Porodica proteina NLR sa pirinskim domenom 3 (NLRP3) (ranije poznata kao NACHT, LRR i PYD domeni koji sadrže protein 3 [NALP3] i kriopirin), jest protein koji je kod ljudi kodiran genom NLRP3 sa dugog kraka hromosoma 1.[5][6]

NLRP3
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

3QF2, 2NAQ

Identifikatori
AliasiNLRP3
Vanjski ID-jeviOMIM: 606416 MGI: 2653833 HomoloGene: 3600 GeneCards: NLRP3
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za NLRP3
Genomska lokacija za NLRP3
Bend1q44Početak247,416,156 bp[1]
Kraj247,449,108 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za NLRP3
Genomska lokacija za NLRP3
Bend11|11 B1.3Početak59,432,394 bp[2]
Kraj59,457,782 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija sequence-specific DNA binding
nucleotide binding
transcription factor binding
GO:0001948, GO:0016582 vezivanje za proteine
peptidoglycan binding
ATP binding
vezivanje identičnih proteina
Ćelijska komponenta citoplazma
citosol
extracellular region
Endoplazmatski retikulum
Inflamasom
jedro
NLRP3 inflammasome complex
Golđijeva membrana
Golđijev aparat
membrana
Biološki proces defense response
detection of biotic stimulus
NLRP3 inflammasome complex assembly
GO:0009373 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
GO:0072468 Transdukcija signala
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
GO:0097285 apoptoza
Urođeni imunski sistem
protein deubiquitination
GO:0051637 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
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_001079821
NM_001127461
NM_001127462
NM_001243133
NM_004895

NM_183395

NM_145827
NM_001359638

RefSeq (bjelančevina)
NP_001073289
NP_001120933
NP_001120934
NP_001230062
NP_004886

NP_899632

NP_665826
NP_001346567

Lokacija (UCSC)Chr 1: 247.42 – 247.45 MbChr 11: 59.43 – 59.46 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

NLRP3 je eksprimiran pretežno u makrofagima i kao komponenta inflamasoma,[7][8]:436 otkriva produkte oštećenih ćelija kao što su vanćelijski ATP i kristali mokraćne kiseline. Aktivirani NLRP3 zauzvrat pokreće imunski odgovor. Mutacije u genu NLRP3 povezane su sa brojnim organskim specifičnim autoimunim bolestima.

Nomenklatura

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NACHT, LRR i PYD su akronimi za:

  • NACHTNAIP (neuronska apoptoza inhibitor proteina), C2TA [aktivator transkripcije klase 2, od MHC, HET-E (eterokarionska inkompatibilnost) i TP1 (protein 1 povezan s telomerazom)
  • LRR – "leucin-rsko ponavljanje"[9][10] i sinonim je za NLR, za ili nukleotid-vezujući domen, bogat leucinskimrponavljanjem"[11]
  • PYD – "PYRIN domen" prama pirinski proteini[12] Naziv gena NLRP3 skraćeno je od porodica "NLR, pirinski domen koji sadrži 3", gdje se NLR odnosi na "domen koji veže nukleotide, ponavljanje bogato leucinom."[11]

Protein 3 koji sadrži NACHT, LRR i PYD domene se također naziva:

  • hladnoćom izazvan autoupalni sindrom 1 (CIAS1),
  • gusjnecoliki receptor 1.1 (CLR1.1), i
  • protein 1 sličan APAF1 (PYPAF1) koji sadrži PYRIN.[13]

Struktura

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Ovaj gen kodira protein sličan pirinu koji sadrži pirinski domen, domenu nukleotidnog vezujućeg mjesta (NBS) i motiv leucinom bogato ponavljanje (LRR). Ovaj protein stupa u interakciju s pirinskim domenom (PYD) proteina nalik na tačkice povezanog s apoptozom koji sadrži CARD (ASC). Pokazalo se da su proteini koji sadrže kaspaza-regrutirani domen, CARD, uključeni u upalu i imunološki odgovor.[5]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 1.036 aminokiselina, a molekulska težina 118.173 Da.

1020304050
MKMASTRCKLARYLEDLEDVDLKKFKMHLEDYPPQKGCIPLPRGQTEKAD
HVDLATLMIDFNGEEKAWAMAVWIFAAINRRDLYEKAKRDEPKWGSDNAR
VSNPTVICQEDSIEEEWMGLLEYLSRISICKMKKDYRKKYRKYVRSRFQC
IEDRNARLGESVSLNKRYTRLRLIKEHRSQQEREQELLAIGKTKTCESPV
SPIKMELLFDPDDEHSEPVHTVVFQGAAGIGKTILARKMMLDWASGTLYQ
DRFDYLFYIHCREVSLVTQRSLGDLIMSCCPDPNPPIHKIVRKPSRILFL
MDGFDELQGAFDEHIGPLCTDWQKAERGDILLSSLIRKKLLPEASLLITT
RPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSDEAQARAAFSLIQ
ENEVLFTMCFIPLVCWIVCTGLKQQMESGKSLAQTSKTTTAVYVFFLSSL
LQPRGGSQEHGLCAHLWGLCSLAADGIWNQKILFEESDLRNHGLQKADVS
AFLRMNLFQKEVDCEKFYSFIHMTFQEFFAAMYYLLEEEKEGRTNVPGSR
LKLPSRDVTVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKI
SQQIRLELLKWIEVKAKAKKLQIQPSQLELFYCLYEMQEEDFVQRAMDYF
PKIEINLSTRMDHMVSSFCIENCHRVESLSLGFLHNMPKEEEEEEKEGRH
LDMVQCVLPSSSHAACSHGLVNSHLTSSFCRGLFSVLSTSQSLTELDLSD
NSLGDPGMRVLCETLQHPGCNIRRLWLGRCGLSHECCFDISLVLSSNQKL
VELDLSDNALGDFGIRLLCVGLKHLLCNLKKLWLVSCCLTSACCQDLASV
LSTSHSLTRLYVGENALGDSGVAILCEKAKNPQCNLQKLGLVNSGLTSVC
CSALSSVLSTNQNLTHLYLRGNTLGDKGIKLLCEGLLHPDCKLQVLELDN
CNLTSHCCWDLSTLLTSSQSLRKLSLGNNDLGDLGVMMFCEVLKQQSCLL
QNLGLSEMYFNYETKSALETLQEEKPELTVVFEPSW

