NLRP3

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" {{cite journal | vauthors = Koonin EV, Aravind L | title = The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation | journal = Trends in Biochemical Sciences | volume = 25 | issue = 5 | pages = 223–4 | date = May 2000 | pmid = 10782090 | doi = 10.1016/S0968-0004(00)01577-2 }}{{cite journal | vauthors = Pueyo I, Jiménez JR, Hernández J, Brugarolas A, García-Morán M, García-Muñiz JL, Arroyo F | title = Carcinoid syndrome treated by hepatic embolization | journal = AJR. American Journal of Roentgenology | volume = 131 | issue = 3 | pages = 511–3 | date = Sep 1978 | pmid = 99001 | doi = 10.2214/ajr.131.3.511 | doi-access = free }} and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"{{cite journal | vauthors = Jha S, Ting JP | title = Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases | journal = Journal of Immunology | volume = 183 | issue = 12 | pages = 7623–9 | date = Dec 2009 | pmid = 20007570 | pmc = 3666034| doi = 10.4049/jimmunol.0902425 }}
• PYD – "PYRIN domain," after the pyrin proteins.{{cite journal | vauthors = Bertin J, DiStefano PS | title = The PYRIN domain: a novel motif found in apoptosis and inflammation proteins | journal = Cell Death and Differentiation | volume = 7 | issue = 12 | pages = 1273–4 | date = Dec 2000 | pmid = 11270363 | doi = 10.1038/sj.cdd.4400774 | department = review | doi-access = free }} 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).{{uniprot|Q96P20}}

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.

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.{{cite journal | vauthors = Martinon F | title = Detection of immune danger signals by NALP3 | journal = Journal of Leukocyte Biology | volume = 83 | issue = 3 | pages = 507–11 | date = Mar 2008 | pmid = 17982111 | doi = 10.1189/jlb.0607362 | department = review | doi-access = free }}

The NLRP3 inflammasome appears to be activated by changes in intracellular potassium{{cite journal |last1=Tapia-Abellán |first1=Ana |last2=Angosto-Bazarra |first2=Diego |last3=Alarcón-Vila |first3=Cristina |last4=Baños |first4=María C. |last5=Hafner-Bratkovič |first5=Iva |last6=Oliva |first6=Baldomero |last7=Pelegrín |first7=Pablo |date=2021-09-17 |title=Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation |journal=Science Advances |language=en |volume=7 |issue=38 |pages=eabf4468 |doi=10.1126/sciadv.abf4468 |issn=2375-2548 |pmc=8443177 |pmid=34524838|bibcode=2021SciA....7.4468T }} caused by potassium efflux from mechanosensitive ion channels located in the cell membrane.{{cite journal | vauthors = Hari A, Zhang Y, Tu Z, Detampel P, Stenner M, Ganguly A, Shi Y | title = Activation of NLRP3 inflammasome by crystalline structures via cell surface contact | journal = Scientific Reports | volume = 4 | year = 2014 | pmid = 25445147 | doi = 10.1038/srep07281 | pages=7281 | pmc=4250918| bibcode = 2014NatSR...4E7281H }} It appears that NLRP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.{{cite journal | vauthors = Haneklaus M, O'Neill LA, Coll RC | title = Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments | journal = Current Opinion in Immunology | volume = 25 | issue = 1 | pages = 40–45 | date = Feb 2013 | pmid = 23305783 | doi = 10.1016/j.coi.2012.12.004 | department = review | hdl = 2262/72554 | hdl-access = free }}

It is suggested that NLRP3 provides protection against Streptococcus pneumoniae infections by activating STAT6 and SPDEF.{{cite journal | vauthors = Fang R, Uchiyama R, Sakai S, Hara H, Tsutsui H, Suda T, Mitsuyama M, Kawamura I, Tsuchiya K | title = ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism | journal = Mucosal Immunology | volume = 12 | issue = 5 | pages = 1092–1103 | date = September 2019 | pmid = 31278375 | doi = 10.1038/s41385-019-0181-1 | doi-access = free }}

Mutations in the NLRP3 gene result in autoactive inflammasomes{{cite journal |last1=Molina-López |first1=Cristina |last2=Hurtado-Navarro |first2=Laura |last3=García |first3=Carlos J. |last4=Angosto-Bazarra |first4=Diego |last5=Vallejo |first5=Fernando |last6=Tapia-Abellán |first6=Ana |last7=Marques-Soares |first7=Joana R. |last8=Vargas |first8=Carmen |last9=Bujan-Rivas |first9=Segundo |last10=Tomás-Barberán |first10=Francisco A. |last11=Arostegui |first11=Juan I. |last12=Pelegrin |first12=Pablo |date=2024-02-06 |title=Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production |journal=Nature Communications |language=en |volume=15 |issue=1 |page=1096 |doi=10.1038/s41467-024-44990-0 |pmid=38321014 |issn=2041-1723|pmc=10847128 |bibcode=2024NatCo..15.1096M }} 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.{{cite journal | vauthors = Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT | title = 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 | journal = American Journal of Ophthalmology | volume = 184 | pages = 41–50| date = Jan 2018 | pmid = 29366613 | doi = 10.1016/j.ajo.2018.01.017 | doi-access = free }}

