NLRP3 — NLR family pyrin domain containing 3

50 sources retrieved · Most recent: April 2026 · Index updated 3 months ago

1,292PubMed Papers

#108 · top 0.6% of 19K genes

25Diseases

#66 · top 0.4%

0Drugs

65Pathogenic Variants

top 20%

OMIM Disease GeneHub GeneHighly StudiedLandmark GeneVariant-RichExperimental GO Evidence

molecular condensate scaffold activityATP bindingATP hydrolysis activityprotein-macromolecule adaptor activityCINCA syndromeMuckle-Wells syndromefamilial cold autoinflammatory syndrome 1keratitis fugax hereditaria

AI Summary

NLRP3 (NLR family pyrin domain containing 3) is a cytosolic pattern recognition receptor that forms the NLRP3 inflammasome, a multiprotein complex crucial for innate immune responses. The primary function of NLRP3 is to activate caspase-1, leading to maturation of pro-inflammatory cytokines IL-1β and IL-18 and induction of pyroptosis 1 2. The NLRP3 inflammasome can be activated by diverse stimuli through a common mechanism involving disassembly of the trans-Golgi network (TGN), where NLRP3 is recruited to dispersed TGN via ionic bonding with phosphatidylinositol-4-phosphate, serving as a scaffold for NLRP3 aggregation and ASC polymerization 3. Activation is regulated by multiple post-translational modifications, including palmitoylation at Cys126 by ZDHHC7 4 and SUMOylation by TRIM28, which stabilizes NLRP3 protein levels 5. Mitochondrial dysfunction positively regulates NLRP3 activation through ROS generation, while autophagy and mitophagy negatively regulate the inflammasome 6 7. Dysregulation of NLRP3 is associated with various autoinflammatory diseases and has been linked to M1 macrophage polarization in inflammatory conditions 8, making it a promising therapeutic target for inflammatory disorders 1.

Sources cited

NLRP3 inflammasome triggers caspase activation and IL-1β maturation, linked to autoinflammatory diseases

PMID: 26549800

NLRP3 inflammasome activates caspase-1, leading to IL-1β/IL-18 maturation and pyroptosis

PMID: 27669650

NLRP3 activation involves recruitment to dispersed trans-Golgi network via PtdIns4P binding

PMID: 30487600

NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation

PMID: 38583156

TRIM28 SUMOylates NLRP3, stabilizing protein levels and facilitating inflammasome activation

PMID: 34373456

Mitochondrial dysfunction and ROS generation positively regulate NLRP3 activation

PMID: 21124315

Autophagy and mitophagy negatively regulate NLRP3 inflammasome activation

PMID: 39417249

NLRP3 inflammasome mediates M1 macrophage polarization and IL-1β production

PMID: 31976565

Disease Associations25

CINCA syndromeOpen Targets

0.84Strong

Muckle-Wells syndromeOpen Targets

0.80Strong

familial cold autoinflammatory syndrome 1Open Targets

0.80Strong

keratitis fugax hereditariaOpen Targets

0.69Moderate

Familial cold urticariaOpen Targets

0.69Moderate

autosomal dominant nonsyndromic hearing lossOpen Targets

0.67Moderate

cryopyrin-associated periodic syndromeOpen Targets

0.58Moderate

autoinflammatory syndromeOpen Targets

0.52Moderate

severe acute respiratory syndromeOpen Targets

0.47Moderate

familial cold autoinflammatory syndromeOpen Targets

0.41Moderate

COVID-19Open Targets

0.40Weak

genetic disorderOpen Targets

0.34Weak

Cerebral arteriovenous malformationOpen Targets

0.33Weak

neurodegenerative diseaseOpen Targets

0.31Weak

FeverOpen Targets

0.26Weak

Pleural effusionOpen Targets

0.26Weak

pericardial effusionOpen Targets

0.26Weak

response to antihypertensive drugOpen Targets

0.26Weak

Tietze syndromeOpen Targets

0.26Weak

Ischemic strokeOpen Targets

0.23Weak

Chronic infantile neurologic cutaneous and articular syndromeUniProt

Deafness, autosomal dominant, 34, with or without inflammationUniProt

Familial cold autoinflammatory syndrome 1UniProt

Keratoendothelitis fugax hereditariaUniProt

Muckle-Wells syndromeUniProt

Pathogenic Variants65

NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|not specified|Cryopyrin associated periodic syndrome|Familial amyloid nephropathy with urticaria AND deafness;Chronic infantile neurological, cutaneous and articular syndrome;Hearing loss, autosomal dominant 34, with or without inflammation;Familial cold autoinflammatory syndrome 1;Keratitis fugax hereditaria|NLRP3-related disorder

★★☆☆2026→ Residue 353

NM_001243133.2(NLRP3):c.1043C>T (p.Thr348Met)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Familial amyloid nephropathy with urticaria AND deafness|Cryopyrin associated periodic syndrome|Autoinflammatory syndrome|Chronic infantile neurological, cutaneous and articular syndrome;Familial amyloid nephropathy with urticaria AND deafness

★★☆☆2025→ Residue 348

NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome|Autoinflammatory syndrome|Keratitis fugax hereditaria;Familial cold autoinflammatory syndrome 1;Familial amyloid nephropathy with urticaria AND deafness;Hearing loss, autosomal dominant 34, with or without inflammation;Chronic infantile neurological, cutaneous and articular syndrome

