NLRP9_HUMAN
ID NLRP9_HUMAN Reviewed; 991 AA.
AC Q7RTR0; B2RN12; Q86W27;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 15-DEC-2003, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 9;
DE AltName: Full=Nucleotide-binding oligomerization domain protein 6;
DE AltName: Full=PYRIN and NACHT-containing protein 12;
GN Name=NLRP9; Synonyms=NALP9, NOD6, PAN12;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=12563287; DOI=10.1038/nrm1019;
RA Tschopp J., Martinon F., Burns K.;
RT "NALPs: a novel protein family involved in inflammation.";
RL Nat. Rev. Mol. Cell Biol. 4:95-104(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION [MRNA] (ISOFORM 1).
RX PubMed=12766759; DOI=10.1038/nri1086;
RA Inohara N., Nunez G.;
RT "NODs: intracellular proteins involved in inflammation and apoptosis.";
RL Nat. Rev. Immunol. 3:371-382(2003).
RN [5]
RP TISSUE SPECIFICITY, AND INDUCTION BY OXIDATIVE STRESS.
RX PubMed=28432035; DOI=10.1016/j.bbi.2017.04.010;
RA Nyul-Toth A., Kozma M., Nagyoszi P., Nagy K., Fazakas C., Hasko J.,
RA Molnar K., Farkas A.E., Vegh A.G., Varo G., Galajda P., Wilhelm I.,
RA Krizbai I.A.;
RT "Expression of pattern recognition receptors and activation of the non-
RT canonical inflammasome pathway in brain pericytes.";
RL Brain Behav. Immun. 64:220-231(2017).
RN [6]
RP FUNCTION, INTERACTION WITH DHX9 AND PYCARD, AND TISSUE SPECIFICITY.
RX PubMed=28636595; DOI=10.1038/nature22967;
RA Zhu S., Ding S., Wang P., Wei Z., Pan W., Palm N.W., Yang Y., Yu H.,
RA Li H.B., Wang G., Lei X., de Zoete M.R., Zhao J., Zheng Y., Chen H.,
RA Zhao Y., Jurado K.A., Feng N., Shan L., Kluger Y., Lu J., Abraham C.,
RA Fikrig E., Greenberg H.B., Flavell R.A.;
RT "Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial
RT cells.";
RL Nature 546:667-670(2017).
RN [7]
RP VARIANT [LARGE SCALE ANALYSIS] ASP-425.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: As the sensor component of the NLRP9 inflammasome, plays a
CC crucial role in innate immunity and inflammation. In response to
CC pathogens, including rotavirus, initiates the formation of the
CC inflammasome polymeric complex, made of NLRP9, PYCARD and CASP1.
CC Recruitment of proCASP1 to the inflammasome promotes its activation and
CC CASP1-catalyzed IL1B and IL18 maturation and release in the
CC extracellular milieu. The active cytokines stimulate inflammatory
CC responses. Inflammasomes can also induce pyroptosis, an inflammatory
CC form of programmed cell death. NLRP9 inflammasome activation may be
CC initiated by DHX9 interaction with viral double-stranded RNA (dsRNA),
CC preferentially to short dsRNA segments. {ECO:0000269|PubMed:28636595}.
CC -!- SUBUNIT: Sensor component of NLRP9 inflammasomes. Inflammasomes are
CC supramolecular complexes that assemble in the cytosol in response to
CC pathogens, such as rotavirus, and play critical roles in innate
CC immunity and inflammation. The core of NLRP9 inflammasomes consists of
CC a signal sensor component (NLRP9), an adapter (ASC/PYCARD), which
CC recruits an effector pro-inflammatory caspase (CASP1). Within the
CC complex, NLRP9 and PYCARD interact via their respective DAPIN/pyrin
CC domains. This interaction initiates speck formation (nucleation) which
CC greatly enhances further addition of soluble PYCARD molecules to the
CC speck in a prion-like polymerization process. Clustered PYCARD
CC nucleates the formation of CASP1 filaments through the interaction of
CC their respective CARD domains, acting as a platform for CASP1
CC polymerization. CASP1 filament formation increases local enzyme
CC concentration, resulting in trans-autocleavage and activation. Active
CC CASP1 then processes IL1B and IL18 precursors, leading to the release
CC of mature cytokines in the extracellular milieu and inflammatory
CC response (PubMed:28636595). Interacts with DHX9 upon rotavirus
CC infection; this interaction may trigger inflammasome activation and
CC inflammatory response (PubMed:28636595). {ECO:0000269|PubMed:28636595}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q66X22}.
CC Inflammasome {ECO:0000269|PubMed:28636595}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q7RTR0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7RTR0-2; Sequence=VSP_025021;
CC -!- TISSUE SPECIFICITY: Expressed in ileum intestinal epithelial cells. Not
CC detected in peripheral blood mononuclear cells (PubMed:28636595).
CC Expressed in cerebral endothelial cells and, at much lower levels, in
CC brain pericytes (PubMed:28432035). {ECO:0000269|PubMed:28432035,
CC ECO:0000269|PubMed:28636595}.
CC -!- INDUCTION: In brain pericytes, up-regulated at the mRNA level in
CC response to oxidative stress. {ECO:0000269|PubMed:28432035}.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
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DR EMBL; AY154464; AAO18160.1; -; mRNA.
DR EMBL; CH471135; EAW72412.1; -; Genomic_DNA.
DR EMBL; BC136583; AAI36584.1; -; mRNA.
DR EMBL; BK001114; DAA01247.1; -; mRNA.
DR CCDS; CCDS12934.1; -. [Q7RTR0-1]
DR RefSeq; NP_789790.2; NM_176820.3. [Q7RTR0-1]
DR PDB; 6Z2G; X-ray; 1.95 A; A=1-97.
DR PDB; 7BSO; X-ray; 2.08 A; A=1-96.
DR PDBsum; 6Z2G; -.
DR PDBsum; 7BSO; -.
DR AlphaFoldDB; Q7RTR0; -.
DR SMR; Q7RTR0; -.
DR BioGRID; 130708; 10.
DR IntAct; Q7RTR0; 1.
DR STRING; 9606.ENSP00000331857; -.
DR iPTMnet; Q7RTR0; -.
DR PhosphoSitePlus; Q7RTR0; -.
DR BioMuta; NLRP9; -.
DR DMDM; 74762418; -.
DR jPOST; Q7RTR0; -.
DR MassIVE; Q7RTR0; -.
DR PaxDb; Q7RTR0; -.
DR PeptideAtlas; Q7RTR0; -.
DR PRIDE; Q7RTR0; -.
DR ProteomicsDB; 68884; -. [Q7RTR0-1]
DR ProteomicsDB; 68885; -. [Q7RTR0-2]
DR Antibodypedia; 51023; 100 antibodies from 24 providers.
DR DNASU; 338321; -.
DR Ensembl; ENST00000332836.7; ENSP00000331857.2; ENSG00000185792.10. [Q7RTR0-1]
DR Ensembl; ENST00000590200.1; ENSP00000465253.1; ENSG00000185792.10. [Q7RTR0-2]
DR GeneID; 338321; -.
DR KEGG; hsa:338321; -.
DR MANE-Select; ENST00000332836.7; ENSP00000331857.2; NM_176820.4; NP_789790.2.
DR UCSC; uc002qly.3; human. [Q7RTR0-1]
DR CTD; 338321; -.
DR DisGeNET; 338321; -.
DR GeneCards; NLRP9; -.
DR HGNC; HGNC:22941; NLRP9.
DR HPA; ENSG00000185792; Not detected.
DR MIM; 609663; gene.
DR neXtProt; NX_Q7RTR0; -.
DR OpenTargets; ENSG00000185792; -.
DR PharmGKB; PA162398029; -.
DR VEuPathDB; HostDB:ENSG00000185792; -.
DR eggNOG; KOG4308; Eukaryota.
DR GeneTree; ENSGT00940000163218; -.
DR HOGENOM; CLU_002274_2_1_1; -.
DR InParanoid; Q7RTR0; -.
DR OMA; PWIDEEY; -.
DR OrthoDB; 114368at2759; -.
DR PhylomeDB; Q7RTR0; -.
DR PathwayCommons; Q7RTR0; -.
DR SignaLink; Q7RTR0; -.
DR BioGRID-ORCS; 338321; 7 hits in 1057 CRISPR screens.
DR GeneWiki; NLRP9; -.
DR GenomeRNAi; 338321; -.
DR Pharos; Q7RTR0; Tbio.
DR PRO; PR:Q7RTR0; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q7RTR0; protein.
DR Bgee; ENSG00000185792; Expressed in secondary oocyte and 32 other tissues.
DR Genevisible; Q7RTR0; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0061702; C:inflammasome complex; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0051607; P:defense response to virus; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0032741; P:positive regulation of interleukin-18 production; ISS:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IBA:GO_Central.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 3.
DR InterPro; IPR004020; DAPIN.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR041267; NLRP_HD2.
DR InterPro; IPR041075; NOD2_WH.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF13516; LRR_6; 3.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR Pfam; PF02758; PYRIN; 1.
DR SMART; SM01289; PYRIN; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50824; DAPIN; 1.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cytoplasm; Immunity;
KW Inflammasome; Inflammatory response; Innate immunity; Leucine-rich repeat;
KW Nucleotide-binding; Reference proteome; Repeat.
FT CHAIN 1..991
FT /note="NACHT, LRR and PYD domains-containing protein 9"
FT /id="PRO_0000286334"
FT DOMAIN 1..94
FT /note="Pyrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00061"
FT DOMAIN 146..465
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 743..763
FT /note="LRR 1"
FT REPEAT 772..793
FT /note="LRR 2"
FT REPEAT 800..820
FT /note="LRR 3"
FT REPEAT 829..850
FT /note="LRR 4"
FT REPEAT 857..877
FT /note="LRR 5"
FT REPEAT 886..907
FT /note="LRR 6"
FT BINDING 152..159
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT VAR_SEQ 949..991
FT /note="LHKSGFDEETQKILMSVEEKIPHLTISHGPWIDEEYKIRGVLL -> NCQKS
FT LGDTVAPGENHCSIKHLLLTLPINMQRQLRLQK (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12563287"
FT /id="VSP_025021"
FT VARIANT 425
FT /note="G -> D (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036386"
FT HELIX 10..15
FT /evidence="ECO:0007829|PDB:6Z2G"
FT HELIX 20..31
FT /evidence="ECO:0007829|PDB:6Z2G"
FT TURN 35..38
FT /evidence="ECO:0007829|PDB:6Z2G"
FT HELIX 44..47
FT /evidence="ECO:0007829|PDB:6Z2G"
FT HELIX 52..62
FT /evidence="ECO:0007829|PDB:6Z2G"
FT HELIX 66..78
FT /evidence="ECO:0007829|PDB:6Z2G"
FT HELIX 82..96
FT /evidence="ECO:0007829|PDB:6Z2G"
SQ SEQUENCE 991 AA; 113312 MW; B9DD003967AB93D9 CRC64;
MAESFFSDFG LLWYLKELRK EEFWKFKELL KQPLEKFELK PIPWAELKKA SKEDVAKLLD
KHYPGKQAWE VTLNLFLQIN RKDLWTKAQE EMRNKLNPYR KHMKETFQLI WEKETCLHVP
EHFYKETMKN EYKELNDAYT AAARRHTVVL EGPDGIGKTT LLRKVMLDWA EGNLWKDRFT
FVFFLNVCEM NGIAETSLLE LLSRDWPESS EKIEDIFSQP ERILFIMDGF EQLKFNLQLK
ADLSDDWRQR QPMPIILSSL LQKKMLPESS LLIALGKLAM QKHYFMLRHP KLIKLLGFSE
SEKKSYFSYF FGEKSKALKV FNFVRDNGPL FILCHNPFTC WLVCTCVKQR LERGEDLEIN
SQNTTYLYAS FLTTVFKAGS QSFPPKVNRA RLKSLCALAA EGIWTYTFVF SHGDLRRNGL
SESEGVMWVG MRLLQRRGDC FAFMHLCIQE FCAAMFYLLK RPKDDPNPAI GSITQLVRAS
VVQPQTLLTQ VGIFMFGIST EEIVSMLETS FGFPLSKDLK QEITQCLESL SQCEADREAI
AFQELFIGLF ETQEKEFVTK VMNFFEEVFI YIGNIEHLVI ASFCLKHCQH LTTLRMCVEN
IFPDDSGCIS DYNEKLVYWR ELCSMFITNK NFQILDMENT SLDDPSLAIL CKALAQPVCK
LRKLIFTSVY FGHDSELFKA VLHNPHLKLL SLYGTSLSQS DIRHLCETLK HPMCKIEELI
LGKCDISSEV CEDIASVLAC NSKLKHLSLV ENPLRDEGMT LLCEALKHSH CALERLMLMY
CCLTSVSCDS ISEVLLCSKS LSLLDLGSNA LEDNGVASLC AALKHPGCSI RELWLMGCFL
TSDSCKDIAA VLICNGKLKT LKLGHNEIGD TGVRQLCAAL QHPHCKLECL GLQTCPITRA
CCDDIAAALI ACKTLRSLNL DWIALDADAV VVLCEALSHP DCALQMLGLH KSGFDEETQK
ILMSVEEKIP HLTISHGPWI DEEYKIRGVL L
