Affinage

PYCARD

Apoptosis-associated speck-like protein containing a CARD · UniProt Q9ULZ3

Length
195 aa
Mass
21.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PYCARD/ASC is a bipartite (PYD + CARD) adaptor that serves as the central scaffold of inflammasome complexes, transducing danger-sensor activation into caspase activation and inflammatory cell death (PMID:11967258). Cytosolic sensors engage ASC through homotypic PYD–PYD contacts—NLRP3-PYD binds ASC-PYD with high affinity (PMID:27432880) and AIM2 couples cytosolic dsDNA detection to ASC (PMID:19158675)—nucleating ASC into micron-scale specks. Assembly is a two-tier process: ASC-PYD polymerizes into a rigid tubular filament core while the mobile CARD cross-links these filaments into the compact speck (PMID:26464513, PMID:27329339, PMID:37945612), a higher-order architecture resolved at atomic and near-native resolution and recapitulated in vivo as intercrossed filament networks (PMID:28701426). Speck formation amplifies caspase-1-dependent IL-1β maturation but is dispensable for gasdermin-D cleavage and pyroptosis, defining ASC oligomerization as a signal-amplification device (PMID:27329339); full-length ASC, not isolated domains, is required for both speck formation and rapid death (PMID:11967258, PMID:28701426). ASC recruits effectors via two distinct death-fold interfaces—procaspase-1 through CARD–CARD contacts, gated by K+-dependent CARD accessibility (PMID:11967258, PMID:37402211), and procaspase-8 through ASC-PYD nucleation of caspase-8 tandem-DED filaments—driving an apoptotic arm including NLRC4- and TH17-associated programs (PMID:23645208, PMID:26468282, PMID:29491424, PMID:26998763). ASC function is tuned by extensive post-translational control: K63-linked ubiquitination (added by Peli1 at K55, removed by USP50) promotes ASC/NLRP3 interaction and oligomerization (PMID:28094437, PMID:34706239), USP3 removes K48 chains to block proteasomal degradation (PMID:36050480), tyrosine status (cAbl phosphorylation at Y146; requisite dephosphorylation at Y60/Y137) governs nucleation (PMID:31333677, PMID:33568399), SUMOylation via ZBTB16 modulates assembly (PMID:38123560), and IKKα/IKKi control nuclear-to-perinuclear translocation (PMID:25266676). Beyond canonical inflammasome signaling, ASC drives MAPK/ERK activation by suppressing DUSP10 (PMID:21487011), acts as a Bax adaptor in p53-dependent mitochondrial apoptosis (PMID:14730312), stabilizes HIF-1α to promote tumor cell invasion (PMID:32883954), and is selectively required for granuloma formation during chronic mycobacterial infection independently of NLRP3 and caspase-1 (PMID:20808838). Released extracellular ASC specks propagate inflammation in a prionoid manner by nucleating soluble ASC in recipient macrophages (PMID:24952505).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 2001 Medium

    Established that ASC engages an upstream pyrin-domain sensor (MEFV/pyrin) and that this interaction modulates ASC-driven speck formation and cell fate, first placing ASC in a PYD-based signaling module.

    Evidence Yeast two-hybrid, co-transfection co-localization, and survival assay in HeLa cells

    PMID:11498534

    Open questions at the time
    • No structural basis for the pyrin–ASC interface
    • Endogenous physiological context not tested
  2. 2002 High

    Defined ASC's bipartite logic—PYD as oligomerization domain, CARD as effector—showing full-length ASC oligomerizes procaspase-1 via CARD–CARD contacts to process pro-IL-1β, answering how an adaptor converts sensing into caspase activation.

    Evidence Co-IP, FKBP-inducible oligomerization domain swap, transfection and THP-1 siRNA

    PMID:11967258

    Open questions at the time
    • Did not resolve filament/speck ultrastructure
    • Sensor specificity upstream not addressed
  3. 2004 High

    Revealed an inflammasome-independent role for ASC as a Bax adaptor in p53-dependent mitochondrial apoptosis, expanding ASC function beyond IL-1β maturation.

    Evidence Reciprocal Co-IP, cytochrome c release, Bax-null cells, siRNA in cell lines

    PMID:14730312

    Open questions at the time
    • Domain requirement for Bax interaction not mapped
    • Relationship to ASC speck formation unclear
  4. 2006 Medium

    Showed ASC routes caspase-1 toward IL-1β processing and away from RIP2/NF-κB signaling, establishing ASC as a switch between inflammatory outputs.

    Evidence NF-κB reporter, Co-IP, siRNA, caspase-1-knockout macrophages

    PMID:16585594

    Open questions at the time
    • Mechanism of caspase-1 partitioning between partners not structurally defined
  5. 2009 High

    Identified AIM2 as a cytosolic dsDNA sensor that recruits ASC via PYD–PYD to assemble a functional caspase-1 inflammasome, broadening the repertoire of ASC-coupled sensors.

    Evidence Co-IP domain mapping, siRNA, NF-κB reporter, caspase-1 assay, viral infection

    PMID:19158675

    Open questions at the time
    • Stoichiometry of AIM2–ASC assembly not resolved
  6. 2011 High

    Demonstrated an inflammasome-independent ASC function in MAPK/ERK signaling through suppression of DUSP10, using genetic epistasis to separate it from NLRP3/NLRC4/caspase-1.

    Evidence shRNA, microarray network analysis, MAPK phosphorylation, multiple knockout macrophages

    PMID:21487011

    Open questions at the time
    • Direct ASC–DUSP10 interaction not demonstrated
    • Domain requirement unknown
  7. 2014 High

    Discovered that released extracellular ASC specks propagate inflammation in a prionoid fashion and act as autoantigens, redefining the speck as an intercellular danger signal.

    Evidence Confocal imaging, cell-free IL-1β maturation, phagocytosis/lysosomal damage assays, patient autoantibody detection

    PMID:24952505

    Open questions at the time
    • Determinants of speck stability in the extracellular milieu unclear
  8. 2014 Medium

    Defined spatial regulation of ASC by IKKα/IKKi-controlled nuclear-to-perinuclear translocation with PP2A relief, explaining how resting macrophages restrain inflammasome assembly.

    Evidence Co-IP, subcellular fractionation, kinase-dead mutants, PP2A recruitment, macrophage assays

    PMID:25266676

    Open questions at the time
    • Phosphosites on ASC mediating retention not mapped
    • Single lab
  9. 2015 High

    Solved the ASC filament architecture—rigid PYD core with mobile CARD—and validated PYD–PYD interfaces functionally, providing the structural basis for speck assembly.

    Evidence Cryo-EM, solid-state NMR, structure-based mutagenesis in macrophages (mouse)

    PMID:26464513

    Open questions at the time
    • CARD cross-linking geometry not resolved at the same resolution
  10. 2015 High

    Showed ASC-PYD nucleates procaspase-8 tandem-DED filaments via a heterotypic death-fold interaction overlapping the self-association surface, mechanistically coupling ASC to the apoptotic caspase-8 arm.

    Evidence In vitro filament nucleation, in vivo co-localization, ASC-PYD mutagenesis, Co-IP

    PMID:26468282

    Open questions at the time
    • Competition between caspase-8 and self-association in cells not quantified
  11. 2016 High

    Dissected speck assembly into PYD filament formation followed by CARD cross-linking and showed speck formation amplifies IL-1β processing but is dispensable for gasdermin-D cleavage/pyroptosis, defining ASC oligomerization as a signal amplifier.

    Evidence Systematic PYD/CARD mutagenesis in primary macrophages, IL-1β, gasdermin-D, pyroptosis readouts

    PMID:27329339

    Open questions at the time
    • Why pyroptosis bypasses speck requirement not fully explained
  12. 2016 Medium

    Quantified NLRP3-PYD/ASC-PYD binding showing higher affinity for the sensor than for self-association, clarifying how NLRP3 seeds ASC fibril nucleation.

    Evidence Solution NMR, analytical ultracentrifugation, structural modeling

    PMID:27432880

    Open questions at the time
    • In-cell relevance of measured affinities not tested
  13. 2016 Medium

    Identified a T cell-intrinsic ASC-NLRP3-caspase-8 inflammasome that sustains TH17 survival via autocrine IL-1β, extending ASC function to adaptive immunity in autoimmunity.

    Evidence T cell-specific ASC KO, caspase-8/IL-1β assays, TCR/ATP stimulation, EAE model

    PMID:26998763

    Open questions at the time
    • Caspase-8 vs caspase-1 dependence in T cells not fully separated
    • Single lab
  14. 2017 High

    Imaged endogenous ASC speck assembly, pyroptosis, and clearance in live zebrafish and resolved in vivo speck ultrastructure as intercrossed filament networks, validating filament-based assembly under native conditions.

    Evidence CRISPR endogenous tagging, live imaging, CLEM, 3D reconstruction (zebrafish)

    PMID:28701426

    Open questions at the time
    • Quantitative kinetics of human speck assembly not directly transferable
  15. 2017 Medium

    Identified USP50 as a K63-deubiquitinase of ASC required for NLRP3-driven caspase-1 cleavage and speck formation, establishing ubiquitin editing of ASC as a checkpoint.

    Evidence Co-IP, K63-DUB assay, USP50 siRNA, caspase-1/IL-1β/speck readouts in THP-1 and BMDM

    PMID:28094437

    Open questions at the time
    • Ubiquitination site on ASC not mapped in this study
    • Apparent context-dependent role versus later degradation findings
  16. 2018 High

    Used an unbiased CRISPR screen and gene-targeted mice to show NLRC4 drives an ASC- and caspase-8-dependent apoptotic program distinct from caspase-1 pyroptosis, formalizing ASC's apoptotic arm.

    Evidence Genome-wide CRISPR screen, ASC/caspase-8 KO mice, caspase-1 catalytic-dead knock-in

    PMID:29491424

    Open questions at the time
    • Molecular trigger choosing apoptosis vs pyroptosis not defined
  17. 2018 High

    Determined crystal structures of zebrafish ASC PYD and CARD and revealed a PYD–PYD caspase recruitment mode in fish, providing evolutionary contrast to mammalian CARD–CARD recruitment.

    Evidence X-ray crystallography, structure-guided mutagenesis, Co-IP of zASC–Caspy (zebrafish)

    PMID:29791979

    Open questions at the time
    • Mammalian PYD surface usage not directly compared functionally here
  18. 2020 Medium

    Revealed an inflammasome-independent ASC function stabilizing HIF-1α by reducing its hydroxylation and ubiquitination, linking ASC to tumor cell migration and invasion.

    Evidence Co-IP, fractionation, HIF-1α hydroxylation/ubiquitination assays, RNA-seq, invasion assays in OSCC

    PMID:32883954

    Open questions at the time
    • Direct enzymatic mechanism by which ASC blocks hydroxylation unclear
    • Single lab/tumor context
  19. 2010 High

    Demonstrated via genetic epistasis that ASC, but not NLRP3 or caspase-1, is required for granuloma formation and host protection in chronic M. tuberculosis infection, cementing an inflammasome-independent in vivo role.

    Evidence Aerosol infection of Pycard-/-, Nlrp3-/-, Casp1-/- mice; survival, burden, histology

    PMID:20808838

    Open questions at the time
    • Molecular effector pathway downstream of ASC in granuloma formation unknown
  20. 2021 High

    Showed cAbl phosphorylates ASC at Y146 to enable oligomerization and inflammasome activation, defining a positive tyrosine-phosphorylation input to assembly.

    Evidence CRISPR cABL KO, Y146A complementation, phospho/oligomerization/IL-1β assays in THP-1

    PMID:33568399

    Open questions at the time
    • Reconciliation with required dephosphorylation at other tyrosines not addressed here
  21. 2021 High

    Identified Peli1-mediated K63 ubiquitination of ASC at K55 as a selective promoter of NLRP3 (but not AIM2/NLRP1/NLRC4) inflammasome activation, mapping a sensor-specific ubiquitin switch.

    Evidence Co-IP, K63/K55-mapping mutagenesis, Peli1 KO cells and mice, peritonitis model

    PMID:34706239

    Open questions at the time
    • Why the modification is NLRP3-selective not mechanistically explained
  22. 2021 High

    Showed a 3'UTR SNP controls Pycard mRNA stability and ASC protein dosage to set inflammasome activity, establishing post-transcriptional regulation of ASC abundance.

    Evidence QTL mapping, mRNA stability, CRISPR single-base 3'UTR editing in mouse macrophages

    PMID:34197316

    Open questions at the time
    • trans-acting factor binding the SNP region not identified
  23. 2022 High

    Identified USP3 as a K48-deubiquitinase that stabilizes ASC against proteasomal degradation, defining abundance control as a determinant of inflammasome output in vivo.

    Evidence Co-IP, K48-DUB assay, proteasome inhibition, USP3-deficient mouse models

    PMID:36050480

    Open questions at the time
    • E3 ligase opposing USP3 on K48 chains not identified
  24. 2022 High

    Showed the ASCb splice isoform, differing only in PYD–CARD linker length, self-assembles more slowly into less compact structures, explaining isoform-specific reduction in inflammasome activity.

    Evidence Real-time NMR, DLS, SEC, TEM, docking with procaspase-1 CARD

    PMID:35007535

    Open questions at the time
    • Physiological abundance and regulation of ASCb in tissues not quantified
  25. 2023 High

    Resolved ASC puncta in NLRP3-activated cells as branched PYD-cored filaments permeated by ribosomes and vesicles, providing near-native cellular context for speck architecture.

    Evidence Correlative cryo-light microscopy and cryo-electron tomography

    PMID:37945612

    Open questions at the time
    • Functional consequence of organelle entrapment in the filament network unknown
  26. 2023 Medium

    Showed low intracellular K+ structurally exposes the ASC CARD to enhance procaspase-1 recruitment independently of NLRP3, linking the canonical K+-efflux trigger directly to ASC conformation.

    Evidence ASC oligomerization under varying K+, CARD accessibility and caspase-1 recruitment assays

    PMID:37402211

    Open questions at the time
    • Structural model of the K+-sensitive conformational change not solved
    • Single lab
  27. 2023 Medium

    Showed ZBTB16-promoted SUMOylation of ASC controls inflammasome assembly, and its ablation mitigates Muckle-Wells pathology, adding SUMO as a regulatory modification.

    Evidence SUMOylation assay, ZBTB16 KO in Muckle-Wells mouse model

    PMID:38123560

    Open questions at the time
    • Exact SUMO site on ASC not defined
    • Direct vs indirect ZBTB16 effect unclear
  28. 2023 High

    Demonstrated that K63 ubiquitination of ASC at K158/161 (driven pharmacologically via USP50 inhibition) targets the AIM2-ASC complex for SQSTM1/p62-mediated selective autophagy, defining an autophagic route for inflammasome termination.

    Evidence Site-specific ubiquitination, DARTS drug-target binding, Co-IP, autophagy flux, p62 siRNA, tendinopathy model

    PMID:37647255

    Open questions at the time
    • Physiological (non-pharmacological) trigger of this pathway not defined
  29. 2008 Low

    Linked stroma-induced PYCARD expression to TNF-α-dependent apoptosis in hematopoietic cells, an early correlative hint of microenvironment-regulated ASC function.

    Evidence Expression profiling, miRNA knockdown, caspase-3/apoptosis assays in co-culture

    PMID:18945969

    Open questions at the time
    • Single knockdown method with correlative expression data; mechanism not established
    • No direct ASC interaction partner identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing post-translational inputs (K63/K48 ubiquitination, tyrosine phosphorylation/dephosphorylation, SUMOylation) are integrated in time and space to license a single speck per cell, and how inflammasome-independent ASC functions are mechanistically partitioned from the canonical pathway, remain unresolved.
  • No unified model coupling modification state to assembly kinetics
  • Structural basis of CARD cross-linking in the speck incomplete
  • Mechanistic effectors of inflammasome-independent roles (granuloma, HIF-1α, MAPK) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005576 extracellular region 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
AIM2BAXCASP1CASP8MEFVNLRP3PELI1USP3
Complex memberships
AIM2 inflammasomeASC speck/filamentNLRC4 inflammasomeNLRP3 inflammasome

