NALP3

NLR family, pyrin domain containing 3
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3QF2​
Identifiers
Symbols	NLRP3 ; AGTAVPRL; AII; AVP; C1orf7; CIAS1; CLR1.1; FCAS; FCAS1; FCU; MWS; NALP3; PYPAF1
External IDs	OMIM: 606416 MGI: 2653833 HomoloGene: 3600 ChEMBL: 1741208 GeneCards: NLRP3 Gene
Gene ontology Molecular function • protein binding • ATP binding • peptidoglycan binding Cellular component • cytoplasm • cytosol • NLRP3 inflammasome complex Biological process • negative regulation of acute inflammatory response • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic process • defense response • inflammatory response • signal transduction • detection of biotic stimulus • negative regulation of NF-kappaB transcription factor activity • interleukin-1 beta production • interleukin-18 production • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • negative regulation of NF-kappaB import into nucleus • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • NLRP3 inflammasome complex assembly • innate immune response • interleukin-1 secretion • negative regulation of interleukin-1 beta secretion • positive regulation of interleukin-1 beta secretion • negative regulation of inflammatory response • positive regulation of NF-kappaB transcription factor activity • protein oligomerization • defense response to virus • cellular response to lipopolysaccharide Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	114548	216799
Ensembl	ENSG00000162711	ENSMUSG00000032691
UniProt	Q96P20	Q8R4B8
RefSeq (mRNA)	NM_001079821	NM_145827
RefSeq (protein)	NP_001073289	NP_665826
Location (UCSC)	Chr 1: 247.42 – 247.45 Mb	Chr 11: 59.54 – 59.57 Mb
PubMed search

NACHT, LRR and PYD domains-containing protein 3 (NALP3) also known by cryopyrin is a protein that in humans is encoded by the NLRP3 gene^[1] located on the long arm of chromosome 1.^[2]

NALP3 is expressed predominantly in macrophages and as a component of the inflammasome,^[3][4]:436 detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NALP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated 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" ^[5][6] and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"^[7]
• PYD – "PYRIN domain," after the pyrin proteins^[8] The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."^[9]

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).^[10]

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.^[1]

Function

NALP3 is a component of the innate immune system that functions as a pathogen recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs).^[11] NALP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NALP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NALP3 inflammasome. NALP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NALP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release of HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NALP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.^[11]

The NALP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane.^[12] It appears that that NALP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.^[13]

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, and neonatal-onset multisystem inflammatory disease (NOMID).^[1]

Defects in this gene have also been linked to familial Mediterranean fever.^[14] In addition, the NALP3 inflammasome has a role in the pathogenesis of gout^[11] and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and Prion diseases.^[15][16][17]

Deregulation of NALP3 has been connected with carcinogenesis. For example, all the components of the NALP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.^[18]

References and notes

1. 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.
2. 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.
3. 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.
4. Lu A, Wu H (Feb 2015). "Structural mechanisms of inflammasome assembly". review. The FEBS Journal 282 (3): 435–44. doi:10.1111/febs.13133. PMID 25354325.
5. 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.
6. 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. PMC 99001. PMID 99001.
7. 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.
8. 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.
9. Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". review. Journal of Immunology 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
10. Q96P20
11. 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.
12. 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. doi:10.1038/srep07281. PMID 25445147.
13. 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. PMID 23305783.
14. 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.
15. 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.
16. 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. doi:10.1038/nature11729. PMC 3812809. PMID 23254930.
17. 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.
18. 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.

Further reading

• Jin T, Xiao TS (Feb 2015). "Activation and assembly of the inflammasomes through conserved protein domain families". review. Apoptosis 20 (2): 151–6. doi:10.1007/s10495-014-1053-5. PMID 25398536.
• Lu A, Wu H (Feb 2015). "Structural mechanisms of inflammasome assembly". review. The FEBS Journal 282 (3): 435–44. doi:10.1111/febs.13133. PMID 25354325.
• Shaw N, Liu ZJ (Jan 2014). "Role of the HIN domain in regulation of innate immune responses". review. Molecular and Cellular Biology 34 (1): 2–15. doi:10.1128/MCB.00857-13. PMC 3911281. PMID 24164899.
• Walsh JG, Muruve DA, Power C (Feb 2014). "Inflammasomes in the CNS". review. Nature Reviews. Neuroscience 15 (2): 84–97. doi:10.1038/nrn3638.
• Schroder K, Tschopp J (Mar 2010). "The inflammasomes". review. Cell 140 (6): 821–32. doi:10.1016/j.cell.2010.01.040. PMID 20303873.
• Jha S, Ting JP (Dec 2009). "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". review. Journal of Immunology 183 (12): 7623–9. doi:10.4049/jimmunol.0902425. PMC 3666034. PMID 20007570.
• Stutz A, Golenbock DT, Latz E (Dec 2009). "Inflammasomes: too big to miss". review. The Journal of Clinical Investigation 119 (12): 3502–11. doi:10.1172/JCI40599. PMC 2786809. PMID 19955661.
• McHale L, Tan X, Koehl P, Michelmore RW (2006). "Plant NBS-LRR proteins: adaptable guards". reviews. Genome Biology 7 (4): 212. doi:10.1186/gb-2006-7-4-212. PMC 1557992. PMID 16677430.
• Fink SL, Cookson BT (Apr 2005). "Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells". review. Infection and Immunity 73 (4): 1907–16. doi:10.1128/IAI.73.4.1907-1916.2005. PMC 1087413. PMID 15784530.
• Martinon F, Tschopp J (Aug 2005). "NLRs join TLRs as innate sensors of pathogens". review. Trends in Immunology 26 (8): 447–54. doi:10.1016/j.it.2005.06.004. PMID 15967716.
• Tschopp J, Martinon F, Burns K (Feb 2003). "NALPs: a novel protein family involved in inflammation". review. Nature Reviews Molecular Cell Biology 4 (2): 95–104. doi:10.1038/nrm1019. PMID 12563287.