Defects in this gene have also been linked to familial Mediterranean fever.{{cite journal | vauthors = Church LD, Cook GP, McDermott MF | title = Primer: inflammasomes and interleukin 1beta in inflammatory disorders | journal = Nature Clinical Practice Rheumatology | volume = 4 | issue = 1 | pages = 34–42 | date = Jan 2008 | pmid = 18172447 | doi = 10.1038/ncprheum0681 | s2cid = 19986204 | department = review }} In addition, the NLRP3 inflammasome has a role in the pathogenesis of gout, hemorrhagic stroke{{cite journal | vauthors = Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J | title = Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update | journal = J Cereb Blood Flow Metab | date = May 2020 | volume = 40 | issue = 9 | pages = 1752–1768 | pmid = 32423330 | doi = 10.1177/0271678X20923551 | pmc = 7446569 }} and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases.{{cite journal | vauthors = Liu-Bryan R | title = Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome | journal = Immunology and Cell Biology | volume = 88 | issue = 1 | pages = 20–3 | date = Jan 2010 | pmid = 19935768 | pmc = 4337950 | doi = 10.1038/icb.2009.93 | department = review }}{{cite journal | vauthors = 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 | title = NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice | journal = Nature | volume = 493 | issue = 7434 | pages = 674–8 | date = Jan 2013 | pmid = 23254930 | pmc = 3812809 | doi = 10.1038/nature11729 | bibcode = 2013Natur.493..674H }}{{cite journal | vauthors = Shi F, Kouadir M, Yang Y | title = NALP3 inflammasome activation in protein misfolding diseases | journal = Life Sciences | volume = 135 | pages = 9–14 | date = Aug 2015 | pmid = 26037399 | doi = 10.1016/j.lfs.2015.05.011 | department = review }} 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.{{cite journal |author3-link=Eran Elinav |vauthors=Levy M, Thaiss CA, Elinav E |year=2015 |title=Taming the inflammasome |url=https://www.nature.com/articles/nm.3808 |journal=Nature Medicine |volume=21 |issue=3 |pages=213–215 |doi=10.1038/nm.3808 |pmid=25742454 |s2cid=6659540|url-access=subscription }} The compound β-hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.{{cite journal | vauthors=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 | title=The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease | journal= Nature Medicine | volume=21 | issue=3 | pages=263–269 | year=2015 | doi= 10.1038/nm.3804| pmid = 25686106 | pmc=4352123 }}

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.{{cite journal | vauthors = Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L | title = Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression | journal = Laboratory Investigation | volume = 94 | issue = 1 | pages = 52–62 | date = Jan 2014 | pmid = 24166187 | doi = 10.1038/labinvest.2013.126 | doi-access = free }}

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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{{cite journal | vauthors = Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA | title = A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases | journal = Nature Medicine | volume = 21 | issue = 3 | pages = 248–55 | date = March 2015 | pmid = 25686105 | pmc = 4392179 | doi = 10.1038/nm.3806 }} able to lock the inactive NLRP3 structure.{{cite journal |last1=Tapia-Abellán |first1=Ana |last2=Angosto-Bazarra |first2=Diego |last3=Martínez-Banaclocha |first3=Helios |last4=de Torre-Minguela |first4=Carlos |last5=Cerón-Carrasco |first5=Jose P. |last6=Pérez-Sánchez |first6=Horacio |last7=Arostegui |first7=Juan I. |last8=Pelegrin |first8=Pablo |date=June 2019 |title=MCC950 closes the active conformation of NLRP3 to an inactive state |journal=Nature Chemical Biology |language=en |volume=15 |issue=6 |pages=560–564 |doi=10.1038/s41589-019-0278-6 |issn=1552-4450 |pmc=7116292 |pmid=31086329}} 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.{{cite web|last=Alzheimer's Drug Discovery Foundation.|first=Dapansutrile.|title=Dapansutrile|url=https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Dapansutrile-Cognitive-Vitality-For-Researchers.pdf}}

{{Reflist}}

• {{PDBe-KB2|Q96P20|NACHT, LRR and PYD domains-containing protein 3}}

{{NOD-like receptors}}

{{DEFAULTSORT:Nalp3}}

Category:LRR proteins

Category:Human proteins

Category:NOD-like receptors