NLRP4

gene
On this page

Also known as PYPAF4FLJ32126PAN2RNH2CLR19.5CT58

Summary

NLRP4 (NLR family pyrin domain containing 4, HGNC:22943) is a protein-coding gene on chromosome 19q13.43, encoding NACHT, LRR and PYD domains-containing protein 4 (Q96MN2). May be involved in inflammation and recognition of cytosolic pathogen-associated molecular patterns (PAMPs) not intercepted by membrane-bound receptors.

The protein encoded by this gene is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family, and is predicted to contain an N-terminal pyrin effector domain (PYD), a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). This gene product has a demonstrated role as a negative regulator of autophagy and type I interferon signaling pathways as a result of protein interactions with its NACHT domain. The PYD domain has also been shown to be important in the inhibition of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells).

Source: NCBI Gene 147945 — RefSeq curated summary.

At a glance

  • GWAS associations: 1
  • Clinical variants (ClinVar): 176 total
  • Druggable target: yes
  • MANE Select transcript: NM_134444

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:22943
Approved symbolNLRP4
NameNLR family pyrin domain containing 4
Location19q13.43
Locus typegene with protein product
StatusApproved
AliasesPYPAF4, FLJ32126, PAN2, RNH2, CLR19.5, CT58
Ensembl geneENSG00000160505
Ensembl biotypeprotein_coding
OMIM609645
Entrez147945

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000301295, ENST00000587464, ENST00000587891, ENST00000589437

RefSeq mRNA: 1 — MANE Select: NM_134444 NM_134444

CCDS: CCDS12936

Canonical transcript exons

ENST00000301295 — 10 exons

ExonStartEnd
ENSE000010527215587082755870997
ENSE000010527245587699655877166
ENSE000011155635586199255862159
ENSE000011155705587879455878964
ENSE000011155735585767455859249
ENSE000011155765586138655861547
ENSE000011155795586770955867876
ENSE000013733885585201655852360
ENSE000017149435583654055836934
ENSE000029018635588147055881855

Expression profiles

Bgee: expression breadth broad, 42 present calls, max score 100.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0884 / max 73.3754, expressed in 27 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter IDTPM avgSamples expressed
1776950.068720
2089440.01166
1776940.00811

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
secondary oocyteCL:0000655100.00gold quality
oocyteCL:000002399.97gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099186.76gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047384.72gold quality
spermCL:000001980.44gold quality
kidney epitheliumUBERON:000481974.68gold quality
epithelial cell of pancreasCL:000008374.45gold quality
testisUBERON:000047367.65gold quality
right testisUBERON:000453467.22gold quality
left testisUBERON:000453366.73gold quality
left ventricle myocardiumUBERON:000656656.68gold quality
lymph nodeUBERON:000002956.26gold quality
cardiac muscle of right atriumUBERON:000337954.94gold quality
adult organismUBERON:000702354.02gold quality
upper arm skinUBERON:000426353.52gold quality
quadriceps femorisUBERON:000137753.18gold quality
vastus lateralisUBERON:000137952.48gold quality
buccal mucosa cellCL:000233652.45gold quality
pancreatic ductal cellCL:000207952.17silver quality
myocardiumUBERON:000234951.55gold quality
vermiform appendixUBERON:000115451.19gold quality
tonsilUBERON:000237251.10gold quality
caecumUBERON:000115348.68gold quality
deltoidUBERON:000147648.29gold quality
layer of synovial tissueUBERON:000761648.14gold quality
tibialis anteriorUBERON:000138547.74silver quality
inferior vagus X ganglionUBERON:000536347.23gold quality
ileal mucosaUBERON:000033147.11silver quality
tendon of biceps brachiiUBERON:000818847.06gold quality
nasal cavity epitheliumUBERON:000538447.03gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

ExperimentMarker?Max mean expression
E-MTAB-3929yes1982.89
E-ANND-3yes3.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting NLRP4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-548AJ-3P99.9673.385345
HSA-MIR-548X-3P99.9673.385345
HSA-MIR-548J-3P99.9472.614881
HSA-MIR-548AE-3P99.9372.664867
HSA-MIR-548AH-3P99.9372.544872
HSA-MIR-548AM-3P99.9372.544872
HSA-MIR-548AQ-3P99.9372.664867
HSA-MIR-568099.9169.833421
HSA-MIR-449399.9066.48977
HSA-MIR-6499-3P99.9066.381212
HSA-MIR-548D-3P99.8770.674362
HSA-MIR-548BB-3P99.8670.584354
HSA-MIR-548AC99.8470.774351
HSA-MIR-548H-3P99.8470.804349
HSA-MIR-548Z99.8470.804349
HSA-MIR-497-3P99.6169.711990
HSA-MIR-4762-5P99.5768.541424
HSA-MIR-427699.5667.662514
HSA-MIR-6733-3P99.5467.801281
HSA-MIR-519099.1567.761234
HSA-MIR-4664-5P98.1765.071020
HSA-MIR-1285-5P98.0168.71779
HSA-MIR-6742-3P97.9564.501490
HSA-MIR-366597.7365.08975
HSA-MIR-3121-5P97.3066.621146
HSA-MIR-519496.7763.911021
HSA-MIR-339-5P96.7366.01820
HSA-MIR-6738-5P96.3363.61815
HSA-MIR-6734-5P95.7065.56950
HSA-MIR-1914-3P95.0763.37762

Literature-anchored findings (GeneRIF, showing 11)

  • NLRP4 is recruited to and accumulates in bacteria-containing phagosomes and transiently dissociates from beclin1 following group A streptococcus infection, thereby controlling the autophagic flux crucial for cell-autonomous antibacterial resistance. (PMID:21209283)
  • Our results provide molecular insight into the mechanisms by which NLRP4-DTX4 targets TBK1 for degradation. (PMID:22388039)
  • Structural and functional analysis of the NLRP4 pyrin domain. (PMID:22928810)
  • Findings suggest that NLR family pyrin domain containing 2 (NLRP2P) is a processed pseudogene that regulates NF-kappaB RelA/p65 activity and thus represents the newest member of the POP family, pyrin-only protein 4 (POP4; NLRP4). (PMID:24871464)
  • This study describes conformational stability of native NLRP14 and mutants in their monomeric and dimeric states and compares them to NLRP4, a representative of a native pyrin domain fold. (PMID:25403012)
  • NLRP4 is an important mediator of cardiac remodeling in vitro and in vivo. (PMID:28486191)
  • NLRP4 binds ARHGDIA (Rho GDP dissociation inhibitor alpha) to regulate Rho GTPase signaling and facilitate actin-mediated xenophagy. (PMID:29099277)
  • The minor allele of rs16986718G > A in NLRP4 may be a genetic marker that predicts asthma exacerbation in adult asthmatics who smoke. (PMID:30526007)
  • Somatic Mutation of NLRP Genes in Gastric and Colonic Cancers. (PMID:34257569)
  • NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy. (PMID:34927309)
  • The hyper-expression of NLRP4 characterizes the occurrence of macrophage activation syndrome assessing STING pathway in adult-onset Still’s disease. (PMID:35467709)

Cross-species orthologs

10 orthologs

OrganismSymbolGene ID
mus_musculusNlrp4fENSMUSG00000032999
mus_musculusNlrp4bENSMUSG00000034087
mus_musculusNlrp4cENSMUSG00000034690
mus_musculusNlrp4aENSMUSG00000040601
mus_musculusNlrp4eENSMUSG00000045693
rattus_norvegicusNlrp4bENSRNOG00000015527
rattus_norvegicusNlrp4ENSRNOG00000021996
rattus_norvegicusNlrp4fENSRNOG00000027705
rattus_norvegicusNlrp4aENSRNOG00000042030
rattus_norvegicusNlrp4al1ENSRNOG00000059733

Paralogs (20): NLRP2 (ENSG00000022556), NLRP1 (ENSG00000091592), NOD1 (ENSG00000106100), NLRC5 (ENSG00000140853), NLRP12 (ENSG00000142405), NLRP14 (ENSG00000158077), NLRX1 (ENSG00000160703), NLRP3 (ENSG00000162711), NOD2 (ENSG00000167207), NLRP7 (ENSG00000167634), NLRC3 (ENSG00000167984), NLRP5 (ENSG00000171487), NLRP13 (ENSG00000173572), NLRP6 (ENSG00000174885), CIITA (ENSG00000179583), NLRP8 (ENSG00000179709), NLRP11 (ENSG00000179873), NLRP10 (ENSG00000182261), NLRP9 (ENSG00000185792), PYDC2 (ENSG00000253548)

Protein

Protein identifiers

NACHT, LRR and PYD domains-containing protein 4Q96MN2 (reviewed: Q96MN2)

Alternative names: Cancer/testis antigen 58, PAAD and NACHT-containing protein 2, PYRIN and NACHT-containing protein 2, PYRIN-containing APAF1-like protein 4, Ribonuclease inhibitor 2

All UniProt accessions (3): Q96MN2, K7ES09, K7ESK5

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in inflammation and recognition of cytosolic pathogen-associated molecular patterns (PAMPs) not intercepted by membrane-bound receptors. Acts as a negative regulator of the type I interferon signaling pathway by serving as an adapter to promote DTX4-mediated ubiquitination of activated TBK1, and its subsequent degradation. Suppresses NF-kappaB induction by the cytokines TNFA and IL1B, suggesting that it operates at a point of convergence in these two cytokine signaling pathways.

Subunit / interactions. Interacts with CHUK/IKKA, inhibiting its kinase activity.

Domain organisation. The pyrin domain is sufficient for suppression of NF-kappaB activity, it adopts a typical death domain fold, but in contrast to several NLRP family pyrin domains it doesn’t bind homotypically to the ASC adapter, which supports the observation that NLRP4 has no effect on IL1B activation.

Similarity. Belongs to the NLRP family.

Isoforms (3)

UniProt IDNamesCanonical?
Q96MN2-11yes
Q96MN2-22
Q96MN2-33

RefSeq proteins (1): NP_604393* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR001611Leu-rich_rptRepeat
IPR004020DAPINDomain
IPR007111NACHT_NTPaseDomain
IPR011029DEATH-like_dom_sfHomologous_superfamily
IPR027417P-loop_NTPaseHomologous_superfamily
IPR032675LRR_dom_sfHomologous_superfamily
IPR041075NOD1/2_WHDomain
IPR041267NLRP_HD2Domain
IPR050637NLRP_innate_immun_regFamily

Pfam: PF02758, PF05729, PF13516, PF17776, PF17779

UniProt features (32 total): repeat 8, sequence conflict 7, sequence variant 6, helix 5, domain 2, splice variant 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
4EWIX-RAY DIFFRACTION2.28

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q96MN2-F189.080.66

Functional residue map

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

Ligand- & substrate-binding residues (1): 155–162

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

IDPathway
R-HSA-1606341IRF3 mediated activation of type 1 IFN
R-HSA-3134975Regulation of innate immune responses to cytosolic DNA
R-HSA-3270619IRF3-mediated induction of type I IFN
R-HSA-1606322ZBP1(DAI) mediated induction of type I IFNs
R-HSA-168249Innate Immune System
R-HSA-168256Immune System
R-HSA-1834941STING mediated induction of host immune responses
R-HSA-1834949Cytosolic sensors of pathogen-associated DNA

MSigDB gene sets: 64 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, AFFAR_YY1_TARGETS_DN, GOBP_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (7): inflammatory response (GO:0006954), negative regulation of innate immune response (GO:0045824), regulation of inflammatory response (GO:0050727), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein K48-linked ubiquitination (GO:0070936), antiviral innate immune response (GO:0140374), protein K33-linked deubiquitination (GO:1990168)

GO Molecular Function (4): ATP binding (GO:0005524), molecular adaptor activity (GO:0060090), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-5 pathways:

CategoryPathways
Cytosolic sensors of pathogen-associated DNA3
ZBP1(DAI) mediated induction of type I IFNs1
STING mediated induction of host immune responses1
Immune System1
Innate Immune System1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
innate immune response2
binding2
cellular anatomical structure2
defense response1
negative regulation of response to biotic stimulus1
negative regulation of defense response1
negative regulation of response to external stimulus1
regulation of innate immune response1
negative regulation of immune response1
inflammatory response1
regulation of defense response1
regulation of response to external stimulus1
ubiquitin-dependent protein catabolic process1
proteasomal protein catabolic process1
protein polyubiquitination1
defense response to virus1
protein deubiquitination1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1
molecular_function1
nucleoside phosphate binding1
heterocyclic compound binding1
intracellular anatomical structure1
cytoplasm1

Protein interactions and networks

STRING

619 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
NLRP4BECN1Q14457986
NLRP4DTX4Q9Y2E6983
NLRP4AIM2O14862860
NLRP4NLRP3Q96P20854
NLRP4NLRP1Q9C000792
NLRP4MEFVO15553761
NLRP4NLRP12P59046758
NLRP4NLRC4Q9NPP4754
NLRP4PYCARDQ9ULZ3742
NLRP4CASP1P29466714
NLRP4NLRP7Q8WX94698
NLRP4NLRP2Q9NX02691
NLRP4TBK1Q9UHD2640
NLRP4NLRP6P59044570
NLRP4NOD1Q9Y239541

IntAct

4 interactions, top by confidence:

ABTypeScore
NLRP4SUGT1psi-mi:“MI:0915”(physical association)0.400
NLRP4PYDC2psi-mi:“MI:0915”(physical association)0.370
ATG16L1ESYT2psi-mi:“MI:0914”(association)0.350

BioGRID (11): NLRP4 (Co-fractionation), NLRP4 (Affinity Capture-Western), NLRP4 (Affinity Capture-Western), NLRP4 (Affinity Capture-MS), NLRP4 (Affinity Capture-MS), NLRP4 (Affinity Capture-Western), TBK1 (Affinity Capture-Western), NLRP4 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), SUGT1 (Affinity Capture-Western), NLRP4 (Affinity Capture-Western)

ESM2 similar proteins: A1Z198, A6QLE5, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5G7, E9Q5R7, P59045, P59046, P59047, Q0GKD5, Q288C4, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q3TKR3, Q3UWY1, Q63035, Q647I9, Q66X01, Q66X03, Q66X05, Q66X19, Q66X22, Q6B966, Q7RTR0, Q7TPX8, Q86W24, Q86W25, Q86W26, Q86W28, Q8BU40, Q8BVP1, Q8C6J9, Q8CCN1

Diamond homologs: A0A2H5Q1B8, P59046, Q6Q4D0, Q96MN2, A0A386CAB9, A1Z198, A6QLE5, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, O15553, P10775, P13489, P29315, P59044, P59045, Q0GKD5, Q288C4, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q3TKR3, Q63035, Q647I9, Q66X01, Q66X03, Q66X19, Q6B966, Q7RTR0, Q86W24, Q86W25, Q86W26, Q86W28, Q8BU40

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance134
Likely benign16
Benign2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1690 predictions. Top by Δscore:

VariantEffectΔscore
19:55859250:G:GGdonor_gain1.0000
19:55861990:A:AGacceptor_gain1.0000
19:55861991:G:GGacceptor_gain1.0000
19:55861991:GA:Gacceptor_gain1.0000
19:55861991:GAATA:Gacceptor_gain1.0000
19:55862155:CTAGC:Cdonor_gain1.0000
19:55862158:GC:Gdonor_gain1.0000
19:55862160:G:GGdonor_gain1.0000
19:55867877:G:GGdonor_gain1.0000
19:55870823:ATAG:Aacceptor_gain1.0000
19:55870825:A:AGacceptor_gain1.0000
19:55870825:AG:Aacceptor_gain1.0000
19:55870825:AGGTT:Aacceptor_gain1.0000
19:55870826:G:GGacceptor_gain1.0000
19:55870826:GG:Gacceptor_gain1.0000
19:55870826:GGT:Gacceptor_gain1.0000
19:55870826:GGTT:Gacceptor_gain1.0000
19:55870826:GGTTG:Gacceptor_gain1.0000
19:55870995:GTG:Gdonor_gain1.0000
19:55876994:AGTTT:Aacceptor_gain1.0000
19:55876995:GTTTG:Gacceptor_gain1.0000
19:55836731:G:GGdonor_gain0.9900
19:55840899:A:AGacceptor_gain0.9900
19:55852107:T:TAacceptor_gain0.9900
19:55852350:G:GTdonor_gain0.9900
19:55855425:A:Tdonor_gain0.9900
19:55855432:G:GTdonor_gain0.9900
19:55857657:T:Aacceptor_gain0.9900
19:55857664:A:AGacceptor_gain0.9900
19:55857664:ACT:Aacceptor_gain0.9900

AlphaMissense

6602 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
19:55852161:A:CK27N0.996
19:55852161:A:TK27N0.996
19:55858741:T:CF450L0.989
19:55858742:T:CF450S0.989
19:55858743:C:AF450L0.989
19:55858743:C:GF450L0.989
19:55852133:T:CL18P0.987
19:55857937:T:CF182L0.986
19:55857939:C:AF182L0.986
19:55857939:C:GF182L0.986
19:55852169:T:CL30P0.985
19:55858601:C:AA403D0.985
19:55858633:T:CF414L0.985
19:55858635:T:AF414L0.985
19:55858635:T:GF414L0.985
19:55867789:T:CL756P0.985
19:55857875:A:TK161I0.984
19:55858076:T:CF228S0.984
19:55858634:T:CF414S0.984
19:55852157:T:CF26S0.983
19:55852160:A:TK27I0.983
19:55852133:T:AL18H0.982
19:55858761:G:CQ456H0.982
19:55858761:G:TQ456H0.982
19:55858768:T:CC459R0.982
19:55857856:G:AG155R0.981
19:55857856:G:CG155R0.981
19:55858507:T:GY372D0.981
19:55870839:C:GC789W0.981
19:55852323:A:CR81S0.980

dbSNP variants (sampled 300 via entrez): RS1000002806 (19:55854826 G>A), RS1000045768 (19:55878635 C>A), RS1000056240 (19:55873316 G>A), RS1000104138 (19:55839938 C>T), RS1000109631 (19:55873033 T>C), RS1000237096 (19:55868778 T>C), RS1000241939 (19:55837339 G>A), RS1000340965 (19:55863752 G>A), RS1000412518 (19:55850779 G>A), RS1000456821 (19:55864029 A>G), RS1000587522 (19:55845891 T>C), RS1000640507 (19:55854572 A>G), RS1000643681 (19:55879850 T>A), RS1000682626 (19:55841154 T>A), RS1000713400 (19:55840967 G>A,T)

Disease associations

OMIM: gene MIM:609645 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

StudyTraitp-value
GCST008369_18Plasma anti-thyroglobulin levels9.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465345 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — NOD-like receptor family

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

ChemicalActions (top 5)PubMed papers
propionaldehydedecreases expression1
CGP 52608affects binding, increases reaction1
abrineincreases expression1
theaflavin-3,3’-digallateaffects expression1
Permethrinincreases expression1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5374772BindingInhibition of NLRP4 inflammasome activation in human PBMC assessed as reduction in IL-1beta secretion at 3 nM preincubated with LPS for 2.5 hrs followed by compound addition for 30 mins by ELISADiscovery of Clinical Candidate NT-0796, a Brain-Penetrant and Highly Potent NLRP3 Inflammasome Inhibitor for Neuroinflammatory Disorders. — J Med Chem

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.