NLRP3

NLRP3
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 3QF2, 2NAQ
Identifikatori
Aliasi	NLRP3
Vanjski ID-jevi	OMIM: 606416 MGI: 2653833 HomoloGene: 3600 GeneCards: NLRP3
Lokacija gena (čovjek) Hrom. Hromosom 1 (čovjek)[1] Bend 1q44 Početak 247,416,156 bp[1] Kraj 247,449,108 bp[1]
Lokacija gena (miš) Hrom. Hromosom 11 (miš)[2] Bend 11|11 B1.3 Početak 59,432,394 bp[2] Kraj 59,457,782 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
Vrste	Čovjek	Miš
Entrez	114548	216799
Ensembl	ENSG00000162711	ENSMUSG00000032691
UniProt	Q96P20	Q8R4B8
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 Mb	Chr 11: 59.43 – 59.46 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

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 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

NACHT, LRR i PYD su akronimi za:

• NACHT – NAIP (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

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

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

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

10		20		30		40		50
MKMASTRCKL		ARYLEDLEDV		DLKKFKMHLE		DYPPQKGCIP		LPRGQTEKAD
HVDLATLMID		FNGEEKAWAM		AVWIFAAINR		RDLYEKAKRD		EPKWGSDNAR
VSNPTVICQE		DSIEEEWMGL		LEYLSRISIC		KMKKDYRKKY		RKYVRSRFQC
IEDRNARLGE		SVSLNKRYTR		LRLIKEHRSQ		QEREQELLAI		GKTKTCESPV
SPIKMELLFD		PDDEHSEPVH		TVVFQGAAGI		GKTILARKMM		LDWASGTLYQ
DRFDYLFYIH		CREVSLVTQR		SLGDLIMSCC		PDPNPPIHKI		VRKPSRILFL
MDGFDELQGA		FDEHIGPLCT		DWQKAERGDI		LLSSLIRKKL		LPEASLLITT
RPVALEKLQH		LLDHPRHVEI		LGFSEAKRKE		YFFKYFSDEA		QARAAFSLIQ
ENEVLFTMCF		IPLVCWIVCT		GLKQQMESGK		SLAQTSKTTT		AVYVFFLSSL
LQPRGGSQEH		GLCAHLWGLC		SLAADGIWNQ		KILFEESDLR		NHGLQKADVS
AFLRMNLFQK		EVDCEKFYSF		IHMTFQEFFA		AMYYLLEEEK		EGRTNVPGSR
LKLPSRDVTV		LLENYGKFEK		GYLIFVVRFL		FGLVNQERTS		YLEKKLSCKI
SQQIRLELLK		WIEVKAKAKK		LQIQPSQLEL		FYCLYEMQEE		DFVQRAMDYF
PKIEINLSTR		MDHMVSSFCI		ENCHRVESLS		LGFLHNMPKE		EEEEEKEGRH
LDMVQCVLPS		SSHAACSHGL		VNSHLTSSFC		RGLFSVLSTS		QSLTELDLSD
NSLGDPGMRV		LCETLQHPGC		NIRRLWLGRC		GLSHECCFDI		SLVLSSNQKL
VELDLSDNAL		GDFGIRLLCV		GLKHLLCNLK		KLWLVSCCLT		SACCQDLASV
LSTSHSLTRL		YVGENALGDS		GVAILCEKAK		NPQCNLQKLG		LVNSGLTSVC
CSALSSVLST		NQNLTHLYLR		GNTLGDKGIK		LLCEGLLHPD		CKLQVLELDN
CNLTSHCCWD		LSTLLTSSQS		LRKLSLGNND		LGDLGVMMFC		EVLKQQSCLL
QNLGLSEMYF		NYETKSALET		LQEEKPELTV		VFEPSW

Funkcija

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

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

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

1. GRCh38: Ensembl release 89: ENSG00000162711 - Ensembl, maj 2017
2. 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. 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.
6. Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (maj 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 (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.
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 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.
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. S2CID 19986204.
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

• Q96P20

Šablon:NOD-oliki receptori