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FLASH GENE
Symbol NLRP3 contributors: mct/shn - updated : 22-09-2019
HGNC name NLR family, pyrin domain containing 3
HGNC id 16400
Corresponding disease
CINCA chronic neurologic cutaneous and articular syndrome
DFNA34 deafness, autosomal dominant 34, with or without inflammation
FCU familial cold urticaria
MWS Muckle-Wells syndrome
Location 1q44      Physical location : 247.579.457 - 247.612.404
Genatlas name Nod-like receptor (NLR) family, pyrin domain containing 3
Synonym name
  • NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3
  • cryopyrin
  • cryopyrin, pyrin-like protein, predominantly expressed in peripheral blood leukocytes
  • chromosome 1 open reading frame 7
  • PYRIN-containing APAF1-like protein 1
  • NACHT, LRR and PYD containing protein 3
  • NACHT, LRR and PYD domains-containing protein 3
  • nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3
  • angiotensin/vasopressin receptor AII/AVP-like
  • caterpiller protein 1.1
  • cold autoinflammatory syndrome 1
    • Synonym symbol(s) PYPAF1, AGTAVPRL, CIS1, NALP3 , FCAS, CIAS1, AII, AVP, CLR1.1, C1orf7, FLJ95925, AII, AVP, FCU, MWS
    DNA
    TYPE functioning gene
    STRUCTURE 32.95 kb     11 Exon(s)
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure promoter region of NLRP3 contains binding sites for AP1, Sp1, Ets, and Myb
    MAPPING cloned Y linked N status provisional
    Map cen - D1S423 - D1S2836 - NLRP3 - D1S2682 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 4470 118 1036 - 2006 16642435
  • also called CIAS1
  • 11 LRR full length
    • 7 splicing 4128 105.8 922 - 2006 16642435
  • alsos called cryopyrin
  • seven LRR
    • 11 splicing 3862 118 1036 Granulocytes, monocytes (very weakly), dendritic cells, and B and T cells. non-keratinizing epithelia in the oropharynx, esophagus,urothelial layer in the bladder and ectocervix 2006 16642435
    9 splicing 4333 112 979 - 2006 16642435
    8 splicing 4299 111.7 979 - 2006 16642435
    - - 4470 - 1034 - 2006 16642435
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow   
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte Homo sapiens
    Blood/Hematopoieticgranulocyte Homo sapiens
    Blood/Hematopoieticleukocyte Homo sapiens
    Blood/Hematopoieticmonocyte Homo sapiens
    Lymphoid/Immuneactivated B lymphocyte Homo sapiensAdult
    Lymphoid/Immuneactivated leukocyte Homo sapiensAdult
    Lymphoid/Immunelymphocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal CARD or pyrin domains needed for homotypic protein-protein interaction
  • a nucleotide binding site (NBS, NACHT subfamily)
  • a leucine rich repeat region (LRR)
    • HOMOLOGY
    interspecies ortholog to Nlrp3, Mus musculus
    ortholog to Nlrp3, Rattus norvegicus
    ortholog to NLRP3, Pan troglodytes
    Homologene
    FAMILY
  • PYD/CARD-containing family of apoptosis regulators and activators of pro-inflammatory caspases
  • NALP subfamily of the CATERPILLER protein family
  • NLRP family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • a potential inducer of apoptosis
  • a key regulator of inflammation, induced to dampen NF-kappaB-dependent proinflammatory signals
  • may play an important role in the development of hypertension, based on inflammation brought on by NFKB activation
  • implicated in the activation of caspase-1 by the Toll-like receptors (TLRs) during the cells response to microbial infection
  • role of the NLRP3 inflammasome in regulating glucose homeostasis
  • controls the inflammasome, a crucial molecular platform that regulates activation of caspase-1 and processing of interleukin (IL)-1beta—two key mediators of inflammation
  • play important roles in both mammalian innate immune system and reproductive system
  • possible involvement of NLRP3-inflammasome in the activation of caspase-1 consequent to geranylgeranyl pyrophosphate decrement
  • redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella
  • NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases (
  • NLRP3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance
  • NLRP3 inflammasome activation in obesity promotes macrophage-mediated T cell activation in adipose tissue and impairs insulin sensitivity
  • signaling by innate immune receptors such as TLR4 and NLRP3 regulate metabolism
  • important activating component of the inflammasome, is involved in neointima formation after vascular injury
  • plays a non-redundant role in vascular damage mediated neointima formation
  • mediates the pathological effect of hydroxyapatite (HA) crystals, suggesting a critical role for the inflammasome in the pathogenesis of osteoarthritis
  • NLRP3 inflammasome plays a pivotal role in the development of HA deposition diseases of joints
  • glucocorticoid-responsive gene in cultured and primary macrophages
  • ability of glucocorticoids to sensitize the NLRP3 inflammasome to ATP could also play a role in enhancing IL1B release during sterile inflammation
  • intracellular receptors, such as NLRP1, NLRP3, NLRP6 and NLRC4, which mediate the assembly of inflammasome complexes leading to the activation of procaspase-1
  • critical role for Ca2+ signaling in activation of the NLRP3 inflammasome
  • Ca2+ and cAMP are two key molecular regulators of the NLRP3 inflammasome that have critical roles in the molecular pathogenesis of cryopyrin-associated periodic syndromes (CAPS)
  • is an important pattern recognition receptor involved in mediating inflammasome activation in response to viral and bacterial infections as well as various proinflammatory stimuli associated with tissue damage or malfunction
  • fundamental role for NLRP3/CASP1 mediated inflammation in behavioural and cognitive dysfunction in Alzheimer disease
  • involvement of the NLRP3 inflammasome in DNA damage responses induced by cellular stress
  • is an upstream target that controls age-related inflammation
  • is involved in the early stages of the inflammatory response by sensing cellular damage or distress due to viral or bacterial infection
  • roles of mitochondria in NLRP3 inflammasome activation
  • regulates chemokine-mediated functions and recruitment of neutrophils, and thereby contributes to hepatic I/R injury independently of inflammasomes
  • is a key component of inflammasomes that assemble in response to a wide variety of endogenous and pathogen-derived danger signals
  • NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an lysophosphatidylcholine (LPC)-induced inflammasome and are important in astrogliosis and microgliosis
    • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS inflammation
    PATHWAY
    metabolism
    signaling signal transduction
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • ASC (
  • ASC, CARD-containing protein Cardinal, and caspase-1
  • nucleotide-binding oligomerization domain containing 2, NOD2
  • PYCARD connects pathogen/danger sensors such as NLRP3 and NLRC4 with caspases and is involved in inflammation and cell death
  • CASP1 interacting with PYCARD, AIM2 and NLRP3 (PYCARD inflammasomes, including AIM2 and NLRP3, are critical for CASP1 activation induced by S. pneumoniae)
  • GBP5 promoted selective NLRP3 inflammasome responses to pathogenic bacteria and soluble but not crystalline inflammasome priming agents
  • endogenous non-coding RNA-induced NLRP3 inflammasome activation results from DICER1 deficiency in a non-immune cell
  • DDIT3, a protein known to regulate Ca2+ release from the ER during ER stress, amplifies NLRP3 inflammasome activation
  • Ca2+ signaling critically regulates NLRP3 inflammasome activation by triggering mitochondrial damage
  • EIF2AK2 physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3)
  • PYCARD interacts with NLRP3 via a homotypic PYD interaction and recruits procaspase-1 via a homotypic caspase recruitment domain interaction
  • is a key component of one of several distinct cytoplasmic multiprotein complexes (inflammasomes) that mediate the maturation of the proinflammatory cytokine IL1B by activating CASP1
  • recognition of extracellular Ca2+ through CASR activates the NLRP3 inflammasome
  • BRCC3, is a critical regulator of NLRP3 activity by promoting its deubiquitination
  • TRPM2 is a key factor that links oxidative stress to the NLRP3 inflammasome activation
  • DHX33 is a cytosolic RNA sensor that activates the NLRP3 inflammasome
  • mitochondria play a critical role in the activation of the NLRP3 inflammasome through the direct binding of NLRP3 to cardiolipin
  • ATG7-induced CTSB overexpression contributes to an NLRP3-dependent proinflammatory response and subsequently impairs glucose-stimulated insulin secretion (GSIS) independently of apoptosis
  • MAVS facilitates the recruitment of NLRP3 to the mitochondria and may enhance its oligomerization and activation by bringing it in close proximity to mitochondrial reactive oxygen species
  • MFN2 is required for the full activation of the NLRP3 inflammasomes in macrophages
  • NLRP3 inflammasome activates CASP1, which cleaves pro–IL1B to mature forms and stimulates their secretion
  • lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1B, via ARRB2 and HCAR1
  • ubiquitination of DHX33 by TRIM33 is lysine 63 specific and is required for the formation of the DHX33-NLRP3 inflammasome complex
