NLRP3

NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 [NALP3] and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene[5] located on the long arm of chromosome 1.[6]

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
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q44 Start 247,416,156 bp[1] End 247,449,108 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B1.3 Start 59,541,568 bp[2] End 59,566,956 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • sequence-specific DNA binding • nucleotide binding • transcription factor binding • GO:0001948 protein binding • peptidoglycan binding • ATP binding • identical protein binding Cellular component • cytoplasm • cytosol • extracellular region • endoplasmic reticulum • inflammasome • cell 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-1 secretion • 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 oligomerization • positive regulation of interleukin-1 beta secretion • 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 • negative regulation of interleukin-1 beta secretion • positive regulation of T-helper 2 cell cytokine production • signal transduction • positive regulation of transcription from RNA polymerase II promoter • apoptotic process • innate immune system • protein deubiquitination • cytokine secretion involved in immune response • 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: 59.54 – 59.57 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome,[7][8]^:436 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" [9][10] and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"[11]
• PYD – "PYRIN domain," after the pyrin proteins[12] The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."[11]

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

• cold induced autoinflammatory syndrome 1 (CIAS1),
• caterpiller-like receptor 1.1 (CLR1.1), and
• PYRIN-containing APAF1-like protein 1 (PYPAF1).[13]

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.[5]

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).[14] 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.[14]

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.[15] It appears that NLRP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.[16]

It is suggested that NLRP3 provides protection against Streptococcus pneumoniae infections by activating STAT6 and SPDEF.[17]

Pathology

Mutations in the NLRP3 gene 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.[5][18]

Defects in this gene have also been linked to familial Mediterranean fever.[19] In addition, the NLRP3 inflammasome has a role in the pathogenesis of gout[14], hemorrhagic stroke[20] and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases.[21][22][23] 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.[24] The compound β-Hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.[25]

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.[26]

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, Wanderer AA, Kolodner RD (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, Brugarolas A, García-Morán M, García-Muñiz JL, Arroyo F (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.
11. Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". Journal of Immunology. 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
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. Hari A, Zhang Y, Tu Z, Detampel P, Stenner M, Ganguly A, Shi Y (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.
16. Haneklaus M, O'Neill LA, Coll RC (Feb 2013). "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". review. Current Opinion in Immunology. 25 (1): 40–45. doi:10.1016/j.coi.2012.12.004. hdl:2262/72554. PMID 23305783.
17. Fang, Rendong; Uchiyama, Ryosuke; Sakai, Shunsuke; Hara, Hideki; Tsutsui, Hiroko; Suda, Takashi; Mitsuyama, Masao; Kawamura, Ikuo; Tsuchiya, Kohsuke (2019). "ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism". Mucosal Immunology. 12 (5): 1092–1103. doi:10.1038/s41385-019-0181-1. ISSN 1933-0219. PMID 31278375.
18. Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT (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.
19. 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.
20. Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J (May 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". J Cereb Blood Flow Metab. doi:10.1177/0271678X20923551. PMID 32423330.
21. 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.
22. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (Jan 2013). "NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice". Nature. 493 (7434): 674–8. Bibcode:2013Natur.493..674H. doi:10.1038/nature11729. PMC 3812809. PMID 23254930.
23. Shi F, Kouadir M, Yang Y (Aug 2015). "NALP3 inflammasome activation in protein misfolding diseases". review. Life Sciences. 135: 9–14. doi:10.1016/j.lfs.2015.05.011. PMID 26037399.
24. Levy M, Thaiss CA, Elinav E (2015). "Taming the inflammasome" (PDF). Nature Medicine. 21 (3): 213–215. doi:10.1038/nm.3808. PMID 25742454.
25. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD (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.
26. Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L (Jan 2014). "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation. 94 (1): 52–62. doi:10.1038/labinvest.2013.126. PMID 24166187.

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.