Funkcija

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NLRP3 je komponenta urođenog imunskog sistema koja funkcionira kao receptor za prepoznavanje uzoraka (PRR) koji prepoznaje molekulskii uzorak povezan s patogenom (PAMP).[14] NLRP3 pripada NOD-olikim receptorima (NLR) potporodice NR-ova i NLRP3 zajedno sa adapterskim ASC proteinom PYCARD formira kaspaza-1 aktivirajući kompleks poznat kao NLRP3 inflamasom. NLRP3 u odsustvu aktivirajućeg signala održava se u neaktivnom stanju u kompleksu sa HSP90 i SGT1 u citoplazmi. NLRP3 inflamasom detektuje signale opasnosti kao što su kristalna mokraćna kiselina i vanćelijski ATP koje oslobađaju oštećene ćelije. Ovi signali oslobađaju HSP90 i SGT1 iz i regrutuju ASC protein i kaspazu-1 u inflamasomski kompleks. Kaspaza-1 unutar aktiviranog kompleksa inflamasoma NLRP3 zauzvrat aktivira upalni citokin, IL-1β.[14]

Čini se da se inflamasom NLRP3 aktivira promjenama unutarćelijskog kalija uzrokovanim izbacivanjem kalija iz mehanosenzitivnih ionskih kanala koji se nalaze u ćelijskoj membrani.[15] Čini se da je NLRP3 također reguliran reaktivnim vrstama kisika (ROS), iako precizni mehanizmi takve regulacije nisu utvrđeni.[16]

Predlaže se da NLRP3 pruža zaštitu od infekcija Streptococcus pneumoniae, aktiviranjem STAT6 i SPDEF.[17]

Klinički značaj

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Mutacije u genu NLRP3 povezane su sa spektrom dominantno naslijeđenih autoupalnih bolesti zvanih periodični sindrom povezan s kriopirinom (CAPS). Ovo uključuje porodični autoupalni sindrom prehlade (FCAS), Muckle-Wellsov sindrom (MWS), hronični dojenački neurološki kožni i zglobni (CINCA) sindrom, novorođenačka multisistemska upalna bolest (NOMID) i keratoendotheliitis fugax hereditaria.[5][18]

Defekti ovog gena su također povezani sa porodičnom mediteranskom groznicom.[19] Osim toga, inflamasom NLRP3 ima ulogu u patogenezi gihta,ref name="Martinon_2008"/> hemorrhagic stroke[20] i neuroinflamacijama koje se javljaju kod bolesti pogrešno savijanja proteina, kao što su Alzheimerova, Parkinsonova i prionska bolest.[21][22][23] Pokazalo se da se poboljšanje kod mišjih modela mnogih bolesti javlja delecijom inflamasoma NLRP3, uključujući giht, dijabetes tipa 2, multiplu sklerozu, Alzheimerovu bolest i aterosklerozu.[24] Pokazalo se da spoj β-hidroksibutirat blokira aktivaciju NLRP3 i stoga može biti od koristi za mnoge od ovih bolesti.[25]

Deregulacija NLRP3 je povezana sa karcinogenezom. Naprimjer, sve komponente inflamasoma NLRP3 su smanjene ili potpuno izgubljene u ljudskom hepatoćelijskom karcinomu.[26]

Inhibicija

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Inflamasom NLRP3 privukao je pažnju kao potencijalna meta lijeka za niz bolesti koje su potpomognute upalom. Diarilsulfonilurea MCC-950 je identificiran kao moćan i selektivan inhibitor NLRP3.[27] Nodthera i Inflazome, ušli su u fazu I kliničkih ispitivanja sa NLRP3 inhibitorima. Drugi antagonist NLRP3 je Dapansutril (OLT1177). Ovaj spoj molekule β-sulfonil nitrila razvilo je Olactec Therapeutics i selektivni je inhibitor NLRP3. Dapansutril, korišten u kliničkim ispitivanjima kao lijek za zatajenje srca, osteoartritis i gihtni artritis.[28]

Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000162711 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032691 - Ensembl, maj 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. ^ a b c 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. Pristupljeno 13. 11. 2015.
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  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 (maj 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.
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  13. ^ Q96P20
  14. ^ a b 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.
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  17. ^ Fang R, Uchiyama R, Sakai S, Hara H, Tsutsui H, Suda T, et al. (septembar 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. 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.
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  20. ^ Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J (maj 2020). "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". J Cereb Blood Flow Metab. 40 (9): 1752–1768. doi:10.1177/0271678X20923551. PMC 7446569. 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. S2CID 6659540. Arhivirano s originala (PDF), 27. 11. 2021. Pristupljeno 23. 3. 2023.
  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.
  27. ^ Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. (mart 2015). "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases". Nature Medicine. 21 (3): 248–55. doi:10.1038/nm.3806. PMC 4392179. PMID 25686105.
  28. ^ Alzheimer's Drug Discovery Foundation., Dapansutrile. "Dapansutrile" (PDF).

Vanjski linkovi

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Šablon:NOD-oliki receptori