Affinage

NLRC4

NLR family CARD domain-containing protein 4 · UniProt Q9NPP4

Length
1024 aa
Mass
116.2 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRC4 is a cytosolic NLR-family CARD-containing adaptor that nucleates an inflammasome to detect intracellular bacterial infection and drive caspase-1-dependent inflammation and cell death (PMID:11390368, PMID:15190255). It contains an N-terminal CARD that binds procaspase-1 directly through CARD-CARD interaction, a central nucleotide-binding domain, and a C-terminal LRR domain that sterically autoinhibits the protein in an ADP-stabilized closed monomeric state (PMID:11390368, PMID:23765277). Activation is initiated by NAIP receptor proteins, which directly bind bacterial flagellin (NAIP5) or type III secretion system rod/needle proteins (NAIP2, human NAIP), then engage NLRC4 and trigger a large conformational rearrangement that exposes a catalytic oligomerization surface; activated NLRC4 propagates its active conformation to recruit successive inactive monomers, building a wheel-like inflammasome that recruits and activates procaspase-1 (PMID:21918512, PMID:26449475, PMID:38177670, PMID:36604500). Through this pathway NLRC4 controls caspase-1 activation, IL-1β/IL-18 maturation, and pyroptosis in response to Salmonella, Legionella, Shigella, and Pseudomonas, restricting bacterial replication by regulating phagosome maturation and downstream caspase-7 activation (PMID:15190255, PMID:16648853, PMID:16648852, PMID:16984919, PMID:18070936, PMID:17935074, PMID:19343209). NLRC4-driven death proceeds through an ordered hierarchy: GSDMD-dependent pyroptosis by default, ASC/caspase-8-dependent apoptosis when pyroptosis is blocked, and caspase-1-triggered intrinsic apoptosis when both are unavailable (PMID:29491424, PMID:29262324, PMID:34678072). NAIP gene expression is transcriptionally licensed by IRF8 and an IRF8/PU.1/Brd4 complex, setting the threshold for inflammasome activation (PMID:29576451, PMID:33535228). Gain-of-function mutations in NLRC4 — including HD1 p.V341A and LRR p.W655C — cause constitutive inflammasome assembly, pyroptosis, and human autoinflammatory disease (PMID:25217960, PMID:25385754, PMID:29778503).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    Established NLRC4 as a caspase-1-engaging adaptor, defining the molecular basis by which it could couple upstream signals to caspase activation.

    Evidence Co-IP and deletion mutagenesis in transfected cells showing CARD-CARD binding to procaspase-1 and caspase-1 activation by an LRR-deleted constitutively active form

    PMID:11390368

    Open questions at the time
    • Did not identify the physiological upstream activator
    • Overexpression-based, not reconstituted with a defined ligand
  2. 2004 High

    Demonstrated a non-redundant physiological role: NLRC4 is the specific conduit linking intracellular bacterial sensing to caspase-1, distinct from ASC-dependent TLR signals.

    Evidence Ipaf-/- macrophages with Salmonella infection and caspase-1/cytokine/cell death readouts

    PMID:15190255

    Open questions at the time
    • The bacterial ligand sensed was not defined
    • Mechanism of NLRC4 engagement unknown
  3. 2006 High

    Identified the activating ligand and its delivery route, showing cytosolic flagellin delivered via a secretion system activates NLRC4 independently of TLR5.

    Evidence Cytoplasmic flagellin delivery and flagellin-mutant bacteria in Ipaf-/- macrophages (two simultaneous studies)

    PMID:16648852 PMID:16648853

    Open questions at the time
    • Direct flagellin-NLRC4 binding was not shown
    • Did not explain flagellin-independent activation by other pathogens
  4. 2006 High

    Extended NLRC4 function to antibacterial defense, showing it restricts intracellular replication by controlling phagosome maturation.

    Evidence Ipaf-/- and caspase-1-/- macrophages with Legionella replication and phagosome maturation tracking, plus in vivo infection

    PMID:16984919

    Open questions at the time
    • Molecular link between caspase-1 and phagosome-lysosome fusion not resolved here
  5. 2007 High

    Revealed pathogen-specific wiring and a link to autophagy, showing NLRC4 drives pyroptosis even when flagellin is dispensable and suppresses autophagy.

    Evidence Ipaf-/- and ASC-/- macrophages infected with Shigella and Pseudomonas, with cell death and autophagy readouts

    PMID:17696608 PMID:17935074 PMID:18070936

    Open questions at the time
    • Identity of the flagellin-independent activating signal unresolved
    • Mechanism of autophagy suppression undefined
  6. 2009 High

    Defined a downstream effector, placing caspase-7 activation under NLRC4/caspase-1 control to mediate bacterial restriction.

    Evidence Nlrc4-/-, caspase-1-/-, caspase-7-/- macrophages and mice with Legionella replication and lysosome fusion assays

    PMID:19343209

    Open questions at the time
    • Caspase-7 substrates in this context not defined
  7. 2011 High

    Solved how NLRC4 acquires ligand specificity, establishing NAIP proteins as the direct ligand receptors that hand off to NLRC4.

    Evidence Direct NAIP5-flagellin binding, NAIP5-NLRC4 co-IP, and reconstitution in non-macrophage cells with NAIP2/NAIP-ligand specificity

    PMID:21918512

    Open questions at the time
    • Structural basis of NAIP-induced NLRC4 conformational change not yet visualized
    • Stoichiometry of the complex unknown
  8. 2013 High

    Defined the autoinhibition mechanism structurally, explaining how NLRC4 is held monomeric until activation.