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ASC functions as a caspase-1-activating adaptor by interacting with procaspase-1 via CARD-CARD interactions and inducing its oligomerization. The PYRIN domain acts as an oligomerization domain while the CARD domain is the effector domain; full-length ASC (but not isolated domains alone) activates procaspase-1 and processes pro-IL-1β in transfected cells. Co-IP, FKBP12-inducible oligomerization domain swap, transfection/overexpression in HEK cells, siRNA knockdown in THP-1 cells The Journal of biological chemistry High 11967258
2001 Pyrin (the MEFV gene product) interacts with ASC via its pyrin domain (exon 1) in a yeast two-hybrid assay and co-localizes with ASC in cytosolic specks in HeLa cells. Co-expression of pyrin with ASC increases speck formation and promotes survival of speck-positive cells, modulating ASC-induced apoptosis. Yeast two-hybrid, co-transfection/immunofluorescence co-localization, cell survival assay The Journal of biological chemistry Medium 11498534
2004 ASC functions as a Bax adaptor in the p53-dependent mitochondrial apoptosis pathway. ASC directly interacts with Bax, co-localizes with Bax at mitochondria, induces cytochrome c release, loss of mitochondrial membrane potential, and activation of caspases-9, -2, and -3. Rapid apoptosis induction is absent in Bax-deficient cells, and siRNA knockdown of ASC inhibits Bax translocation to mitochondria after p53 or genotoxic insult. Co-IP, co-localization by fluorescence microscopy, cytochrome c release assay, mitochondrial membrane potential assay, Bax-deficient cell lines, siRNA knockdown Nature cell biology High 14730312
2009 AIM2 (PYHIN family member) binds cytosolic dsDNA via its HIN200 domain, while its pyrin domain associates with ASC. This AIM2-ASC interaction activates both NF-κB and caspase-1 as a functional inflammasome. Knockdown of AIM2 abrogates caspase-1 activation in response to cytoplasmic dsDNA. Co-IP (PYD-PYD interaction), siRNA knockdown, reporter assay for NF-κB, caspase-1 activity assay, viral infection model Nature High 19158675
2013 Procaspase-8 localizes to ASC inflammasome specks and binds directly to the pyrin domain of ASC. AIM2 and NLRP3 inflammasomes activate caspase-8 and caspase-1 leading to both apoptotic and pyroptotic cell death, with caspase-8 being the apical caspase in the ASC-dependent apoptotic pathway (with little requirement for caspase-9). Gene knockdown, fluorescence co-localization of procaspase-8 with ASC specks, direct binding assay (PYD-procaspase-8 interaction), cell death quantification with varying DNA concentrations Cell death and differentiation Medium 23645208
2014 After pyroptosis, ASC specks accumulate in the extracellular space where they continue to promote IL-1β maturation. Phagocytosis of extracellular ASC specks by macrophages causes lysosomal damage and nucleation of soluble ASC, activating IL-1β in recipient cells (prionoid propagation). Autoantibodies to ASC specks develop in patients and mice with autoimmune pathologies. Cell imaging (confocal microscopy), cell-free IL-1β maturation assay with extracellular specks, phagocytosis assay with lysosomal damage readout, autoantibody detection in patient samples Nature immunology High 24952505
2014 IKKα negatively regulates ASC-dependent inflammasomes by interacting with ASC in the nucleus of resting macrophages in an IKKα kinase-dependent manner. IKKi (IKK-related kinase) facilitates translocation of ASC from nucleus to perinuclear area during inflammasome activation; upon NLRP3 signal 2, PP2A is recruited and inhibits IKKα kinase activity, releasing ASC to participate in inflammasome assembly. Co-IP (ASC-IKKα interaction), subcellular fractionation/localization, kinase-dead mutant analysis, PP2A recruitment assay, macrophage inflammasome activation assays Nature communications Medium 25266676
2015 The structure of the mouse ASC filament was determined at atomic resolution by combining cryo-EM and solid-state NMR spectroscopy. ASC-PYD forms the rigid core of the filament while the CARD domain is highly mobile relative to this core. NMR identified specific PYD-PYD binding interfaces, and structure-based mutagenesis validated their functional relevance in macrophage inflammasome activation. Cryo-electron microscopy, solid-state NMR spectroscopy, structure-based site-directed mutagenesis, macrophage functional assays Proceedings of the National Academy of Sciences of the United States of America High 26464513
2016 ASC speck assembly involves two steps: oligomerization of ASC-PYD into filaments, and cross-linking of these filaments by ASC-CARD. ASC mutants with non-functional CARD only assemble filaments but not specks and disrupt endogenous specks. ASC speck formation is required for efficient IL-1β processing but is dispensable for gasdermin-D cleavage and pyroptosis induction, indicating that ASC oligomerization serves as a signal amplification mechanism for caspase-1-dependent cytokine production. Systematic site-directed mutagenesis of ASC-PYD, ASC-CARD mutant expression in primary macrophages, IL-1β processing assay, gasdermin-D cleavage assay, pyroptosis assay Nature communications High 27329339
2006 ASC directs caspase-1 away from RIP2-mediated NF-κB activation toward caspase-1-mediated IL-1β processing. ASC interferes with the caspase-1/RIP2 interaction in a dose-dependent manner, and siRNA knockdown of ASC in THP-1 cells decreases caspase-1 activity while enhancing NF-κB signaling. Co-transfection with NF-κB reporter gene assay, Co-IP (caspase-1/RIP2 interaction), siRNA knockdown, caspase-1-knockout macrophages Journal of immunology Medium 16585594
2011 ASC/PYCARD regulates MAPK (ERK) phosphorylation in an inflammasome-independent manner by suppressing the dual-specificity phosphatase DUSP10/MKP5. ASC also regulates chemokine induction independently of caspase-1 and IL-1β. MAPK activation by pathogen was abrogated in Asc-/- but not Nlrp3-/-, Nlrc4-/-, or Casp1-/- macrophages. ASC shRNA knockdown, microarray/network analysis, MAPK phosphorylation assay, comparison of Asc-/-, Nlrp3-/-, Nlrc4-/-, Casp1-/- macrophages The Journal of biological chemistry High 21487011
2015 ASC filaments nucleate procaspase-8 death effector domain (DED) filaments in vitro and in vivo. Interaction between ASC-PYD and procaspase-8 tandem DEDs requires both DEDs and represents a heterotypic interaction between death fold superfamily domains. ASC PYD mutagenesis showed that procaspase-8 interaction surfaces overlap with those required for ASC self-association. In vitro filament nucleation assay, in vivo co-localization, ASC-PYD mutagenesis, co-IP of ASC and procaspase-8 The Journal of biological chemistry High 26468282
2016 ASC-PYD self-associates and binds NLRP3-PYD through equivalent protein regions (located at opposite sides of the protein), with higher affinity for NLRP3-PYD than for itself. NLRP3-PYD coexists as monomer and large oligomeric species in solution. These binding interfaces allow multimeric complex formation consistent with ASC-PYD fibril assemblies. Solution NMR spectroscopy, analytical ultracentrifugation, structural modeling The Journal of biological chemistry Medium 27432880
2017 The deubiquitinating enzyme USP50 binds ASC and deubiquitinates K63-linked polyubiquitin chains on ASC. USP50 knockdown in THP-1 cells and BMDMs significantly decreases procaspase-1 cleavage, IL-1β/IL-18 secretion, and ASC speck formation/oligomerization upon NLRP3 stimuli. Co-IP (USP50-ASC binding), deubiquitination assay (K63-linked Ub), siRNA knockdown of USP50, caspase-1 cleavage assay, IL-1β/IL-18 ELISA, ASC speck formation assay FEBS letters Medium 28094437
2019 Tyrosine dephosphorylation of ASC is required for NLRP3 and AIM2 inflammasome activation. Site-directed mutagenesis identified tyrosine residues Y60 and Y137 of ASC as critical for inflammasome assembly and function (ASC nucleation, caspase-1 activation, IL-1β/IL-18 processing, and pyroptosis). Site-directed mutagenesis of ASC tyrosine residues (Y60, Y137), pharmacological PTPase inhibition (phenylarsine oxide), caspase-1 activation assay, IL-1β/IL-18 release assay, pyroptosis assay Frontiers in immunology Medium 31333677
2021 The E3 ubiquitin ligase Peli1 conjugates K63-linked ubiquitin chains specifically to lysine 55 of ASC, which facilitates ASC/NLRP3 interaction and ASC oligomerization, thereby promoting NLRP3 inflammasome activation. Peli1 deficiency impairs NLRP3-induced (but not AIM2, NLRP1, or NLRC4) caspase-1 activation and IL-1β maturation. Co-IP (ASC-Peli1 interaction), ubiquitination assay (K63-specific, lysine-55 mapping by mutagenesis), Peli1 knockout macrophages and mice, IL-1β secretion assay, peritonitis mouse model Cell reports High 34706239
2021 cAbl kinase phosphorylates ASC at tyrosine 146 (Y146), and this phosphorylation is required for ASC oligomerization and inflammasome activation. CRISPR/Cas9 deletion of cABL in THP-1 cells inhibits inflammasome function and reduces phosphorylated ASC release after LPS/ATP stimulation. Complementation of ASC-knockout cells with Y146A-mutant ASC abrogates inflammasome activation and ASC oligomerization. CRISPR/Cas9 cABL knockout, site-directed mutagenesis (Y146A), ASC phosphorylation assay, IL-18/IL-1β release assay, ASC oligomerization assay Journal of immunology High 33568399
2022 USP3 is a deubiquitinating enzyme that directly binds ASC, removes K48-linked ubiquitin chains, and stabilizes ASC protein by blocking proteasomal degradation. USP3 promotes inflammasome activation, confirmed in mouse models of alum-induced peritonitis, F. novicida infection, and flagellin-induced pneumonia. Co-IP (USP3-ASC), deubiquitination assay (K48-linked Ub), proteasome inhibitor experiments, USP3-deficient mice models (peritonitis, F. novicida, flagellin pneumonia) Cellular & molecular immunology High 36050480
2023 ZBTB16 (a nuclear zinc-finger/BTB domain protein) promotes SUMOylation of ASC, which controls ASC function in inflammasome assembly. Ablation of ZBTB16 in a mouse model of Muckle-Wells syndrome reduces acute inflammatory pathogenesis driven by constitutively hyperactive inflammasome. SUMOylation assay (ASC-SUMO modification), ZBTB16 knockout in Muckle-Wells mouse model, inflammasome activation assays Nature communications Medium 38123560
2023 Low intracellular K+ concentration causes a structural change in ASC oligomers that makes the ASC CARD domain more accessible for recruitment of the pro-caspase-1 CARD domain, thereby enhancing caspase-1 activation. This structural change in ASC is independent of NLRP3. ASC oligomerization assays under varying K+ conditions, domain accessibility experiments, caspase-1 recruitment assays The Journal of cell biology Medium 37402211
2023 Cryo-electron tomography of NLRP3-activated cells reveals that ASC puncta are composed of branched filaments with a tubular core formed by the PYD. Ribosomes and Golgi-like/endosomal vesicles permeate the ASC filament network. Mitochondria are not associated with ASC filaments but show outer-membrane discontinuities consistent with gasdermin D pores. Correlative cryo-light microscopy and cryo-electron tomography of NLRP3-activated cells Nature communications High 37945612
2017 In live zebrafish, CRISPR/Cas9-tagging of endogenous ASC showed strong expression in skin epithelia. Toxic stimulus triggered speck formation followed by rapid pyroptosis in keratinocytes, and macrophages engulfed and digested speck-containing pyroptotic debris. 3D ultrastructural reconstruction (CLEM) revealed compact networks of highly intercrossed filaments in in vivo specks. Full-length ASC (not PYD or CARD alone) is required to form a single compact speck and rapidly induce cell death. CRISPR/Cas9 endogenous tagging in zebrafish, live imaging, correlative light and electron microscopy (CLEM), 3D ultrastructural reconstruction The Journal of cell biology High 28701426
2022 The ASC alternative splicing isoform ASCb (differing from ASC only in the linker length between PYD and CARD) self-associates more slowly and into less compact macrostructures than ASC, with a reduced tendency to form densely packed filaments. This kinetic/structural difference, attributable solely to linker length, explains ASCb's reduced ability to activate the inflammasome compared to ASC. Real-time NMR, dynamic light scattering (DLS), size-exclusion chromatography, transmission electron microscopy, molecular docking with procaspase-1 CARD The Journal of biological chemistry High 35007535
2021 A SNP in the 3' UTR of the mouse Pycard gene (DBA/2 vs. AKR alleles) regulates ASC mRNA stability without altering transcription rate, leading to higher Pycard mRNA and ASC protein levels in DBA/2 macrophages and increased inflammasome speck formation. CRISPR/Cas9 editing of the DBA/2 3'UTR SNP to the AKR allele reduced Pycard expression and inflammasome activity, confirming a post-transcriptional regulatory mechanism. QTL mapping, mRNA stability assay, ASC protein quantification, inflammasome speck formation, CRISPR/Cas9 single-base editing of 3'UTR SNP eLife High 34197316
2010 PYCARD/ASC, but not NLRP3 or caspase-1, is required for granuloma formation and host protection during chronic Mycobacterium tuberculosis infection in vivo, revealing an inflammasome-independent role for ASC. Pycard-/- mice showed abrupt decrease in survival with defective granuloma formation, whereas Nlrp3-/- and Casp1-/- mice showed no difference from wild-type. Pycard-/-, Nlrp3-/-, and Casp1-/- mouse aerosol infection model, survival analysis, bacterial burden measurement, histological granuloma assessment, macrophage IL-1β secretion assay PloS one High 20808838
2020 ASC stabilizes HIF-1α protein in oral squamous cell carcinoma cells under normoxia by interacting with HIF-1α in both cytoplasm and nucleus. ASC interaction decreases HIF-1α hydroxylation (HIF-1α-OH) and ubiquitination without affecting VHL or PHD2 levels, thereby promoting HIF-1α-dependent transcription of genes driving cell migration and invasion. Co-IP (ASC-HIF-1α), subcellular fractionation, HIF-1α hydroxylation and ubiquitination assays, transcriptomic analysis (RNA-seq), HIF-1α synthesis inhibitor treatment, migration/invasion assays Cell death & disease Medium 32883954
2007 Pyrin-only protein 2 (POP2) co-localizes with ASC in perinuclear specks and disrupts ASC:CLR (CIAS1/NALP3) interactions, inhibiting speck formation by NLRP3. POP2 also modulates NF-κB activity through changes in nuclear import or distribution. Co-transfection/immunofluorescence co-localization, NF-κB reporter assay, speck formation assay with NLRP3 co-expression Journal of immunology Medium 17339483
2018 NLRC4 activates an ASC- and caspase-8-dependent apoptotic pathway that is distinct from caspase-1-mediated pyroptosis. A genome-wide CRISPR/Cas9 screen and gene-targeted mouse validation confirmed that ASC and caspase-8 are required for the NLRC4-dependent alternative apoptotic program. Caspase-1 catalytic dead knock-in BMDMs confirm that caspase-1 does not compete with ASC for NLRC4 interactions. Genome-wide CRISPR/Cas9 screen, gene-targeted (caspase-8, ASC knockout) mice, caspase-1 catalytic dead knock-in mice, cell death characterization Scientific reports High 29491424
2016 T cell-intrinsic ASC-NLRP3-caspase-8 inflammasome in TH17 cells drives IL-1β production upon ATP stimulation of the T cell antigen receptor, promoting autocrine TH17 cell survival during experimental autoimmune encephalomyelitis (EAE). T cell-specific ASC knockout, caspase-8 activation assay in T cells, IL-1β production assay, ATP stimulation of TCR-activated TH17 and TH1 cells, EAE mouse model Nature immunology Medium 26998763
2023 Pristimerin (PM) promotes K63-linked ubiquitination of ASC at K158/161 by inhibiting the deubiquitinase USP50 (through covalent binding at Cys53), which serves as a recognition signal for SQSTM1/p62-mediated selective autophagic degradation of the AIM2-ASC complex, thereby suppressing AIM2 inflammasome activation. Ubiquitination assay (K63-specific, K158/161 mapping), DARTS assay (PM binding to USP50 at Cys53), co-IP (AIM2-ASC), autophagy flux assay, SQSTM1/p62 siRNA, tendinopathy mouse model Autophagy High 37647255
2018 Zebrafish ASC (zASC) forms speck and filament structures when overexpressed in vitro and in vivo. Crystal structures of the N-terminal PYD and C-terminal CARD of zASC were determined. Structure-guided mutagenesis revealed functional relevance of the PYD hydrophilic surface. The fish caspase-1 homolog Caspy (not Caspy2) interacts with zASC via PYD-PYD interactions, differing from the mammalian CARD-CARD recruitment mechanism. Crystal structure determination (X-ray crystallography), structure-guided mutagenesis, co-IP (zASC-Caspy PYD-PYD interaction), in vitro and in vivo speck formation assays The FEBS journal High 29791979
2008 PYCARD expression is induced in hematopoietic KG1a cells by contact-dependent stroma-derived signals (co-culture with stromal cell line HS5), and suppression of PYCARD by miRNA inhibits stroma-dependent TNF-α-induced apoptosis and caspase-3 activation. Gene expression profiling (microarray), miRNA knockdown of PYCARD, caspase-3 activation assay, TNF-α-induced apoptosis assay in co-culture Blood Low 18945969

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2131 19158675
2011 Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature immunology 1492 21478880
2014 The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nature immunology 640 24952505
2002 The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. The Journal of biological chemistry 475 11967258
2013 AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell death and differentiation 439 23645208
2016 ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nature communications 343 27329339
2013 ASC speck formation as a readout for inflammasome activation. Methods in molecular biology (Clifton, N.J.) 259 23852599
2019 Propofol directly induces caspase-1-dependent macrophage pyroptosis through the NLRP3-ASC inflammasome. Cell death & disease 249 31316052
2001 Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. The Journal of biological chemistry 238 11498534
2004 ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nature cell biology 204 14730312
2014 ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Science translational medicine 163 25080478
2020 The ASC-1 Complex Disassembles Collided Ribosomes. Molecular cell 156 32579943
2020 β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia. Cell reports 153 32187546
2016 T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nature immunology 136 26998763
2015 Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy. Proceedings of the National Academy of Sciences of the United States of America 132 26464513
2010 Granuloma formation and host defense in chronic Mycobacterium tuberculosis infection requires PYCARD/ASC but not NLRP3 or caspase-1. PloS one 132 20808838
2010 Cutting edge: critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 128 20368281
2018 ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages. Scientific reports 121 29491424
2010 Exercise effects on methylation of ASC gene. International journal of sports medicine 115 20200803
2019 A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation. PLoS genetics 103 31086376
2006 ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions. Journal of immunology (Baltimore, Md. : 1950) 102 16585594
2014 IKKα negatively regulates ASC-dependent inflammasome activation. Nature communications 97 25266676
2021 Squamous intraepithelial lesions (SIL: LSIL, HSIL, ASCUS, ASC-H, LSIL-H) of Uterine Cervix and Bethesda System. CytoJournal 93 34345247
2018 The intra- and extracellular functions of ASC specks. Immunological reviews 88 29247990
2007 Pyrin-only protein 2 modulates NF-kappaB and disrupts ASC:CLR interactions. Journal of immunology (Baltimore, Md. : 1950) 88 17339483
2015 The Inflammasome Adaptor ASC Induces Procaspase-8 Death Effector Domain Filaments. The Journal of biological chemistry 84 26468282
2004 TMS1/ASC: the cancer connection. Apoptosis : an international journal on programmed cell death 81 14739594
2011 Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response. Proceedings of the National Academy of Sciences of the United States of America 80 22109549
2014 ASC-J9 suppresses renal cell carcinoma progression by targeting an androgen receptor-dependent HIF2α/VEGF signaling pathway. Cancer research 77 24924778
2021 Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway. Cell reports 76 34551296
2016 ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Using Equivalent Binding Interfaces. The Journal of biological chemistry 75 27432880
2014 NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling. Annals of the rheumatic diseases 73 25135254
2011 The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome. The Journal of biological chemistry 64 21487011
2020 The Inflammasome Adaptor Protein ASC in Mild Cognitive Impairment and Alzheimer's Disease. International journal of molecular sciences 61 32630059
2007 ASC/PYCARD and caspase-1 regulate the IL-18/IFN-gamma axis during Anaplasma phagocytophilum infection. Journal of immunology (Baltimore, Md. : 1950) 61 17878377
2019 Structure, interactions and self-assembly of ASC-dependent inflammasomes. Archives of biochemistry and biophysics 59 31152698
2021 Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases. Cell death & disease 58 34903717
2021 Peli1 facilitates NLRP3 inflammasome activation by mediating ASC ubiquitination. Cell reports 54 34706239
2007 ASC, Ipaf and Cryopyrin/Nalp3: bona fide intracellular adapters of the caspase-1 inflammasome. Microbes and infection 51 17382568
2022 Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases. Journal of neuroinflammation 48 36577999
2021 Asc-Seurat: analytical single-cell Seurat-based web application. BMC bioinformatics 48 34794383
2017 Dynamics of in vivo ASC speck formation. The Journal of cell biology 48 28701426
2020 The Inflammasome Signaling Proteins ASC and IL-18 as Biomarkers of Psoriasis. Frontiers in pharmacology 46 32903782
2021 Luteolin inhibits NLRP3 inflammasome activation via blocking ASC oligomerization. The Journal of nutritional biochemistry 41 33705947
2022 Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo. EMBO molecular medicine 40 35438238
2019 Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 40 31216943
2017 The deubiquitinating enzyme, ubiquitin-specific peptidase 50, regulates inflammasome activation by targeting the ASC adaptor protein. FEBS letters 38 28094437
2015 Prion pathogenesis in the absence of NLRP3/ASC inflammasomes. PloS one 35 25671600
2016 ASC contributes to metastasis of oral cavity squamous cell carcinoma. Oncotarget 33 27367024
2023 ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities. Journal of neuroinflammation 32 36740674
2023 Pristimerin suppresses AIM2 inflammasome by modulating AIM2-PYCARD/ASC stability via selective autophagy to alleviate tendinopathy. Autophagy 32 37647255
2023 Atranorin inhibits NLRP3 inflammasome activation by targeting ASC and protects NLRP3 inflammasome-driven diseases. Acta pharmacologica Sinica 31 36964308
2023 Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization. Nature communications 31 37945612
2020 Dual Role of Inflammasome Adaptor ASC in Cancer. Frontiers in cell and developmental biology 31 32117971