★★☆☆2025→ Residue 439

NM_001243133.2(NLRP3):c.1699G>A (p.Glu567Lys)Pathogenic

Familial cold autoinflammatory syndrome 1|Cryopyrin associated periodic syndrome|not provided

★★☆☆2025→ Residue 567

NM_001243133.2(NLRP3):c.902G>A (p.Gly301Asp)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome

★★☆☆2025→ Residue 301

NM_001243133.2(NLRP3):c.778C>T (p.Arg260Ter)Pathogenic

Familial amyloid nephropathy with urticaria AND deafness|Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome|Autoinflammatory syndrome

★★☆☆2025→ Residue 260

NM_001243133.2(NLRP3):c.778_780delinsTGG (p.Arg260Trp)Pathogenic

not provided|Chronic infantile neurological, cutaneous and articular syndrome|Cryopyrin associated periodic syndrome

★★☆☆2025→ Residue 260

NM_001243133.2(NLRP3):c.907G>A (p.Asp303Asn)Pathogenic

Familial amyloid nephropathy with urticaria AND deafness|Chronic infantile neurological, cutaneous and articular syndrome|Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome

★★☆☆2025→ Residue 303

NM_001243133.2(NLRP3):c.1307C>T (p.Thr436Ile)Pathogenic

Familial cold autoinflammatory syndrome 1|Cryopyrin associated periodic syndrome|not provided

★★☆☆2025→ Residue 436

NM_001243133.2(NLRP3):c.2575T>C (p.Tyr859His)Pathogenic

not provided|Familial amyloid nephropathy with urticaria AND deafness;Hearing loss, autosomal dominant 34, with or without inflammation;Familial cold autoinflammatory syndrome 1;Chronic infantile neurological, cutaneous and articular syndrome;Keratitis fugax hereditaria|Cryopyrin associated periodic syndrome|NLRP3-related disorder

★★☆☆2024→ Residue 859

NM_001243133.2(NLRP3):c.2576A>G (p.Tyr859Cys)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Chronic infantile neurological, cutaneous and articular syndrome;Familial amyloid nephropathy with urticaria AND deafness;Hearing loss, autosomal dominant 34, with or without inflammation;Familial cold autoinflammatory syndrome 1;Keratitis fugax hereditaria|Familial amyloid nephropathy with urticaria AND deafness

★★☆☆2024→ Residue 859

NM_001243133.2(NLRP3):c.931G>A (p.Glu311Lys)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Familial amyloid nephropathy with urticaria AND deafness|Cryopyrin associated periodic syndrome|Chronic infantile neurological, cutaneous and articular syndrome;Familial amyloid nephropathy with urticaria AND deafness;Keratitis fugax hereditaria;Familial cold autoinflammatory syndrome 1;Hearing loss, autosomal dominant 34, with or without inflammation

★★☆☆2024→ Residue 311

NM_001243133.2(NLRP3):c.1315G>A (p.Ala439Thr)Pathogenic

Familial cold autoinflammatory syndrome 1|Cryopyrin associated periodic syndrome|not provided

★★☆☆2024→ Residue 439

NM_001243133.2(NLRP3):c.1217T>C (p.Met406Thr)Pathogenic

Cryopyrin associated periodic syndrome|not provided

★★☆☆2024→ Residue 406

NM_001243133.2(NLRP3):c.1054G>A (p.Ala352Thr)Likely pathogenic

Familial cold autoinflammatory syndrome 1|Cryopyrin associated periodic syndrome|Chronic infantile neurological, cutaneous and articular syndrome

★★☆☆2023→ Residue 352

NM_001243133.2(NLRP3):c.910G>A (p.Glu304Lys)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome

★★☆☆2022→ Residue 304

NM_001243133.2(NLRP3):c.1213A>C (p.Thr405Pro)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome

★★☆☆2021→ Residue 405

NM_001243133.2(NLRP3):c.914T>C (p.Leu305Pro)Pathogenic

Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome|Autoinflammatory syndrome

★★☆☆2021→ Residue 305

NM_001243133.2(NLRP3):c.1055C>T (p.Ala352Val)Pathogenic

Familial amyloid nephropathy with urticaria AND deafness|Familial cold autoinflammatory syndrome 1|not provided|Cryopyrin associated periodic syndrome

★★☆☆2020→ Residue 352

NM_001243133.2(NLRP3):c.914T>G (p.Leu305Arg)Likely pathogenic

not provided

★☆☆☆2026→ Residue 305

Tissue Expression6 tissues

Bone Marrow

100%

Lung

Brain

Heart

Liver

Ovary

Gene Interaction Network6 neighbors

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Structure23 PDB hits

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PDB3QF2 · 1.70 Å · X-ray

View on RCSB

ConstraintgnomAD v4.1

LOEUFⓘ

0.64LoF Tolerant

pLIⓘ

0.00Tolerant

Observed/Expected LoF0.50 [0.40–0.64]

Rankings3 dim

Where NLRP3 stands among ~20K protein-coding genes

#108of 20,598
Most Researched1,292 · top 1%
#1,109of 5,509
Most Pathogenic Variants65 · top quartile
#4,557of 17,882
Most Constrained (LOEUF)0.64