NLRP3

This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NALP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID). Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Oct 2008]

NLR Family Pyrin Domain Containing 3

As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu (PubMed:28847925, PubMed:33231615, PubMed:34133077, PubMed:34341353).
Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494).
The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:34133077).
Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K+ efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. Activation upon, at least, K+ efflux is mediated by the interaction wit NEK7 (By similarity).
Activation in presence of cytosolic dsRNA is mediated by DHX33 (PubMed:23871209).
Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (By similarity).
During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity).

Apoptotic process1 PublicationNAS:UniProtKB
Cellular response to lipopolysaccharideManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to virusManual Assertion Based On ExperimentIDA:UniProtKB
Defense responseManual Assertion Based On ExperimentTAS:HGNC-UCL
Detection of biotic stimulusManual Assertion Based On ExperimentTAS:HGNC-UCL
Inflammatory responseManual Assertion Based On ExperimentIMP:UniProtKB
Innate immune responseIEA:UniProtKB-KW
Negative regulation of acute inflammatory responseManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of inflammatory responseManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of interleukin-1 beta productionManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentIDA:HGNC-UCL
Negative regulation of NIK/NF-kappaB signalingManual Assertion Based On ExperimentIDA:HGNC-UCL
NLRP3 inflammasome complex assemblyManual Assertion Based On ExperimentIDA:UniProtKB
Osmosensory signaling pathway1 PublicationIC:ComplexPortal
Pattern recognition receptor signaling pathway1 PublicationIC:ComplexPortal
Positive regulation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentIDA:HGNC-UCL
Positive regulation of inflammatory response1 PublicationIC:ComplexPortal
Positive regulation of interleukin-1 beta productionManual Assertion Based On ExperimentIDA:HGNC-UCL
Positive regulation of interleukin-4 productionISS:UniProtKB
Positive regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of T-helper 2 cell cytokine productionISS:UniProtKB
Positive regulation of T-helper 2 cell differentiationISS:UniProtKB
Positive regulation of transcription by RNA polymerase IIISS:UniProtKB
Positive regulation of type 2 immune responseISS:UniProtKB
Pyroptosis1 PublicationIC:ComplexPortal
Signal transduction1 PublicationNAS:UniProtKB

Cytoplasm, cytosol
Inflammasome
Endoplasmic reticulum
Secreted
Nucleus
In macrophages, under resting conditions, mainly located in the cytosol, on the endoplasmic reticulum. After stimulation with inducers of the NLRP3 inflammasome, mitochondria redistribute in the vicinity of the endoplasmic reticulum in the perinuclear region, which results in colocalization of NLRP3 on the endoplasmic reticulum and PYCARD on mitochondria, allowing the activation of inflammasome assembly. After the induction of pyroptosis, inflammasome specks are released into the extracellular space where they can further promote IL1B processing and where they can be engulfed by macrophages. Phagocytosis induces lysosomal damage and inflammasome activation in the recipient cells (PubMed:24952504).
In the Th2 subset of CD4+ helper T-cells, mainly located in the nucleus. Nuclear localization depends upon KPNA2. In the Th1 subset of CD4+ helper T-cells, mainly cytoplasmic (By similarity).
Golgi apparatus membrane
(Microbial infection) Upon HRSV infection, the protein is mainly located in lipid rafts in the Golgi membrane.

Familial cold autoinflammatory syndrome 1 (FCAS1):
A rare autosomal dominant systemic inflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. Rarely, some patients may also develop late-onset renal amyloidosis.
Muckle-Wells syndrome (MWS):
A hereditary periodic fever syndrome characterized by fever, chronic recurrent urticaria, arthralgias, progressive sensorineural deafness, and reactive renal amyloidosis. The disease may be severe if generalized reactive amyloidosis occurs.
Chronic infantile neurologic cutaneous and articular syndrome (CINCA):
Rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation.
Keratoendothelitis fugax hereditaria (KEFH):
An autosomal dominant corneal disease that periodically, and fleetingly, affects the corneal endothelium, stroma, and vision, eventually leading to central corneal stromal opacities in some patients. The disease is characterized by unilateral attacks of ocular pain, pericorneal injection, and photophobia. The acute symptoms vanish in 1-2 days but vision remains blurry for several weeks. The attacks start at the age of 3-12 years and can affect either eye. They generally decrease in frequency and get milder with age.
Deafness, autosomal dominant, 34, with or without inflammation (DFNA34):
A form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA34 is a postlingual, slowly progressive form with variable severity and variable additional features. Some DFNA34 patients have autoinflammatory manifestations.

The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation.
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. Ubiquitination does not lead to degradation, but inhibits inflammasome activation (By similarity).
Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly. This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP.