NLRP1
NLRP1 je protein koji ljudi kodira NACHT, LRR, FIIND, CARD domen i protein 1 sa domenima PYD sa hromosoma 17[5][6][7] NLRP1 je bio prvi protein za koji je pokazano da formira inflamasom.[8] NLRP1 se eksprimira u raznim tipovima ćelija, koji su pretežno epitelne ili hematopoetske. Ekspresija se također vidi unutar žljezdanih epitelnih struktura uključujući sluznicu tankog crijeva, želuca, epitel dišnih puteva i u koži bez dlake ili goloj koži.[9] > NLRP1 polimorfizmi su povezani sa kožnim ekstra-intestinalnim manifestacijama u CD-u.[9] Njegova najveća ekspresija je otkrivena u ljudskoj koži, psorijazi i vitiligu. Polimorfizmi NLRP1 pronađeni su kod lupus erythematosus i dijabetesa tipa 1.[10] Utvrđeno je da se varijante mišjeg NLRP1 aktiviraju nakon cijepanja N-terminala pomoću smrtonosnog faktora proteaza u antraksu.[8]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 1.473 aminokiseline, a molekulska težina 165.866 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MAGGAWGRLA | CYLEFLKKEE | LKEFQLLLAN | KAHSRSSSGE | TPAQPEKTSG | ||||
| MEVASYLVAQ | YGEQRAWDLA | LHTWEQMGLR | SLCAQAQEGA | GHSPSFPYSP | ||||
| SEPHLGSPSQ | PTSTAVLMPW | IHELPAGCTQ | GSERRVLRQL | PDTSGRRWRE | ||||
| ISASLLYQAL | PSSPDHESPS | QESPNAPTST | AVLGSWGSPP | QPSLAPREQE | ||||
| APGTQWPLDE | TSGIYYTEIR | EREREKSEKG | RPPWAAVVGT | PPQAHTSLQP | ||||
| HHHPWEPSVR | ESLCSTWPWK | NEDFNQKFTQ | LLLLQRPHPR | SQDPLVKRSW | ||||
| PDYVEENRGH | LIEIRDLFGP | GLDTQEPRIV | ILQGAAGIGK | STLARQVKEA | ||||
| WGRGQLYGDR | FQHVFYFSCR | ELAQSKVVSL | AELIGKDGTA | TPAPIRQILS | ||||
| RPERLLFILD | GVDEPGWVLQ | EPSSELCLHW | SQPQPADALL | GSLLGKTILP | ||||
| EASFLITART | TALQNLIPSL | EQARWVEVLG | FSESSRKEYF | YRYFTDERQA | ||||
| IRAFRLVKSN | KELWALCLVP | WVSWLACTCL | MQQMKRKEKL | TLTSKTTTTL | ||||
| CLHYLAQALQ | AQPLGPQLRD | LCSLAAEGIW | QKKTLFSPDD | LRKHGLDGAI | ||||
| ISTFLKMGIL | QEHPIPLSYS | FIHLCFQEFF | AAMSYVLEDE | KGRGKHSNCI | ||||
| IDLEKTLEAY | GIHGLFGAST | TRFLLGLLSD | EGEREMENIF | HCRLSQGRNL | ||||
| MQWVPSLQLL | LQPHSLESLH | CLYETRNKTF | LTQVMAHFEE | MGMCVETDME | ||||
| LLVCTFCIKF | SRHVKKLQLI | EGRQHRSTWS | PTMVVLFRWV | PVTDAYWQIL | ||||
| FSVLKVTRNL | KELDLSGNSL | SHSAVKSLCK | TLRRPRCLLE | TLRLAGCGLT | ||||
| AEDCKDLAFG | LRANQTLTEL | DLSFNVLTDA | GAKHLCQRLR | QPSCKLQRLQ | ||||
| LVSCGLTSDC | CQDLASVLSA | SPSLKELDLQ | QNNLDDVGVR | LLCEGLRHPA | ||||
| CKLIRLGLDQ | TTLSDEMRQE | LRALEQEKPQ | LLIFSRRKPS | VMTPTEGLDT | ||||
| GEMSNSTSSL | KRQRLGSERA | ASHVAQANLK | LLDVSKIFPI | AEIAEESSPE | ||||
| VVPVELLCVP | SPASQGDLHT | KPLGTDDDFW | GPTGPVATEV | VDKEKNLYRV | ||||
| HFPVAGSYRW | PNTGLCFVMR | EAVTVEIEFC | VWDQFLGEIN | PQHSWMVAGP | ||||
| LLDIKAEPGA | VEAVHLPHFV | ALQGGHVDTS | LFQMAHFKEE | GMLLEKPARV | ||||
| ELHHIVLENP | SFSPLGVLLK | MIHNALRFIP | VTSVVLLYHR | VHPEEVTFHL | ||||
| YLIPSDCSIR | KAIDDLEMKF | QFVRIHKPPP | LTPLYMGCRY | TVSGSGSGML | ||||
| EILPKELELC | YRSPGEDQLF | SEFYVGHLGS | GIRLQVKDKK | DETLVWEALV | ||||
| KPGDLMPATT | LIPPARIAVP | SPLDAPQLLH | FVDQYREQLI | ARVTSVEVVL | ||||
| DKLHGQVLSQ | EQYERVLAEN | TRPSQMRKLF | SLSQSWDRKC | KDGLYQALKE | ||||
| THPHLIMELW | EKGSKKGLLP | LSS |
Funkcija
urediOvaj gen kodira člana Ced-4 porodice apoptoznih proteina. Članovi Ced porodice sadrže domen regrutacije kaspaze (CARD) i poznato je da su ključni posrednici programirane ćelijske smrti. Kodirani protein sadrži poseban N-terminalni pirin-oliki motiv, koji je možda uključen u interajcije protein-protein. Protein NLRP1 snažno reaguje sa kaspazom 2 i slabo sa kaspazom 9. Pokazalo se da prekomjerna ekspresija ovog gena u ćelijama izaziva piroptozu. Višestruke alternativno prerađene varijante transkripta koje kodiraju različite izoforme su pronađene za ovaj gen, ali biološka valjanost nekih varijanti nije utvrđena.[7]
Mehanizam aktivacije
urediNLRP1 aktivira antibakterijski ili antivirusni imunski odgovor. Antibakterijski imunski odgovor nadoknađuje gubitak MAP kinaznog odgovora. Ljudi proizvode NLRP1, ali ljudski NLRP1 nije aktiviran smrtonosnim faktorom.[8] NLRP1 bi se mogao aktivirati proteoliskim cijepanjem, što rezultira uklanjanjem autoinhibitornog PYD i oslobađanjem CARD domena, odgovornog za regrutovanje i aktivacija prokapaze-1 u aktivnom obliku kaspaze-1.[8] Ljudska aktivacija NLRP1 može se izazvati na nekoliko načina uključujući enterovirusnu 3C- proteaze.[11] njegov funkdcija je u munsti tek je počela da se shvata.[8]
Interakcije
urediPokazano je da NLRP1 reaguje sa kaspazom 9[12][13] i APAF1.[12] Preko svog FIIND domena, NLRP1 je u direktnoj interakciji sa DPP9 i DPP8, koji su potrebni za sprečavanje aktivacije NLRP1.[14]
Gubitak DPP9 kod ljudi i miševa dovodi do aktivacije NLRP1.[15]
Varijante NLRP1 kod ljudi
urediKako su objavili Bruno Reversade i kolege, opisano je nekoliko mendelovskih bolesti uzrokovanih mutacijama zametne linije NLRP1.[16] To uključuje višestruki samoizlječivi palmoplantarni karcinom, porodičnu Nikamovu bolest i autoupaluđu s artritisom i diskeratozom. Mutacije u NLRP1, bilo da su dominantne ili recesivne, imaju tendenciju da budu aleli pojačanja funkcije koji pokreću inflamasomnu signalizaciju sa IL1B i IL18.
Varijante NLRP1 kod miševa
urediMiševi imaju tri paraloga gena Nlrp1 (Nlrp1a, b, c). Nlrp1c je pseudogen.[17] Mišji NLRP1B se ne aktivira mehanizmom tipa receptor-ligand. NLRP1B varijante određenih inbred sojeva miševa, BALB/c i 129, mogu se aktivirati smrtonosnim faktorom (LF) proteaza. Smrtonosni faktor proteaza proizvodi i luči Bacillus anthracis, agens antraksa.[18] Zajedno sa zaštitnim antigenom (PA), LF formira bipartitni toksin, smrtonosni toksin. Uloga PA je da formira hromosomski translocacijski kanal koji isporučuje LF u citosol ćelije domaćina gdje LF ima ulogu u imunskom odgovoru, cijepanjem i inaktivacijom MAP kinaza.[19][20] LF takođe direktno ciepa NLRP1B proksimalno do njegovog N-terminala, što je neophodno i dovoljno za formiranje NLRP1B inflamasoma i aktivaciju CASP1.[21] Aktivacija NLRP1B-ovisnih inflamafomskih odgovora pojavljuje se u odbrani domaćina s mehanizmom poput IL-1β i neutrofila.[22][23] NLRP1B može funkcionirati kao senzor bakterijskih proteaza, imunski odgovori su specifično aktivirani faktorima virulencija.[24][25]
Nije jasno koji bi stimulansi mogli aktivirati NLRP1A, drugi poznati funkcionalni mišji paralog NLRP1. Studija je identifikovala miša koji je nosio misens mutacijsko pojačanje funkcije u NLRP1A (Q593P) koji aktivira inflamasomne odgovore. Mehanizam aktivacije divljeg tips NLRP1A ---nije jasan.[26]
Reference
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Materijal je kopiran iz ovog izvora, koji je dostupan na linku Creative Commons Attribution 4.0 International License. Greška kod citiranja: Neispravna oznaka <ref>; naziv ":0" definiran je nekoliko puta s različitim sadržajem - ^ a b Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, et al. (maj 2007). "Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response". The Journal of Histochemistry and Cytochemistry. 55 (5): 443–52. doi:10.1369/jhc.6A7101.2006. PMID 17164409.
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