    Evidence X-ray crystal structure of mouse NLRC4 with mutagenesis of ADP-binding and domain-interface residues

    PMID:23765277

    Open questions at the time
    • Captured only the closed monomer, not the active oligomer
    • Did not show NAIP engagement
  9. 2015 High

    Visualized the active inflammasome, revealing self-propagating wheel-like oligomerization seeded by a single NAIP.

    Evidence Cryo-EM of reconstituted PrgJ-NAIP2-NLRC4 complex at 6.6 Å with oligomerization-interface analysis

    PMID:26449475

    Open questions at the time
    • Resolution limited atomic-level interpretation
    • Human complex not structurally resolved
  10. 2024 High

    Provided atomic-level mechanism for human inflammasome assembly via a lock-key NAIP activation model.

    Evidence Cryo-EM of human NAIP/NLRC4 with T3SS needle protein; plus unliganded NAIP5 cryo-EM defining the conformational trigger

    PMID:36604500 PMID:38177670

    Open questions at the time
    • Dynamics of protomer recruitment not directly observed
    • How priming modifications affect this transition unresolved
  11. 2012 High

    Proposed a priming step, identifying PKCδ phosphorylation of NLRC4 Ser533 as required for inflammasome function.

    Evidence Knock-in mice, in vitro PKCδ kinase assay, S533A/S533D reconstitution, and Prkcd-/- macrophages

    PMID:22885697

    Open questions at the time
    • Whether phosphorylation is universally required was later contested
    • Relationship to NAIP engagement initially unclear
  12. 2015 High

    Reconciled phosphorylation with ligand sensing as a biphasic model: Ser533 priming via flagellin D0 precedes NAIP5 sensing of the flagellin C-terminus.

    Evidence Naip5-/- and Nlrc4-/- macrophages, flagellin domain mutants, and H. pylori vs Y. enterocolitica infection with phospho-Ser533 readout

    PMID:25605939

    Open questions at the time
    • Kinase responsible in all settings not fully resolved
    • In vivo requirement remained debated
  13. 2020 Medium

    Challenged the Ser533 priming requirement, finding no need for the phosphorylation in vivo with new genetic models.

    Evidence New Nlrc4-/-, S533D, and S533A knock-in mice with caspase-1/IL-1β/pyroptosis assays and melanoma model

    PMID:32342103

    Open questions at the time
    • Negative result contradicting prior positive findings (PMID 22885697)
    • Strain or model differences not fully resolved
    • Single lab
  14. 2016 High

    Uncovered functional crosstalk between inflammasome scaffolds, showing NLRC4 can recruit NLRP3/ASC.

    Evidence Reciprocal co-IP of NLRC4-NLRP3 and genetic epistasis with S533A knock-in and Nlrp3-/- BMDMs

    PMID:27139490

    Open questions at the time
    • NLRP3 requirement contested by later work (PMID 32342103)
    • Physiological contribution of crosstalk unclear
  15. 2018 High

    Identified transcriptional licensing of the pathway, with IRF8 controlling Naip gene expression to enable NLRC4 activation selectively for bacterial sensors.

    Evidence IRF8-/- BMDMs, RNA-seq, ChIP at Naip promoters, and in vivo bacterial infection

    PMID:29576451

    Open questions at the time
    • Signals controlling IRF8 activity in this context not defined
  16. 2021 High

    Extended transcriptional control, showing Brd4 cooperates with IRF8/PU.1 to maintain Naip transcription.

    Evidence Brd4 conditional KO BMDMs/mice, ChIP of Brd4/IRF8/PU.1 at Naip promoters, and Salmonella infection

    PMID:33535228

    Open questions at the time
    • Whether Brd4 has direct inflammasome roles beyond transcription unknown
  17. 2018 High

    Defined alternative death programs, establishing that NLRC4 drives ASC/caspase-8 apoptosis when caspase-1/pyroptosis is unavailable.

    Evidence Caspase-1-/- macrophages and organoids, CRISPR screen, FADD/caspase-8/ASC genetic models, and c-FLIP regulation

    PMID:29262324 PMID:29491424

    Open questions at the time
    • In vivo relevance of the apoptotic branch quantified later
  18. 2021 High

    Established the full hierarchy of NLRC4-driven death as three ordered, complementary pathways.

    Evidence Combinatorial deletion of caspase-1, GSDMD, ASC, caspase-8, caspase-9 with mouse lethality and Salmonella infection

    PMID:34678072

    Open questions at the time
    • Tissue-specific contributions of each branch not dissected
  19. 2014 High

    Connected NLRC4 to human disease, showing gain-of-function mutations cause constitutive inflammasome activation and autoinflammation.

    Evidence Exome sequencing, patient macrophage functional assays (V341A), and transgenic mouse modeling of an autoinflammatory mutation

    PMID:25217960 PMID:25385754

    Open questions at the time
    • Genotype-phenotype correlation across mutations incomplete
  20. 2018 Medium

    Defined a structural mechanism for one disease mutation, implicating an LRR-LRR oligomerization interface.

    Evidence CRISPR knock-in THP-1 cells with W655C and mutagenesis of opposing LRR interface residues

    PMID:29778503

    Open questions at the time
    • Single lab; LRR-LRR interface model not corroborated structurally here
    • Generalizability to other mutations unclear
  21. 2021 High

    Identified a NAIP-independent NLRC4 inflammasome triggered by endogenous RNA, broadening the activation repertoire toward sterile/autoimmune contexts.