  • is a transcriptional target of NR1I2 (NR1I2 regulates innate immunity via activation of NLRP3 inflammasome in vascular endothelial cells)
  • GPSM3 acts as a direct negative regulator of NLRP3 function
  • ARRB1 plays a critical role in the assembly and activation of two major canonical inflammasomes, NLRC4, NLRP3
  • BTK physically interacts with PYCARD and NLRP3
  • CASP4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells
  • PLIN2 inhibits insulin&
    • 8209;induced glucose uptake by activating NLRP3, CASP1 and IL1B, leading to a decreased IRS1 expression
  • LRRFIP2 and FLII is required for the co-localization of the NLRP3 and F-actin as well as for the inhibition of NLRP3 inflammasome activity
  • TRIM31 is a feedback suppressor of NLRP3 inflammasome
  • bile acids and NR1H4 play pivotal roles in sepsis via controlling the NLRP3 inflammasome
  • endogenous NLRC3 interacts with both PYCARD and pro-caspase-1 but not with NLRP3, disrupts PYCARD speck formation through its CARD, and impairs the PYCARD and pro-caspase-1 interaction
  • CXCL1 and CXCL2 regulate NLRP3 inflammasome activation via G-Protein-Coupled Receptor CXCR2
  • MAP3K5, MAP3K6 was required for NLRP3 up-regulation after lipopolysaccharide treatment in primary bone marrow-derived macrophages and lung fibroblasts as well as during infection with Burkholderia thailandensis and influenza virus
  • HSPD1 further activates NLRP3 inflammasome by elevating NLRP3 expression both at RNA and protein levels
  • STAMBP is a negative regulator of the NLRP3 inflammasome
  • non-degradative ubiquitination of NLRP3 by STAMBP to limit excessive inflammasome activation and to reduce injurious IL1B signaling
  • TRIM28 binds NLRP3, promotes SUMO1, SUMO2 and SUMO3 modification of NLRP3, and thereby inhibits NLRP3 ubiquitination and proteasomal degradation
    • cell & other
    REGULATION
    activated by by elevated levels of glucose, cholesterol crystals, and amyloid beta
    inhibited by recruited by ASC to distinct cytoplasmic loci and inducing NF-kappa B activation and caspase 1 cytokine processing
    Other is rapidly and directly regulated by glucocorticoids
    activation of the NLRP3 inflammasome requires Ca2+ signaling
    ASSOCIATED DISORDERS
    corresponding disease(s) FCU , MWS , CINCA , DFNA34
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    in autoinflammatory disease
    constitutional     --over  
    higher in MVK patients higher than in untreated healthy controls
    constitutional       gain of function
    in age-related macular degeneration (AMD)
    constitutional germinal mutation      
    in NLRP3 in ischemic heart tissues but not in non-ischemic control tissue
    constitutional       loss of function
    deficiency leads to decreased APP levels and deposition
    constitutional       gain of function
    activation of the NLRP1 and NLRP3 inflammasomes in Alzheimer disease
    Susceptibility
  • to essential hypertension
  • to autoinflammatory disease and to psoriatic juvenile idiopathic arthritis
  • to Crohn disease
    • Variant & Polymorphism SNP , insertion/deletion
  • homozygote of 12 repeat allele VNTR was significantly higher in patients with hypertension
  • SNP increasing the risk of Crohn disease
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cardiovascularaquired 
    could open new avenues to therapeutic intervention
    miscelleaneoussenescence 
    innovative therapeutic strategy to lower NLRP3 activity to delay multiple age-related chronic diseases
    neurosensorialvisualdegenerative
    therapeutic inhibition of both VEGFA and IL1B or the NLRP3 inflammasome is therefore likely to suppress both forms of AMD
    neurologyneurodegenerativealzheimer
    NLRP3 inflammasome inhibition represents a novel therapeutic intervention for AD
    ANIMAL & CELL MODELS
  • Nlrp3(-/-) mice displa high susceptiblity of infection with a pathogenic influenza A virus (
  • mice carrying a mutation in the Nlrp3 gene produce massive amounts of IL-1beta upon stimulation with microbial stimuli, skin inflammation characterized by neutrophil infiltration and a Th17 cytokine-dominant response (
  • Nlrp3(-/-) mice exhibited delayed neuroinflammation, demyelination, and oligodendrocyte loss
  • ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling
  • mice lacking Nlrp3 or caspase-1 showed decreased joint pathology in an ank-deficient model of arthritis
  • Nlrp3-/- mice are resistant to the development of Experimental autoimmune encephalomyelitis (EAE), suggesting the association of the NLRP3 inflammasome with EAE development