migration (GO:2000406), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), regulation of intrinsic apoptotic signaling pathway (GO:2001242), immune system process (GO:0002376), defense response (GO:0006952), defense response to bacterium (GO:0042742), regulation of apoptotic process (GO:0042981), response to other organism (GO:0051707)

+1 more (showing top 60).

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 (20): 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), NLRP1 inflammasome complex (GO:0072558), NLRP3 inflammasome complex (GO:0072559), AIM2 inflammasome complex (GO:0097169), NLRP6 inflammasome complex (GO:0140738), canonical inflammasome complex (GO:0061702)

Reactome top-level categories

15 top-level categories:

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

showing 60 of 87 GO namespaces:

Category	Terms
protein binding	5
positive regulation of cytokine production	4
cellular anatomical structure	4
canonical inflammasome complex	4
intracellular membrane-bounded organelle	3
cytoplasm	3
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
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
regulation of biological quality	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
chemokine production	1
regulation of chemokine production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
enzyme binding	1
cytokine receptor binding	1
growth factor receptor binding	1
cytoskeletal protein binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 57 of 96 annotations. The rest are phylogenetic / computational / electronic (IEA).

57 experimentally-supported GO terms:

GO term	NS	Evidence
NLRP3 inflammasome complex assembly	BP	direct assay
apoptotic signaling pathway	BP	mutant phenotype
cellular response to interleukin-1	BP	direct assay
cellular response to lipopolysaccharide	BP	direct assay
cellular response to tumor necrosis factor	BP	direct assay
defense response to Gram-negative bacterium	BP	mutant phenotype
defense response to virus	BP	direct assay
intrinsic apoptotic signaling pathway by p53 class mediator	BP	mutant phenotype
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	BP	mutant phenotype
myeloid dendritic cell activation	BP	mutant phenotype
negative regulation of canonical NF-kappaB signal transduction	BP	direct assay
negative regulation of cytokine production involved in inflammatory response	BP	mutant phenotype
negative regulation of interferon-beta production	BP	mutant phenotype
negative regulation of protein serine/threonine kinase activity	BP	direct assay
positive regulation of ERK1 and ERK2 cascade	BP	mutant phenotype
positive regulation of JNK cascade	BP	mutant phenotype
positive regulation of T cell activation	BP	mutant phenotype
positive regulation of adaptive immune response	BP	mutant phenotype
positive regulation of apoptotic process	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	direct assay
positive regulation of chemokine production	BP	mutant phenotype
positive regulation of extrinsic apoptotic signaling pathway	BP	direct assay
positive regulation of inflammatory response	BP	direct assay
positive regulation of interleukin-1 beta production	BP	direct assay
positive regulation of interleukin-10 production	BP	mutant phenotype
positive regulation of interleukin-6 production	BP	mutant phenotype
positive regulation of interleukin-8 production	BP	mutant phenotype
positive regulation of non-canonical NF-kappaB signal transduction	BP	physical interaction
positive regulation of release of cytochrome c from mitochondria	BP	direct assay
positive regulation of tumor necrosis factor production	BP	mutant phenotype
protein homooligomerization	BP	direct assay
regulation of inflammatory response	BP	direct assay
regulation of intrinsic apoptotic signaling pathway	BP	direct assay
regulation of tumor necrosis factor-mediated signaling pathway	BP	mutant phenotype
tumor necrosis factor-mediated signaling pathway	BP	direct assay
AIM2 inflammasome complex	CC	direct assay
Golgi membrane	CC	direct assay
NLRP1 inflammasome complex	CC	direct assay
NLRP3 inflammasome complex	CC	direct assay
NLRP6 inflammasome complex	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
mitochondrion	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
protein-containing complex	CC	direct assay
BMP receptor binding	MF	physical interaction
Pyrin domain binding	MF	physical interaction
enzyme binding	MF	physical interaction
identical protein binding	MF	direct assay
interleukin-6 receptor binding	MF	physical interaction
myosin I binding	MF	physical interaction
protease binding	MF	physical interaction
protein dimerization activity	MF	direct assay
protein homodimerization activity	MF	direct assay
protein-macromolecule adaptor activity	MF	direct assay
tropomyosin binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,580 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PYCARD	CASP1	P29466	966
PYCARD	NLRP3	Q96P20	958
PYCARD	NLRC4	Q9NPP4	921
PYCARD	IL18	Q14116	903
PYCARD	IL1B	P01584	888
PYCARD	AIM2	O14862	882
PYCARD	NLRP2	Q9NX02	870
PYCARD	CASP5	P51878	861
PYCARD	NLRP7	Q8WX94	838
PYCARD	NLRP6	P59044	823
PYCARD	NLRP12	P59046	800
PYCARD	GSDMD	P57764	791
PYCARD	CARD8	Q9Y2G2	765
PYCARD	TLR4	O00206	731
PYCARD	NOD1	Q9Y239	725

IntAct

Human interaction partners of PYCARD in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

26 partners by confidence:

Partner	Interaction type	MIscore	Records
NLRP3	direct interaction	0.950	16
AIM2	physical association	0.890	12
CASP1	association	0.860	8
MEFV	physical association	0.800	10
BAX	physical association	0.620	7
PYDC2	physical association	0.600	4
SYK	physical association	0.590	2
EXOC5	physical association	0.560	5
NLRC3	physical association	0.560	3
NLRP1	physical association	0.560	1
NLRC4	physical association	0.550	1
IKBKB	association	0.510	3
CHUK	colocalization	0.510	1
PYDC1	physical association	0.460	2
N	association	0.430	4
SQSTM1	colocalization	0.430	2
CASP8	physical association	0.400	2
RIPK1	physical association	0.400	2
PAK1	physical association	0.400	1
PML	physical association	0.400	1
PRKAR1A	physical association	0.370	2
BCL10	association	0.350	1
GOT1	association	0.350	1
MYO1C	association	0.350	1
LAMP1	colocalization	0.270	1
RALB	colocalization	0.270	1

BioGRID (155 interactions; top human partners by supporting records): NLRP3 (Affinity Capture-Western; 18 records), SQSTM1 (Affinity Capture-Western; 8 records), CASP1 (Affinity Capture-Western; 5 records), USP3 (Affinity Capture-Western; 4 records), USP50 (Affinity Capture-Western; 4 records), BRCA1 (Affinity Capture-Western; 3 records), CASP8 (Affinity Capture-Western; 3 records), IFI16 (Co-localization; 3 records), ZFP91 (Affinity Capture-Western; 3 records), ARIH2 (Co-purification; 2 records), BIRC5 (Affinity Capture-MS; 2 records), CDK15 (Affinity Capture-MS; 2 records), CHUK (Affinity Capture-Western; 2 records), CUL2 (Affinity Capture-MS; 2 records), FCF1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

6 signaling 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

Protein complexes (CORUM) (20)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

20 complexes by size:

Complex	Subunits	Members
AIM2 PANoptosome complex	9	PYCARD, AIM2, MEFV, RIPK1, RIPK3, ZBP1, CASP1, CASP8, FADD
PANoptosome	7	CASP8, FADD, NLRP3, PYCARD, RIPK1, RIPK3, ZBP1
NLRP3-NLRC4 inflammasome	5	CASP1, CASP8, NLRC4, NLRP3, PYCARD
BCL10-CARD9-CASP8-MALT1-PYCARD inflammasome complex	5	MALT1, PYCARD, BCL10, CARD9, CASP8
NLRP1 inflammasome (CASP5)	4	CASP1, CASP5, NLRP1, PYCARD
Cardinal-NLRP3 inflammasome	4	CARD8, CASP1, NLRP3, PYCARD
Cardinal-NLRP2 inflammasome	4	CARD8, CASP1, NLRP2, PYCARD
NEK7-NLRP3 inflammasome	4	PYCARD, CASP1, NEK7, NLRP3
DHX9-NLRP9-PYCARD complex	3	DHX9, NLRP9, PYCARD
NLRP6 inflammasome	3	CASP1, NLRP6, PYCARD
NLRP7 inflammasome	3	NLRP7, PYCARD, CASP1
AIM2 inflammasome	3	PYCARD, AIM2, CASP1
AIM2 inflammasome (CASP8)	3	AIM2, CASP8, PYCARD
IFI16 inflammasome	3	CASP1, IFI16, PYCARD
MALT1-ASC-CASP8 inflammasome	3	CASP8, MALT1, PYCARD
NLRP12 inflammasome	3	CASP1, NLRP12, PYCARD
Pyrin inflammasome	3	PYCARD, CASP1, MEFV
NLRP1 inflammasome	3	PYCARD, CASP1, NLRP1
NLRP3 inflammasome	3	CASP1, NLRP3, PYCARD
DDX58-PYCARD complex	2	PYCARD, RIGI