    Evidence Co-IP of DDX17-NLRC4-NLRP3-ASC complex, DDX17 KD/KO with functional readouts, SLE PBMCs, and AMD model

    PMID:34860583

    Open questions at the time
    • How DDX17 engages NLRC4 without NAIP undefined
    • Structural basis of the non-canonical complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NLRC4 priming, scaffold crosstalk (NLRP3), and non-canonical/NAIP-independent activation are integrated under physiological conditions remains unresolved, with the Ser533 and NLRP3 requirements directly contested.
  • Reconciliation of contradictory Ser533/NLRP3 requirements
  • Physiological scope of non-canonical DDX17 and PANoptosome complexes
  • Mechanism of NAIP-independent assembly

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CASP1DDX17NAIP2NAIP5NLRP3PRKCDPYCARDTBK1
Complex memberships
NAIP-NLRC4 inflammasomeNLRC4-NLRP3-ASC non-canonical inflammasomePANoptosome

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NLRC4 (Ipaf) was identified as a human Apaf-1-related protein containing an N-terminal CARD domain, a central nucleotide-binding domain, and a C-terminal LRR domain. Ipaf associates directly and specifically with the CARD domain of procaspase-1 through CARD-CARD interaction. An LRR-domain-deleted constitutively active form of Ipaf induced autocatalytic processing and activation of procaspase-1 and caspase-1-dependent apoptosis in transfected cells. Co-immunoprecipitation, overexpression in transfected cells, deletion mutagenesis, caspase activation assays The Journal of biological chemistry High 11390368
2004 Ipaf (NLRC4)-deficient macrophages fail to activate caspase-1 in response to intracellular Salmonella typhimurium but retain ATP-driven, TLR-stimulated caspase-1 activation (which requires ASC). Cell death triggered by caspase-1-engaging stimuli was ablated in macrophages lacking Ipaf, establishing Ipaf as providing a specific conduit to the inflammasome for intracellular pathogen signals. Knockout macrophages (Ipaf-/-, ASC-/-, RIP2-/- mice), caspase-1 activation assays, IL-1β/IL-18 maturation, cell death assays, Salmonella infection Nature High 15190255
2006 Cytosolic bacterial flagellin activates caspase-1 and IL-1β secretion through NLRC4 (Ipaf) independently of TLR5. Introduction of purified flagellin directly into the macrophage cytoplasm recapitulates Ipaf-dependent caspase-1 activation; a functional SPI1 type III secretion system is required to deliver flagellin to the cytosol. Ipaf-/- macrophages, cytoplasmic flagellin microinjection/delivery, caspase-1 activation and IL-1β secretion assays, flagellin mutant bacteria, TLR5 independence confirmed Nature immunology High 16648852 16648853
2006 Ipaf (NLRC4) restricts Legionella pneumophila replication in mouse macrophages by regulating phagosome maturation: in the absence of Ipaf or caspase-1 activation, the Legionella-containing phagosome acquires ER-derived vesicles and avoids lysosomal fusion, permitting bacterial replication. Flagellin and a competent type IV secretion system are required to activate caspase-1 through Ipaf. Ipaf-/- and caspase-1-/- macrophages, intracellular bacterial replication assays, phagosome maturation tracking, flagellin-deficient Legionella mutants, in vivo mouse infection The Journal of biological chemistry High 16984919
2007 NLRC4 (Ipaf) mediates caspase-1 activation and pyroptosis in Shigella-infected macrophages independently of flagellin (unlike Salmonella/Legionella). Ipaf is critical for pyroptosis while ASC is dispensable for cell death; absence of Ipaf or caspase-1 (but not ASC) markedly increases autophagy, revealing that Ipaf/caspase-1 suppresses autophagy during Shigella infection. Ipaf-/- and ASC-/- macrophages, caspase-1 activation assays, cell death (pyroptosis) measurement, autophagy quantification, 3-methyladenine inhibitor, flagellin-deficient Shigella PLoS pathogens High 17696608
2007 NLRC4 (IPAF) is required for caspase-1 activation and IL-1β release in macrophages infected with Pseudomonas aeruginosa in a flagellin-independent manner. IPAF- or caspase-1-deficient macrophages are markedly resistant to P. aeruginosa-induced cell death. The P. aeruginosa effector ExoU inhibits IPAF-dependent caspase-1-driven cytokine production. IPAF-/- and caspase-1-/- macrophages, P. aeruginosa infection, caspase-1 activation, IL-1β release, cell death assays, ExoU-expressing bacterial strains The Journal of experimental medicine High 17935074 18070936
2009 Caspase-7 is activated downstream of the NLRC4 inflammasome in a caspase-1-dependent manner during Legionella pneumophila infection of murine macrophages; this requires flagellin and functional Naip5. Caspase-7-deficient mice and macrophages are permissive to L. pneumophila replication due to defective lysosomal delivery and delayed cell death. Nlrc4-/-, caspase-1-/-, caspase-7-/- macrophages and mice, L. pneumophila infection, bacterial replication assays, lysosome fusion tracking PLoS pathogens High 19343209
2011 NAIP5 is a universal component of the flagellin-NLRC4 pathway: NAIP5 directly and specifically binds flagellin, and upon engagement promotes a physical NAIP5-NLRC4 association, enabling full reconstitution of a flagellin-responsive NLRC4 inflammasome in non-macrophage cells. NAIP2 functions analogously as a specific inflammasome receptor for T3SS rod proteins (e.g., PrgJ). Human NAIP (sole human NAIP) recognizes the T3SS needle protein CprI. Direct binding assays (NAIP5-flagellin), co-immunoprecipitation (NAIP5-NLRC4), reconstitution in non-macrophage cells, NAIP2/NAIP5 specificity assays with multiple bacterial ligands, genetic analysis with C. violaceum infection Nature High 21918512
2012 NLRC4 is phosphorylated on a single conserved residue Ser533 by PKCδ following Salmonella infection of macrophages. Phosphorylation of Ser533 is critical for NLRC4 inflammasome function: NLRC4 S533A fails to activate caspase-1, pyroptosis, or recruit procaspase-1, and does not assemble inflammasome specks. Phosphomimetic S533D causes rapid pyroptosis without infection. PKCδ phosphorylates NLRC4 S533 in vitro, and Prkcd-/- macrophages show attenuated caspase-1 activation specifically in response to S. typhimurium. Knock-in mice (NLRC4-3xFlag), phospho-Ser533 antibody, reconstitution with S533A/S533D mutants in Nlrc4-/- macrophages, in vitro kinase assay with recombinant PKCδ, immunodepletion of PKCδ from lysates, Prkcd-/- macrophages Nature High 22885697
2013 Crystal structure of mouse NLRC4 reveals its autoinhibition mechanism: ADP-mediated interaction between the NBD and WHD stabilizes the closed conformation; HD2 repressively contacts a conserved α-helix of the NBD; the LRR domain sterically occludes one face of the NBD to maintain NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions causes constitutive NLRC4 activation. X-ray crystallography (crystal structure of mouse NLRC4), site-directed mutagenesis of ADP-binding and domain-interface residues, functional activation assays Science High 23765277
2014 A de novo gain-of-function mutation in NLRC4 (p.Val341Ala) in the HD1 domain causes constitutive IL-1 family cytokine production, macrophage cell death, and an autoinflammatory syndrome. Macrophages from affected individuals show constitutive inflammasome component aggregation and pyroptosis. Whole-exome sequencing, in vitro functional assays in patient macrophages (cytokine production, cell death, inflammasome staining), cosegregation analysis Nature genetics High 25217960
2014 A missense mutation in NLRC4 promotes formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase IL-1β production, causing a familial cold autoinflammatory syndrome. Transgenic mice expressing mutant Nlrc4 develop dermatitis and arthritis dependent on IL-1β-mediated IL-17A production from neutrophils. Patient genetic analysis, in vitro inflammasome activation assays, transgenic mouse model, IL-1β/IL-17A cytokine measurements The Journal of experimental medicine High 25385754
2015 Cryo-EM structure of a PrgJ-NAIP2-NLRC4 complex at 6.6 Å reveals a wheel-like architecture in which NLRC4 activation involves substantial structural reorganization creating one oligomerization (catalytic) surface. Once activated, NLRC4 uses this catalytic surface to activate an inactive NLRC4 monomer, self-propagating its active conformation. NAIP proteins possess a catalytic surface matching only the receptor surface of NLRC4, ensuring one NAIP initiates NLRC4 oligomerization. Cryo-EM structure determination (6.6 Å resolution), biochemical reconstitution of PrgJ-NAIP2-NLRC4 complex, structural analysis of oligomerization interfaces Science High 26449475
2015 NLRC4 Ser533 phosphorylation occurs independently of NAIP5 detection of flagellin (Naip5 deletion abolishes caspase-1 activation but not NLRC4 phosphorylation). H. pylori flagellin triggers NLRC4 Ser533 phosphorylation but fails to activate caspase-1, establishing a biphasic activation mechanism: Ser533 phosphorylation (via the flagellin D0 domain) primes NLRC4 for subsequent activation by the flagellin sensor NAIP5 (which requires the flagellin C-terminus). Naip5-/- macrophages, Nlrc4-/- macrophages, H. pylori flagellin and Y. enterocolitica infection, flagellin domain deletion mutants, phospho-Ser533 antibody, caspase-1/IL-1β/pyroptosis assays Proceedings of the National Academy of Sciences of the United States of America High 25605939
2016 NLRP3 associates with NLRC4 (via the NLRC4 NACHT domain) in macrophages infected with Salmonella typhimurium or transfected with flagellin. When NLRC4 Ser533 phosphorylation is absent (S533A), NLRC4 can still activate caspase-1 by recruiting NLRP3 and its adaptor ASC, revealing an unexpected functional overlap between the two inflammasome scaffolds. Co-immunoprecipitation (NLRC4-NLRP3 association), Nlrc4(S533A/S533A) knock-in BMDMs, Nlrc4(S533A/S533A)/Nlrp3-/- double mutant BMDMs, caspase-1 activation assays The Journal of experimental medicine High 27139490