2019 Neuromodulatory Effect of NLRP3 and ASC in Neonatal Hypoxic Ischemic Encephalopathy. Neonatology 30 30909283
2008 Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD. Blood 30 18945969
2022 Inflammasome Activation and Pyroptosis via a Lipid-regulated SIRT1-p53-ASC Axis in Macrophages From Male Mice and Humans. Endocrinology 29 35136993
2021 Unknown/enigmatic functions of extracellular ASC. Immunology 29 34042182
2018 ASC-J9® suppresses prostate cancer cell invasion via altering the sumoylation-phosphorylation of STAT3. Cancer letters 29 29425687
2018 Apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) contributes to osteoblast differentiation and osteogenesis. Journal of cellular physiology 29 30171612
2013 Epigenetic regulation of ASC/TMS1 expression: potential role in apoptosis and inflammasome function. Cellular and molecular life sciences : CMLS 29 24287895
2020 Comprehensive review of ASC structure and function in immune homeostasis and disease. Molecular biology reports 28 32124174
2019 ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism. Mucosal immunology 28 31278375
2023 Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC. Nature communications 27 38123560
2017 Toxoplasma gondii GRA7-Targeted ASC and PLD1 Promote Antibacterial Host Defense via PKCα. PLoS pathogens 27 28125719
2017 Creation and Transplantation of an Adipose-derived Stem Cell (ASC) Sheet in a Diabetic Wound-healing Model. Journal of visualized experiments : JoVE 26 28809824
2014 NLRP3 and ASC differentially affect the lung transcriptome during pneumococcal pneumonia. American journal of respiratory cell and molecular biology 26 24164497
2024 Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD. Apoptosis : an international journal on programmed cell death 25 38652339
2023 TIGAR deficiency induces caspase-1-dependent trophoblasts pyroptosis through NLRP3-ASC inflammasome. Frontiers in immunology 25 37122710
2023 ASC-expressing pyroptotic extracellular vesicles alleviate sepsis by protecting B cells. Molecular therapy : the journal of the American Society of Gene Therapy 25 38093517
2019 Tyrosine Dephosphorylation of ASC Modulates the Activation of the NLRP3 and AIM2 Inflammasomes. Frontiers in immunology 25 31333677
2019 Adenovirus VA RNAI Blocks ASC Oligomerization and Inhibits NLRP3 Inflammasome Activation. Frontiers in immunology 25 31849970
2018 Detection of ASC Speck Formation by Flow Cytometry and Chemical Cross-linking. Methods in molecular biology (Clifton, N.J.) 25 29177861
2018 Functional and structural characterization of zebrafish ASC. The FEBS journal 25 29791979
2022 HDAC3 promotes pulmonary fibrosis by activating NOTCH1 and STAT1 signaling and up-regulating inflammasome components AIM2 and ASC. Cytokine 24 35306425
2020 Evolution of ASC Immunophenotypical Subsets During Expansion In Vitro. International journal of molecular sciences 24 32093036
2022 The Crosstalk Between Adipose-Derived Stem or Stromal Cells (ASC) and Cancer Cells and ASC-Mediated Effects on Cancer Formation and Progression-ASCs: Safety Hazard or Harmless Source of Tropism? Stem cells translational medicine 22 35274703
2022 USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation. Cellular & molecular immunology 22 36050480
2021 Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization. Toxicology and applied pharmacology 22 34019860
2020 Cutaneous wound healing: canine allogeneic ASC therapy. Stem cell research & therapy 22 32600465
2016 Silencing of ASC in Cutaneous Squamous Cell Carcinoma. PloS one 22 27768771
2021 Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes. JCI insight 21 34423792
2019 The Inflammasome Adaptor ASC Intrinsically Limits CD4+ T-Cell Proliferation to Help Maintain Intestinal Homeostasis. Frontiers in immunology 21 31379813
2018 Nanoscaled and microscaled parallel topography promotes tenogenic differentiation of ASC and neotendon formation in vitro. International journal of nanomedicine 21 30013341
2023 ASC oligomer favors caspase-1CARD domain recruitment after intracellular potassium efflux. The Journal of cell biology 20 37402211
2022 Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1. International journal of molecular sciences 19 35269698
2021 ASC Speck Formation after Inflammasome Activation in Primary Human Keratinocytes. Oxidative medicine and cellular longevity 19 34777694
2018 Alendronate augments lipid A-induced IL-1β release and Smad3/NLRP3/ASC-dependent cell death. Life sciences 19 29438662
2019 ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy. Annals of neurology 18 31794073
2017 ASC Methylation and Interleukin-1β Are Associated with Aerobic Capacity in Heart Failure. Medicine and science in sports and exercise 18 28072632
2014 Lidocaine-induced ASC apoptosis (tumescent vs. local anesthesia). Aesthetic plastic surgery 18 25099499
2012 ASC-dependent RIP2 kinase regulates reduced PGE2 production in chronic periodontitis. Journal of dental research 18 22828789
2024 FAM19A4 and hsa-miR124-2 Double Methylation as Screening for ASC-H- and CIN1 HPV-Positive Women. Pathogens (Basel, Switzerland) 16 38668267
2023 Salmonella Enteritidis T1SS protein SiiD inhibits NLRP3 inflammasome activation via repressing the mtROS-ASC dependent pathway. PLoS pathogens 16 37155697
2022 Inflammasome regulation by adaptor isoforms, ASC and ASCb, via differential self-assembly. The Journal of biological chemistry 16 35007535
2015 Purification and analysis of the interactions of caspase-1 and ASC for assembly of the inflammasome. Applied biochemistry and biotechnology 16 25567507
2022 Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC), the same or different entities? Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 15 35871081
2021 cAbl Kinase Regulates Inflammasome Activation and Pyroptosis via ASC Phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 15 33568399
2021 Genetic variant in 3' untranslated region of the mouse pycard gene regulates inflammasome activity. eLife 15 34197316
2020 ASC modulates HIF-1α stability and induces cell mobility in OSCC. Cell death & disease 15 32883954

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