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Leishmania infection	5	35.5×	2e-05
Parasitic Infection Pathways	5	35.5×	2e-05
CLEC7A (Dectin-1) signaling	5	31.0×	3e-05
Innate Immune System	8	8.9×	5e-05
Infectious disease	5	5.4×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
pattern recognition receptor signaling pathway	6	237.9×	1e-11
pyroptotic inflammatory response	7	143.0×	8e-12
positive regulation of interleukin-1 beta production	8	83.0×	8e-12
positive regulation of inflammatory response	7	40.7×	2e-08
protein maturation	5	32.7×	2e-05
positive regulation of canonical NF-kappaB signal transduction	7	20.3×	2e-06
positive regulation of apoptotic process	6	13.6×	1e-04
inflammatory response	8	12.1×	9e-06

Disease & clinical

Genetic variants

Variant evidence for PYCARD: 14 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 110):

Position(s)	Effect	Δscore	Sites
16:31202415–31202416	donor_loss	1.0000	5
16:31201842–31201843	acceptor_loss	0.9900	6
16:31202415	donor_loss	0.9700
16:31202145–31202146	donor_loss	0.9500	5
16:31202145	donor_loss	0.9300
16:31201848	acceptor_gain	0.9200
16:31202319	acceptor_gain	0.9000
16:31202325	acceptor_gain	0.9000
16:31202204–31202205	acceptor_loss	0.8600	6
16:31202212	acceptor_loss	0.8500

AlphaMissense

361 missense substitutions predicted likely pathogenic (of 1,247 scored), across 113 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M159	9	0.798	0.956
F114	8	0.855	0.978
D134	8	0.827	0.897
D51	8	0.602	0.730
F23	7	0.934	0.988
W169	7	0.899	0.983
F163	7	0.796	0.900
D54	7	0.795	0.890
K174	6	0.913	0.979
K24	6	0.880	0.981
D48	6	0.782	0.874
R125	6	0.770	0.887
R5	6	0.764	0.889
V149	6	0.736	0.943
D191	6	0.717	0.850
K158	5	0.836	0.962
K26	5	0.833	0.910
Y146	5	0.821	0.884
H118	5	0.819	0.920
F165	5	0.819	0.899

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	2.18e-05

Disease associations

OMIM: gene MIM:606838 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST003262_827	Post bronchodilator FEV1	1e-6

EFO canonical traits (from GWAS)

1 canonical traits:

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 (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

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

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]propanoyl]amino]-3-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	2252398: Binding affinity to Alexa647-labeled ASC (unknown origin) assessed as dissociation constant incubated for 5 mins by fluorescence spectra based analysis	kd	0.0580	uM
(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylpentanoyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]propanoyl]amino]-3-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	2252398: Binding affinity to Alexa647-labeled ASC (unknown origin) assessed as dissociation constant incubated for 5 mins by fluorescence spectra based analysis	kd	0.8500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases reaction, increases abundance, increases expression, decreases expression, affects cotreatment	8
Acetylcysteine	decreases reaction, increases expression, increases reaction	7
Lipopolysaccharides	increases expression, increases reaction, decreases expression, affects response to substance, affects cotreatment (+1 more)	7
Valproic Acid	increases expression, affects expression, decreases expression, affects cotreatment	6
Adenosine Triphosphate	affects cotreatment, decreases reaction, increases expression, decreases expression, affects reaction	5
Air Pollutants	increases abundance, decreases expression	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 cotreatment, increases expression, affects reaction, decreases reaction	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	increases expression, increases reaction, affects methylation, affects expression	3
Ethanol	decreases reaction, increases expression, affects cotreatment, increases abundance	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Uric Acid	increases expression, affects reaction, increases secretion, affects binding, decreases reaction (+1 more)	3
ruscogenin	decreases reaction, increases expression	2
puerarin	increases expression, increases reaction, decreases reaction	2
entinostat	increases expression, affects cotreatment	2
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases reaction, increases expression, increases abundance	2
Arsenic Trioxide	increases expression, affects cotreatment, decreases methylation	2
Panobinostat	increases expression, affects cotreatment	2
Cadmium	affects reaction, increases abundance, increases expression	2
Cisplatin	decreases reaction, increases expression, affects cotreatment	2
Glucose	decreases reaction, increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	increases reaction, decreases reaction, increases expression	2
Smoke	decreases expression, increases abundance	2
Sodium Chloride	decreases expression, decreases reaction, increases expression, increases reaction, affects cotreatment (+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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PYCARD across ~30M SureChEMBL compounds — explore on Sugi Predict.