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NLRP3 inflammasome complex assembly
Definition
Target type: biologicalprocess
The aggregation, arrangement and bonding together of a set of components to form the NLRP3 inflammasome complex, occurring at the level of an individual cell. [GOC:jl, PMID:21048113]
The NLRP3 inflammasome is a multiprotein complex that plays a critical role in the innate immune response to a variety of pathogens and danger signals. Its assembly is a tightly regulated process that involves multiple steps. The NLRP3 inflammasome is composed of three key components: NLRP3, ASC, and caspase-1.
1. **NLRP3 Activation:** The process begins with the activation of NLRP3, a member of the NOD-like receptor (NLR) family. NLRP3 activation can be triggered by a variety of stimuli, including microbial products (e.g., bacterial flagellin, lipopolysaccharide), environmental irritants (e.g., silica, asbestos), and cellular stress signals (e.g., reactive oxygen species, mitochondrial dysfunction).
2. **ASC Recruitment:** Upon activation, NLRP3 undergoes a conformational change, exposing its CARD domain. This allows NLRP3 to bind to the PYD domain of ASC, an adaptor protein. ASC is characterized by its PYD and CARD domains, which facilitate protein-protein interactions.
3. **Caspase-1 Recruitment:** ASC, in turn, interacts with pro-caspase-1 via its CARD domain. Pro-caspase-1 is an inactive precursor of the pro-inflammatory caspase-1. This association of NLRP3, ASC, and pro-caspase-1 forms the NLRP3 inflammasome complex.
4. **Caspase-1 Activation:** Within the inflammasome complex, pro-caspase-1 undergoes auto-cleavage and activation. This step is crucial for the complex's effector function.
5. **Inflammasome Activation:** The activated caspase-1 then cleaves the pro-inflammatory cytokines IL-1β and IL-18, converting them into their mature, bioactive forms. These cytokines are released from the cell and contribute to inflammation.
6. **Pyroptosis:** Activated caspase-1 also induces a form of programmed cell death called pyroptosis, characterized by cell swelling and lysis. Pyroptosis is a defense mechanism that eliminates infected cells and prevents the spread of pathogens.
The assembly and activation of the NLRP3 inflammasome is tightly regulated to prevent excessive inflammation and tissue damage. Aberrant inflammasome activation has been linked to a range of inflammatory diseases, including gout, type 2 diabetes, and inflammatory bowel disease.'
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Proteins (3)
| Protein | Definition | Taxonomy |
|---|---|---|
| NACHT, LRR and PYD domains-containing protein 3 | A NACHT, LRR and PYD domains-containing protein 3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96P20] | Homo sapiens (human) |
| NAD-dependent protein deacetylase sirtuin-2 | An NAD-dependent protein deacetylase sirtuin-2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8IXJ6] | Homo sapiens (human) |
| ATP-sensitive inward rectifier potassium channel 8 | An ATP-sensitive inward rectifier potassium channel 8 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q15842] | Homo sapiens (human) |
Compounds (48)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| niacinamide | nicotinamide : A pyridinecarboxamide that is pyridine in which the hydrogen at position 3 is replaced by a carboxamide group. | pyridine alkaloid; pyridinecarboxamide; vitamin B3 | anti-inflammatory agent; antioxidant; cofactor; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; EC 3.5.1.98 (histone deacetylase) inhibitor; Escherichia coli metabolite; geroprotector; human urinary metabolite; metabolite; mouse metabolite; neuroprotective agent; Saccharomyces cerevisiae metabolite; Sir2 inhibitor |
| bisindolylmaleimide i | bisindolylmaleimide I: a bis(indolyl)maleimide | ||
| 2-(1-(2-(1-methylpyrrolidino)ethyl)-1h-indol-3-yl)maleimide | bisindolylmaleimide II: protein kinase C inhibitor; see also bisindolylmaleimide I | ||
| bisindolylmaleimide iv | indoles; maleimides | ||
| bisindolylmaleimide v | bisindolylmaleimide V: used as a negative control compound for protein kinase C inhibition; structure in first source; | indoles | |
| glyburide | glyburide : An N-sulfonylurea that is acetohexamide in which the acetyl group is replaced by a 2-(5-chloro-2-methoxybenzamido)ethyl group. Glyburide: An antidiabetic sulfonylurea derivative with actions like those of chlorpropamide | monochlorobenzenes; N-sulfonylurea | anti-arrhythmia drug; EC 2.7.1.33 (pantothenate kinase) inhibitor; EC 3.6.3.49 (channel-conductance-controlling ATPase) inhibitor; hypoglycemic agent |
| go 6976 | indolocarbazole; organic heterohexacyclic compound | EC 2.7.11.13 (protein kinase C) inhibitor | |
| idebenone | 1,4-benzoquinones; primary alcohol | antioxidant; ferroptosis inhibitor | |
| nsc 664704 | kenpaullone : An indolobenzazepine that is paullone in which the hydrogen at position 9 is replaced by a bromo substituent. It is an ATP-competitive inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3beta (GSK3beta). kenpaullone: inhibits CDK1/cyclin B; structure in first source | indolobenzazepine; lactam; organobromine compound | cardioprotective agent; EC 2.7.11.22 (cyclin-dependent kinase) inhibitor; EC 2.7.11.26 (tau-protein kinase) inhibitor; geroprotector |
| fenamic acid | fenamic acid : An aminobenzoic acid that is the N-phenyl derivative of anthranilic acid. It acts as a parent skeleton for the synthesis of several non-steroidal anti-inflammatory drugs. fenamic acid: has chloride and potassium channel-blocking activity; RN given refers to parent cpd | aminobenzoic acid; secondary amino compound | membrane transport modulator |
| ro 31-8220 | Ro 31-8220: a protein kinase C inhibitor | imidothiocarbamic ester; indoles; maleimides | EC 2.7.11.13 (protein kinase C) inhibitor |
| fenofibrate | benzochromenone; delta-lactone; naphtho-alpha-pyrone | platelet aggregation inhibitor; Sir2 inhibitor | |
| suramin | suramin : A member of the class of phenylureas that is urea in which each of the amino groups has been substituted by a 3-({2-methyl-5-[(4,6,8-trisulfo-1-naphthyl)carbamoyl]phenyl}carbamoyl)phenyl group. An activator of both the rabbit skeletal muscle RyR1 and sheep cardiac RyR2 isoform ryanodine receptor channels, it has been used for the treatment of human African trypanosomiasis for over 100 years. Suramin: A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. | naphthalenesulfonic acid; phenylureas; secondary carboxamide | angiogenesis inhibitor; antinematodal drug; antineoplastic agent; apoptosis inhibitor; EC 2.7.11.13 (protein kinase C) inhibitor; GABA antagonist; GABA-gated chloride channel antagonist; purinergic receptor P2 antagonist; ryanodine receptor agonist; trypanocidal drug |
| suramin sodium | suramin sodium : An organic sodium salt that is the hexasodium salt of suramin. It is an FDA approved drug for African sleeping sickness and river blindness. | organic sodium salt | angiogenesis inhibitor; antinematodal drug; antineoplastic agent; apoptosis inhibitor; EC 2.7.11.13 (protein kinase C) inhibitor; GABA antagonist; GABA-gated chloride channel antagonist; purinergic receptor P2 antagonist; ryanodine receptor agonist; trypanocidal drug |
| n-cyano-n'-(1,1-dimethylpropyl)-n''-(3-pyridinyl)guanidine | N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine: potassium channel opener | pyridines | |
| toxoflavin | toxoflavin : A pyrimidotriazine that is 1,6-dimethyl-1,5,6,7-tetrahydropyrimido[5,4-e][1,2,4]triazine with oxo groups at positions 5 and 7. toxoflavin: azapteridine antibiotic; structure | carbonyl compound; pyrimidotriazine | antibacterial agent; antineoplastic agent; apoptosis inducer; bacterial metabolite; toxin; virulence factor; Wnt signalling inhibitor |
| cromakalim | Cromakalim: A potassium-channel opening vasodilator that has been investigated in the management of hypertension. It has also been tried in patients with asthma. (Martindale, The Extra Pharmacopoeia, 30th ed, p352) | ||
| zeneca zd 6169 | Zeneca ZD 6169: an ATP-sensitive potassium channel opener; structure given in first source | ||
| paullone | paullone : An indolobenzazepine that is 5,6,7,12-tetrahydroindolo[3,2-d][1]benzazepine carrying an oxo substituent at position 6. paullone: structure in first source | indolobenzazepine; lactam | EC 2.7.11.22 (cyclin-dependent kinase) inhibitor; EC 2.7.11.26 (tau-protein kinase) inhibitor |
| hyperforin | hyperforin : A cyclic terpene ketone that is a prenylated carbobicyclic acylphloroglucinol derivative produced by St. John's Wort, Hypericum perforatum. hyperforin: a prenylated acylphloroglucinol derivative; antibiotic component of novoimanine; psychoactive agent in St. John's wort; Russian; structure; | ||
| micheliolide | micheliolide: has antineoplastic activity; structure in first source | sesquiterpene lactone | |
| cromakalim | 1-benzopyran | ||
| resveratrol | trans-resveratrol : A resveratrol in which the double bond has E configuration. | resveratrol | antioxidant; phytoalexin; plant metabolite; quorum sensing inhibitor; radical scavenger |
| isoliquiritigenin | chalcones | antineoplastic agent; biological pigment; EC 1.14.18.1 (tyrosinase) inhibitor; GABA modulator; geroprotector; metabolite; NMDA receptor antagonist | |
| 1,6-anhydro-3,4-dideoxy-beta-d-glycero-hex-3-enopyran-2-ulose | 1,6-anhydro-3,4-dideoxyhex-3-enopyran-2-ulose: structure in first source | anhydrohexose; deoxyketohexose | |
| curcumin | curcumin : A beta-diketone that is methane in which two of the hydrogens are substituted by feruloyl groups. A natural dyestuff found in the root of Curcuma longa. Curcumin: A yellow-orange dye obtained from tumeric, the powdered root of CURCUMA longa. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. | aromatic ether; beta-diketone; diarylheptanoid; enone; polyphenol | anti-inflammatory agent; antifungal agent; antineoplastic agent; biological pigment; contraceptive drug; dye; EC 1.1.1.205 (IMP dehydrogenase) inhibitor; EC 1.1.1.21 (aldehyde reductase) inhibitor; EC 1.1.1.25 (shikimate dehydrogenase) inhibitor; EC 1.6.5.2 [NAD(P)H dehydrogenase (quinone)] inhibitor; EC 1.8.1.9 (thioredoxin reductase) inhibitor; EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor; EC 3.5.1.98 (histone deacetylase) inhibitor; flavouring agent; food colouring; geroprotector; hepatoprotective agent; immunomodulator; iron chelator; ligand; lipoxygenase inhibitor; metabolite; neuroprotective agent; nutraceutical; radical scavenger |
| 3-(1-azepanylsulfonyl)-n-(3-bromphenyl)benzamide | 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide: a sirtuin 2 inhibitor; structure in first source | ||
| 3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone | 3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone: a cystic fibrosis transmembrane conductance regulator inhibitor; structure in first source | ||
| 1,4-bis[2-(4-hydroxyphenyl)ethylamino]anthracene-9,10-dione | anthraquinone | ||
| sirtinol | aldimine; benzamides; naphthols | anti-inflammatory agent; EC 3.5.1.98 (histone deacetylase) inhibitor; Sir2 inhibitor | |
| cambinol | cambinol: inhibitor of human silent information regulator 2 enzymes; structure in first source | ||
| (4-chlorophenyl)-[4-(8-nitro-5-quinolinyl)-1-piperazinyl]methanone | N-arylpiperazine | ||
| ex 527 | 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide : A member of the class of carbazoles that is 2,3,4,9-tetrahydro-1H-carbazole which is substituted at position 1 by an aminocarbohyl group and at position 6 by a chlorine. 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide: structure in first source | carbazoles; monocarboxylic acid amide; organochlorine compound | |
| zm226600 | ZM226600: an ATP-sensitive potassium channel opener; structure in first source | anilide | |
| apigenin | Chamomile: Common name for several daisy-like plants (MATRICARIA; TRIPLEUROSPERMUM; ANTHEMIS; CHAMAEMELUM) native to Europe and Western Asia, now naturalized in the United States and Australia. | trihydroxyflavone | antineoplastic agent; metabolite |
| su 11248 | monocarboxylic acid amide; pyrroles | angiogenesis inhibitor; antineoplastic agent; EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor; immunomodulator; neuroprotective agent; vascular endothelial growth factor receptor antagonist | |
| panobinostat | panobinostat : A hydroxamic acid obtained by formal condensation of the carboxy group of (2E)-3-[4-({[2-(2-methylindol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enoic acid with the amino group of hydroxylamine. A histone deacetylase inhibitor used (as its lactate salt) in combination with bortezomib and dexamethasone for the treatment of multiple myeloma. Panobinostat: An indole and hydroxamic acid derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used as an antineoplastic agent in combination with BORTEZOMIB and DEXAMETHASONE for the treatment of MULTIPLE MYELOMA. | cinnamamides; hydroxamic acid; methylindole; secondary amino compound | angiogenesis modulating agent; antineoplastic agent; EC 3.5.1.98 (histone deacetylase) inhibitor |
| way 133537 | |||
| mcc-950 | |||
| oblongifolin c | oblongifolin C: has antineoplastic activity; isolated from Garcinia yunnanensis; structure in first source | ||
| quisinostat | indoles | ||
| srt1460 | SRT1460: small molecule activator of SIRT1 as therapeutics for the treatment of type 2 diabetes; structure in first source | ||
| srt1720 | |||
| srt2183 | SRT2183: small molecule activator of SIRT1 as therapeutics for the treatment of type 2 diabetes; structure in first source | ||
| tenovin-6 | tenovin-6 : A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-(dimethylamino)pentanoic acid with the aromatic amino group of N-[(4-aminophenyl)carbamothioyl]-4-tert-butylbenzamide. | monocarboxylic acid amide; tertiary amino compound; thioureas | antineoplastic agent; p53 activator; Sir2 inhibitor |
| acy-1215 | ricolinostat: an HDAC6 inhibitor; structure in first source | pyrimidinecarboxylic acid | |
| aristoforin | Aristoforin: derivative of hyperforin, is a potent anticancer agent; structure in first source | ||
| n-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide |