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NLRP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3QF2, 2NAQ
Identifiers
Aliases	NLRP3, AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1, FCAS, FCAS1, FCU, MWS, NALP3, PYPAF1, NLR family, pyrin domain containing 3, NLR family pyrin domain containing 3, DFNA34, KEFH
External IDs	OMIM: 606416; MGI: 2653833; HomoloGene: 3600; GeneCards: NLRP3; OMA:NLRP3 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q44 Start 247,416,156 bp End 247,449,108 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11|11 B1.3 Start 59,432,394 bp End 59,457,782 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte blood bone marrow cells gallbladder testicle right lung appendix upper lobe of left lung spleen Top expressed in granulocyte blood stroma of bone marrow morula calvaria spleen submandibular gland gastrula olfactory epithelium meninges More reference expression data BioGPS More reference expression data
Gene ontology Molecular function sequence-specific DNA binding nucleotide binding transcription factor binding protein binding peptidoglycan binding ATP binding identical protein binding Cellular component cytoplasm cytosol extracellular region endoplasmic reticulum inflammasome complex nucleus NLRP3 inflammasome complex Golgi membrane Golgi apparatus membrane Biological process defense response detection of biotic stimulus NLRP3 inflammasome complex assembly regulation of transcription, DNA-templated negative regulation of acute inflammatory response positive regulation of interleukin-5 production interleukin-18 production immune system process positive regulation of interleukin-4 production transcription, DNA-templated positive regulation of cysteine-type endopeptidase activity involved in apoptotic process positive regulation of interleukin-13 production positive regulation of T-helper 17 cell differentiation defense response to virus protein complex oligomerization positive regulation of T-helper 2 cell differentiation regulation of inflammatory response interleukin-1 beta production positive regulation of type 2 immune response inflammatory response negative regulation of NF-kappaB transcription factor activity activation of cysteine-type endopeptidase activity involved in apoptotic process negative regulation of inflammatory response cellular response to lipopolysaccharide positive regulation of T-helper 2 cell cytokine production signal transduction positive regulation of transcription by RNA polymerase II apoptotic process innate immune response protein deubiquitination defense response to Gram-positive bacterium positive regulation of NF-kappaB transcription factor activity cellular response to peptidoglycan negative regulation of NIK/NF-kappaB signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 114548 216799 Ensembl ENSG00000162711 ENSMUSG00000032691 UniProt Q96P20 Q8R4B8 RefSeq (mRNA) NM_001079821 NM_001127461 NM_001127462 NM_001243133 NM_004895 NM_183395 NM_145827 NM_001359638 RefSeq (protein) NP_001073289 NP_001120933 NP_001120934 NP_001230062 NP_004886 NP_899632 NP_665826 NP_001346567 Location (UCSC) Chr 1: 247.42 – 247.45 Mb Chr 11: 59.43 – 59.46 Mb PubMed search
Wikidata
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NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR, and PYD domains-containing protein 3 and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome, detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

Nomenclature

NACHT, LRR, and PYD are respectively acronyms for:

• NACHT – NAIP (neuronal apoptosis inhibitor protein), C2TA [class 2 transcription activator, of the MHC, HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1)
• LRR – "leucine-rich repeat" and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"
• PYD – "PYRIN domain," after the pyrin proteins. The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."

The NACHT, LRR and PYD domains-containing protein 3 is also called:

• cold induced autoinflammatory syndrome 1 (CIAS1),
• caterpillar-like receptor 1.1 (CLR1.1), and
• PYRIN-containing APAF1-like protein 1 (PYPAF1).

Structure

This gene encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with pyrin domain (PYD) of apoptosis-associated speck-like protein containing a CARD (ASC). Proteins which contain the caspase recruitment domain, CARD, have been shown to be involved in inflammation and immune response.

Function

NLRP3 is a component of the innate immune system that functions as a pattern recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs). NLRP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NLRP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NLRP3 inflammasome. NLRP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NLRP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NLRP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.

The NLRP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane. It appears that NLRP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.

It is suggested that NLRP3 provides protection against Streptococcus pneumoniae infections by activating STAT6 and SPDEF.

Pathology

Mutations in the NLRP3 gene result in autoactive inflammasomes and have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS). This includes familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria.

Defects in this gene have also been linked to familial Mediterranean fever. In addition, the NLRP3 inflammasome has a role in the pathogenesis of gout, hemorrhagic stroke and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases. Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout, type 2 diabetes, multiple sclerosis, Alzheimer's disease, and atherosclerosis. The compound β-hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.

Deregulation of NLRP3 has been connected with carcinogenesis. For example, all the components of the NLRP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.

Inhibition

The NLRP3 inflammasome has garnered attention as a potential drug target for a variety of diseases underpinned by inflammation. The diarylsulfonylurea MCC-950 has been identified as a potent and selective NLRP3 inhibitor able to lock the inactive NLRP3 structure. Nodthera and Inflazome, have entered phase I clinical trials with NLRP3 inhibitors. Another NLRP3 antagonist is Dapansutrile (OLT1177). This β-sulfonyl nitrile molecule compound was developed by Olactec Therapeutics, and is a selective NLRP3 inhibitor. Dapansutrile, been used in clinical trials as a remedy for heart failure, osteoarthritis and gouty arthritis.

References and notes

1. ^ GRCh38: Ensembl release 89: ENSG00000162711 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000032691 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human)], Gene ID: 114548 (updated on 13-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015.
6. Hoffman HM, Wright FA, Broide DH, et al. (May 2000). "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics. 66 (5): 1693–8. doi:10.1086/302874. PMC 1378006. PMID 10741953.
7. Tao JH, Zhang Y, Li XP (Dec 2013). "P2X7R: a potential key regulator of acute gouty arthritis". review. Seminars in Arthritis and Rheumatism. 43 (3): 376–80. doi:10.1016/j.semarthrit.2013.04.007. PMID 23786870.
8. Lu A, Wu H (Feb 2015). "Structural mechanisms of inflammasome assembly". review. The FEBS Journal. 282 (3): 435–44. doi:10.1111/febs.13133. PMC 6400279. PMID 25354325.
9. Koonin EV, Aravind L (May 2000). "The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation". Trends in Biochemical Sciences. 25 (5): 223–4. doi:10.1016/S0968-0004(00)01577-2. PMID 10782090.
10. Pueyo I, Jiménez JR, Hernández J, et al. (Sep 1978). "Carcinoid syndrome treated by hepatic embolization". AJR. American Journal of Roentgenology. 131 (3): 511–3. doi:10.2214/ajr.131.3.511. PMID 99001.
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12. Bertin J, DiStefano PS (Dec 2000). "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". review. Cell Death and Differentiation. 7 (12): 1273–4. doi:10.1038/sj.cdd.4400774. PMID 11270363.
13. Q96P20
14. ^ Martinon F (Mar 2008). "Detection of immune danger signals by NALP3". review. Journal of Leukocyte Biology. 83 (3): 507–11. doi:10.1189/jlb.0607362. PMID 17982111.
15. Tapia-Abellán A, Angosto-Bazarra D, Alarcón-Vila C, et al. (2021-09-17). "Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation". Science Advances. 7 (38): eabf4468. Bibcode:2021SciA....7.4468T. doi:10.1126/sciadv.abf4468. ISSN 2375-2548. PMC 8443177. PMID 34524838.
16. Hari A, Zhang Y, Tu Z, et al. (2014). "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports. 4: 7281. Bibcode:2014NatSR...4E7281H. doi:10.1038/srep07281. PMC 4250918. PMID 25445147.
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19. Molina-López C, Hurtado-Navarro L, García CJ, et al. (2024-02-06). "Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production". Nature Communications. 15 (1): 1096. Bibcode:2024NatCo..15.1096M. doi:10.1038/s41467-024-44990-0. ISSN 2041-1723. PMC 10847128. PMID 38321014.
20. Turunen JA, Wedenoja J, Repo P, et al. (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184: 41–50. doi:10.1016/j.ajo.2018.01.017. PMID 29366613.
21. Church LD, Cook GP, McDermott MF (Jan 2008). "Primer: inflammasomes and interleukin 1beta in inflammatory disorders". review. Nature Clinical Practice Rheumatology. 4 (1): 34–42. doi:10.1038/ncprheum0681. PMID 18172447. S2CID 19986204.
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23. Liu-Bryan R (Jan 2010). "Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome". review. Immunology and Cell Biology. 88 (1): 20–3. doi:10.1038/icb.2009.93. PMC 4337950. PMID 19935768.
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27. Youm YH, Nguyen KY, Grant RW, et al. (2015). "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease". Nature Medicine. 21 (3): 263–269. doi:10.1038/nm.3804. PMC 4352123. PMID 25686106.
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31. Alzheimer's Drug Discovery Foundation D. "Dapansutrile" (PDF).

External links

• Overview of all the structural information available in the PDB for UniProt: Q96P20 (NACHT, LRR and PYD domains-containing protein 3) at the PDBe-KB.

• Genes on human chromosome 1
• LRR proteins
• Human proteins
• NOD-like receptors