2018 IRF8 transcription factor is required for optimal NLRC4 inflammasome activation specifically in response to flagellin/T3SS-expressing bacteria (Salmonella, Burkholderia, Pseudomonas) but not for NLRP3, AIM2, or Pyrin inflammasomes. IRF8 governs transcription of Naip genes, thereby enabling NAIP-dependent NLRC4 inflammasome activation. IRF8-deficient BMDMs, bacterial infection assays, caspase-1/IL-1β/pyroptosis readouts, RNA-seq, ChIP (IRF8 binding to Naip promoters), in vivo mouse infection Cell High 29576451
2018 NLRC4 activates an alternative ASC- and caspase-8-dependent apoptotic cell death program in caspase-1-deficient macrophages (morphologically distinct from pyroptosis). Caspase-1 catalytically dead knock-in macrophages confirm that caspase-1 protease activity suppresses this alternative caspase-8/ASC apoptotic pathway downstream of NLRC4. GSDME/DFNA5 is dispensable for secondary necrosis following NLRC4-mediated apoptosis. Caspase-1-/- BMDMs, genome-wide CRISPR/Cas9 screen, gene-targeted mice (Casp1 C284A KI, FADD, caspase-8, ASC), cell death morphology, flow cytometry Scientific reports High 29491424
2018 NLRC4 (CARD-based sensor) triggers caspase-8-mediated apoptosis as an alternative cell death in caspase-1-/- macrophages and intestinal epithelial organoids. FADD is recruited to ASC specks which serve as cytosolic platforms for caspase-8 activation. TLR-induced c-FLIP expression inhibits caspase-8-mediated apoptosis downstream of ASC speck assembly without affecting pyroptosis. Caspase-1-/- macrophages, intestinal epithelial organoids, ASC speck formation assay, co-immunoprecipitation (FADD-ASC specks), c-FLIP overexpression, flow cytometry Cell reports High 29262324
2010 Ipaf (NLRC4) interacts with Sug1 (a component of the 26S proteasome) via amino acids 91-253 of Ipaf (the same region that the LRR domain binds intramolecularly). Sug1 co-expression enables ubiquitination of Ipaf, leading to cytoplasmic aggregate formation, caspase-8 recruitment and activation, and cell death independently of caspase-1. The LRR domain of Ipaf negatively regulates this apoptosis-inducing function by competing with Sug1 binding. Yeast two-hybrid screen, co-immunoprecipitation (Ipaf-Sug1), co-localization imaging, ubiquitination assays, RNAi, dominant-negative approaches, caspase activation assays The Biochemical journal Medium 20085538
2005 Ipaf (NLRC4) is a p53-inducible gene: p53 directly induces Ipaf transcription via a functional p53-binding site in the Ipaf promoter. A dominant-negative Ipaf mutant and Ipaf-directed shRNA both inhibit p53-dependent and doxorubicin-induced apoptosis by ~50%. Reporter gene assay (p53-binding site in Ipaf promoter), p53 overexpression, doxorubicin treatment of p53-positive and p53-negative cell lines, dominant-negative Ipaf, shRNA knockdown Oncogene Medium 15580302
2006 Ipaf (NLRC4) activated by caspase-1 causes Bax activation at mitochondria, leading to mitochondrial membrane permeabilization and release of cytochrome c and Omi, functioning as an initiator upstream of mitochondrial events. Bcl2 inhibits mitochondrial permeabilization induced downstream of Ipaf/caspase-1 but not caspase-1 activation itself. Dominant-negative Ipaf, shRNA, caspase-1 overexpression, Bcl2 overexpression, dominant-negative caspase-9, Bax activation assay, mitochondrial membrane potential assay The FEBS journal Medium 16817903
2021 DDX17, a DExD/H box RNA helicase, senses endogenous SINE RNAs (retrotransposon-derived short interspersed nuclear elements) and licenses assembly of a non-canonical NLRC4 inflammasome comprising NLRC4, NLRP3, and ASC, inducing caspase-1 activation and cytokine release independently of NAIPs. DDX17 inhibition decreased IL-18 in SLE patient PBMCs and prevented retinal degeneration in an AMD model. Co-immunoprecipitation (DDX17-NLRC4-NLRP3-ASC complex), DDX17 knockdown/knockout, caspase-1 activation assays, in vivo AMD mouse model, ex vivo SLE patient PBMCs Science immunology High 34860583
2023 NLRC4 promotes cGAS-STING-mediated antiviral innate immunity by facilitating CBL (E3 ubiquitin ligase)-mediated K63-linked polyubiquitination of TBK1. NLRC4 enhances the TBK1-CBL interaction; Nlrc4-/- macrophages and mice show attenuated TBK1 phosphorylation, reduced IFN-β/ISG transcription, and increased HSV-1 replication. NLRC4 overexpression/knockdown/knockout, co-immunoprecipitation (NLRC4-TBK1-CBL), K63-ubiquitination assay, IFN-β promoter reporter, Nlrc4-/- mice with HSV-1 infection Journal of medical virology Medium 37537877
2021 NLRC4 inflammasome-dependent cell death executes through three complementary pathways in a specific order: (1) caspase-1/GSDMD-dependent pyroptosis (default); (2) when pyroptosis is blocked, ASC-mediated caspase-8-dependent apoptosis; (3) when both are blocked, caspase-1-triggered intrinsic apoptosis. Only combined genetic deletion of all three pathways prevents NLRC4-mediated cell death and mouse lethality. Genetic deletion of caspase-1, GSDMD, ASC, caspase-8, caspase-9 in various combinations; mouse lethality assays; cytokine measurements; Salmonella infection model Science advances High 34678072
2018 A gain-of-function mutation in the LRR domain of NLRC4 (p.W655C) causes autoinflammatory disease by engaging an LRR-LRR oligomerization interface. Residues D1010, D1011, L1012, and I1015 on the opposing LRR domain participate in LRR-LRR oligomerization triggered by mutant NLRC4 or PrgI stimulation. ASC contributes to cytokine release but not cell death downstream of this mutation. CRISPR/Cas9-generated THP-1 cells with WT or W655C NLRC4, ASC speck formation (flow cytometry), cell death and IL-1β/IL-18 ELISA, mutagenesis of LRR interface residues The Journal of allergy and clinical immunology Medium 29778503
2024 Cryo-EM structure of human NAIP/NLRC4 inflammasome assembled with B. thailandensis T3SS needle protein reveals that human NAIP senses T3SS pathogen components via a 'lock-key' activation model involving a lasso-like motif and large structural rearrangement, driving a cascade of NLRC4 protomer assembly to form the full human NLRC4 inflammasome. Cryo-EM structure determination of human NAIP/NLRC4 complex, biochemical reconstitution with T3SS needle protein, structural analysis Nature structural & molecular biology High 38177670
2023 Cryo-EM structure of unliganded mouse NAIP5 reveals an unprecedented wide-open conformation with the nucleating surface fully exposed, accessible to recruit inactive NLRC4. Upon ligand binding, the WHD of NAIP5 undergoes ~20° rotation causing a steric clash with inactive NLRC4, triggering NLRC4 conformational change from inactive to active. The rotated WHD 17-18 loop directly contacts active NLRC4 to stabilize the NAIP5-NLRC4 complex. Cryo-EM structure of unliganded NAIP5, comparative structural analysis of ligand-bound vs. unbound states, biochemical binding assays Nature structural & molecular biology High 36604500
2020 Serially conducted genetic experiments using a new Nlrc4-/- mouse line, Nlrc4-S533D phosphomimetic, and Nlrc4-S533A non-phosphorylatable mice fail to detect a requirement for Ser533 phosphorylation in NLRC4 inflammasome function in vivo and in vitro. No role for NLRP3 in NLRC4 function was found using these models (contradicting some earlier claims about NLRP3 rescue). New Nlrc4-/- mouse line, S533D and S533A knock-in mice, caspase-1 activation, IL-1β, pyroptosis assays in vivo and in vitro, melanoma tumor model The Journal of experimental medicine Medium 32342103
2019 High glucose (hyperglycemia) induces NLRC4 phosphorylation in macrophages, which activates the NF-κB/Caspase-1 cascade via an IRF8-dependent pathway, driving macrophage senescence and SASP factor secretion. Deletion of NLRC4 or IRF8 abolishes hyperglycemia-induced cellular senescence and SASP. Metformin inhibits NLRC4 phosphorylation and reduces senescence in this context. NLRC4-/- and IRF8-/- macrophages, diabetic mouse model (gingival tissue), NLRC4 phosphorylation assay, NF-κB/caspase-1 activation, senescence markers, metformin treatment The Journal of biological chemistry Medium 31676687
2021 Brd4 forms a complex with IRF8/PU.1 and binds to the promoters of Naip genes to maintain their transcription, thereby enabling NLRC4 inflammasome activation. Brd4-deficient BMDMs show impaired caspase-1 activation, ASC oligomerization, IL-1β maturation, GSDMD cleavage, and pyroptosis in response to Salmonella; Brd4 myeloid conditional KO mice show increased susceptibility. Brd4 conditional KO BMDMs and mice, RNA-seq, RT-PCR, ChIP (Brd4/IRF8/PU.1 at Naip promoters), caspase-1/IL-1β/pyroptosis assays, in vivo Salmonella infection The Journal of cell biology High 33535228
2016 The tick salivary protein sialostatin L2 binds annexin A2, which impairs NLRC4 inflammasome oligomerization and caspase-1 activation. Annexin A2-deficient macrophages show defective NLRC4 inflammasome oligomerization and reduced IL-1β/IL-18 secretion during Anaplasma phagocytophilum infection. Annexin a2-/- mice are more susceptible to A. phagocytophilum infection. Sialostatin L2 binding assay to annexin A2, annexin A2-/- macrophages, NLRC4 oligomerization assay, caspase-1 activation, IL-1β/IL-18 ELISA, in vivo mouse infection Infection and immunity Medium 27045038
2021 NLRC4, NLRP3, AIM2, and Pyrin form a large multi-sensor PANoptosome complex (together with ASC, caspase-1, caspase-8, and RIPK3) when cells are exposed to multiple simultaneous PAMPs/DAMPs, driving PANoptosis (combined pyroptosis/apoptosis/necroptosis). This multiprotein complex can be released extracellularly and induce inflammation in neighboring macrophages upon engulfment. Co-immunoprecipitation of multi-sensor complex, CRISPR knockout of individual sensors, cell death assays (pyroptosis/apoptosis/necroptosis), extracellular complex characterization, macrophage engulfment assay Cellular & molecular immunology Medium 38008850

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 1483 15190255
2011 The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 1065 21918512
2006 Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nature immunology 932 16648853
2006 Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nature immunology 931 16648852
2007 Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS pathogens 433 17696608
2007 Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. The Journal of experimental medicine 425 18070936
2014 Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nature genetics 395 25217960
2001 Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. The Journal of biological chemistry 380 11390368
2006 Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. The Journal of biological chemistry 379 16984919
2017 NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. The Journal of experimental medicine 340 28404595
2013 Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science (New York, N.Y.) 325 23765277
2015 Structural and biochemical basis for induced self-propagation of NLRC4. Science (New York, N.Y.) 290 26449475
2012 Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 254 22885697
2010 Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. Journal of clinical immunology 233 20490635
2015 AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proceedings of the National Academy of Sciences of the United States of America 231 25775556
2007 TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Seminars in immunopathology 228 17690885
2014 An inherited mutation in NLRC4 causes autoinflammation in human and mice. The Journal of experimental medicine 212 25385754
2007 Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation. European journal of immunology 211 17935074
2016 Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nature communications 198 27708283
2014 Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science (New York, N.Y.) 182 25395539
2015 The NAIP-NLRC4 inflammasome in innate immune detection of bacterial flagellin and type III secretion apparatus. Immunological reviews 173 25879286
2009 Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection. PLoS pathogens 165 19343209
2015 The NAIP/NLRC4 inflammasomes. Current opinion in immunology 161 25621709
2018 IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation. Cell 160 29576451
2018 Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke. Brain, behavior, and immunity 158 30195027
2009 Asc and Ipaf Inflammasomes direct distinct pathways for caspase-1 activation in response to Legionella pneumophila. Infection and immunity 157 19237518
2020 NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Molecular neurodegeneration 139 32295623
2023 Integrated NLRP3, AIM2, NLRC4, Pyrin inflammasome activation and assembly drive PANoptosis. Cellular & molecular immunology 137 38008850
2013 NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen. Mucosal immunology 127 24280936
2016 NLRP3 recruitment by NLRC4 during Salmonella infection. The Journal of experimental medicine 124 27139490
2018 ASC- and caspase-8-dependent apoptotic pathway diverges from the NLRC4 inflammasome in macrophages. Scientific reports 121 29491424
2017 Caspase-1 Engagement and TLR-Induced c-FLIP Expression Suppress ASC/Caspase-8-Dependent Apoptosis by Inflammasome Sensors NLRP1b and NLRC4. Cell reports 121 29262324
2012 Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic challenges. Mucosal immunology 114 22318495
2010 TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin. European journal of immunology 110 21072873
2008 NAIP and Ipaf control Legionella pneumophila replication in human cells. Journal of immunology (Baltimore, Md. : 1950) 106 18453601
2021 Advances in Understanding Activation and Function of the NLRC4 Inflammasome. International journal of molecular sciences 104 33494299
2017 NLRC4 inflammasomopathies. Current opinion in allergy and clinical immunology 103 28957823
2015 Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. Proceedings of the National Academy of Sciences of the United States of America 102 25605939
2020 NAIP-NLRC4-deficient mice are susceptible to shigellosis. eLife 85 33074100
2020 Salmonella Flagellin Activates NAIP/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages. Journal of immunology (Baltimore, Md. : 1950) 85 33380493
2020 The NAIP/NLRC4 inflammasome in infection and pathology. Molecular aspects of medicine 75 32499055
2020 Molecular mechanisms activating the NAIP-NLRC4 inflammasome: Implications in infectious disease, autoinflammation, and cancer. Immunological reviews 75 32729154
2016 NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. The Journal of clinical investigation 70 27617861
2022 Human NAIP/NLRC4 and NLRP3 inflammasomes detect Salmonella type III secretion system activities to restrict intracellular bacterial replication. PLoS pathogens 66 35073381
2019 Variants in NLRP3 and NLRC4 inflammasome associate with susceptibility and severity of multiple sclerosis. Multiple sclerosis and related disorders 66 30658261
2008 NLRC4/IPAF: a CARD carrying member of the NLR family. Clinical immunology (Orlando, Fla.) 64 18819842
2019 Hyperglycemia-induced inflamm-aging accelerates gingival senescence via NLRC4 phosphorylation. The Journal of biological chemistry 63 31676687
2021 LncRNA-Fendrr protects against the ubiquitination and degradation of NLRC4 protein through HERC2 to regulate the pyroptosis of microglia. Molecular medicine (Cambridge, Mass.) 61 33858325
2022 Salmonella enterica Serovar Typhimurium Induces NAIP/NLRC4- and NLRP3/ASC-Independent, Caspase-4-Dependent Inflammasome Activation in Human Intestinal Epithelial Cells. Infection and immunity 58 35678562
2021 Updating the NLRC4 Inflammasome: from Bacterial Infections to Autoimmunity and Cancer. Frontiers in immunology 56 34276697
2018 Autoinflammatory mutation in NLRC4 reveals a leucine-rich repeat (LRR)-LRR oligomerization interface. The Journal of allergy and clinical immunology 55 29778503
2014 Emerging Concepts about NAIP/NLRC4 Inflammasomes. Frontiers in immunology 53 25071770
2020 NLRC4 inflammasome activation is NLRP3- and phosphorylation-independent during infection and does not protect from melanoma. The Journal of experimental medicine 52 32342103
2005 Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis. Oncogene 52 15580302
2017 Methylene blue inhibits NLRP3, NLRC4, AIM2, and non-canonical inflammasome activation. Scientific reports 51 28963531
2007 ASC, Ipaf and Cryopyrin/Nalp3: bona fide intracellular adapters of the caspase-1 inflammasome. Microbes and infection 51 17382568
2021 NLRC4 inflammasome-dependent cell death occurs by a complementary series of three death pathways and determines lethality in mice. Science advances 50 34678072
2021 DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs. Science immunology 47 34860583
2013 Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes. Journal of immunology (Baltimore, Md. : 1950) 47 24337744
2016 Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy. PloS one 46 27706238
2018 The Salmonella pathogenicity island-2 subverts human NLRP3 and NLRC4 inflammasome responses. Journal of leukocyte biology 43 30368901
2016 The Tick Protein Sialostatin L2 Binds to Annexin A2 and Inhibits NLRC4-Mediated Inflammasome Activation. Infection and immunity 41 27045038
2019 NLRC4 inflammasome activation regulated by TNF-α promotes inflammatory responses in nonalcoholic fatty liver disease. Biochemical and biophysical research communications 37 30824190
2019 Involvement of NLRC4 inflammasome through caspase-1 and IL-1β augments neuroinflammation and contributes to memory impairment in an experimental model of Alzheimer's like disease. Brain research bulletin 37 31715312
2016 Interstitial lung disease and myositis-specific and associated autoantibodies: Clinical manifestations, survival and the performance of the new ATS/ERS criteria for interstitial pneumonia with autoimmune features (IPAF). Respiratory medicine 37 28137500
2010 Interaction with Sug1 enables Ipaf ubiquitination leading to caspase 8 activation and cell death. The Biochemical journal 37 20085538
2022 LCN2 Mediates Skin Inflammation in Psoriasis through the SREBP2‒NLRC4 Axis. The Journal of investigative dermatology 36 35120997
2021 The pivotal role of the NLRC4 inflammasome in neuroinflammation after intracerebral hemorrhage in rats. Experimental & molecular medicine 36 34848837
2019 Helicobacter pylori Exploits the NLRC4 Inflammasome to Dampen Host Defenses. Journal of immunology (Baltimore, Md. : 1950) 36 31511355
2020 NLRC4, ASC and Caspase-1 Are Inflammasome Components that Are Mediated by P2Y2R Activation in Breast Cancer Cells. International journal of molecular sciences 34 32397236
2023 Human and mouse NAIP/NLRC4 inflammasome responses to bacterial infection. Current opinion in microbiology 33 37058933
2022 Curcumin activates NLRC4, AIM2, and IFI16 inflammasomes and induces pyroptosis by up-regulated ISG3 transcript factor in acute myeloid leukemia cell lines. Cancer biology & therapy 33 35435150
2015 Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin. Cellular & molecular immunology 33 25914934
2022 Low-ratio somatic NLRC4 mutation causes late-onset autoinflammatory disease. Annals of the rheumatic diseases 32 35428651
2021 Brd4 regulates NLRC4 inflammasome activation by facilitating IRF8-mediated transcription of Naips. The Journal of cell biology 32 33535228
2023 NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1. Journal of medical virology 31 37537877
2023 Targeting Desulfovibrio vulgaris flagellin-induced NAIP/NLRC4 inflammasome activation in macrophages attenuates ulcerative colitis. Journal of advanced research 30 37586642
2020 NLRC4 biology in immunity and inflammation. Journal of leukocyte biology 30 32531834
2022 Aprepitant attenuates NLRC4-dependent neuronal pyroptosis via NK1R/PKCδ pathway in a mouse model of intracerebral hemorrhage. Journal of neuroinflammation 29 35922848
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2021 Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus. Journal of clinical immunology 28 34783940
2019 Involvement of NLRP3 and NLRC4 Inflammasome in Uropathogenic E. coli Mediated Urinary Tract Infections. Frontiers in microbiology 28 31551961
2018 Epigenetic hypomethylation and upregulation of NLRC4 and NLRP12 in Kawasaki disease. Oncotarget 28 29721174
2019 A novel de novo NLRC4 mutation reinforces the likely pathogenicity of specific LRR domain mutation. Clinical immunology (Orlando, Fla.) 26 31870725
2014 Redundant and cooperative interactions between TLR5 and NLRC4 in protective lung mucosal immunity against Pseudomonas aeruginosa. Journal of innate immunity 26 25402425
2021 A unique NLRC4 receptor from echinoderms mediates Vibrio phagocytosis via rearrangement of the cytoskeleton and polymerization of F-actin. PLoS pathogens 25 34898657
2023 Mechanism of NAIP-NLRC4 inflammasome activation revealed by cryo-EM structure of unliganded NAIP5. Nature structural & molecular biology 24 36604500
2022 Association of Tim-3/Gal-9 Axis with NLRC4 Inflammasome in Glioma Malignancy: Tim-3/Gal-9 Induce the NLRC4 Inflammasome. International journal of molecular sciences 23 35216164
2022 Circ_0000181 regulates miR-667-5p/NLRC4 axis to promote pyroptosis progression in diabetic nephropathy. Scientific reports 23 35835791
2015 Molecular Characterization of the NLRC4 Expression in Relation to Interleukin-18 Levels. Circulation. Cardiovascular genetics 22 26362438
2024 Structural basis of the human NAIP/NLRC4 inflammasome assembly and pathogen sensing. Nature structural & molecular biology 21 38177670
2024 Eriocitrin ameliorates hepatic fibrosis and inflammation: The involvement of PPARα-mediated NLRP1/NLRC4 inflammasome signaling cascades. Journal of ethnopharmacology 21 39557108
2023 Toxoplasma gondii Induces Pyroptosis in Human Placental Trophoblast and Amniotic Cells by Inducing ROS Production and Activation of Cathepsin B and NLRP1/NLRP3/NLRC4/AIM2 Inflammasome. The American journal of pathology 21 37741453
2021 Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4. Frontiers in immunology 21 34335562
2020 Inflammasome activation by NLRP1 and NLRC4 in patients with coronary stenosis. Immunobiology 21 32276737
2022 NLRC4 Deficiency Leads to Enhanced Phosphorylation of MLKL and Necroptosis. ImmunoHorizons 20 35301258
2018 Novel aspects of the assembly and activation of inflammasomes with focus on the NLRC4 inflammasome. International immunology 20 29617808
2016 Clinical Association of Chemokine (C-X-C motif) Ligand 1 (CXCL1) with Interstitial Pneumonia with Autoimmune Features (IPAF). Scientific reports 20 27958346
2006 Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis. The FEBS journal 20 16817903
2021 Discovery and characterization of small-molecule inhibitors of NLRP3 and NLRC4 inflammasomes. The Journal of biological chemistry 19 33781745

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