NLRC3_HUMAN
ID NLRC3_HUMAN Reviewed; 1065 AA.
AC Q7RTR2; Q5EY36; Q8NF48; Q8NI01; Q8NI02; Q8TEL3;
DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot.
DT 24-JUL-2007, sequence version 2.
DT 03-AUG-2022, entry version 153.
DE RecName: Full=NLR family CARD domain-containing protein 3;
DE AltName: Full=CARD15-like protein;
DE AltName: Full=Caterpiller protein 16.2 {ECO:0000303|PubMed:15705585};
DE Short=CLR16.2 {ECO:0000303|PubMed:15705585};
DE AltName: Full=NACHT, LRR and CARD domains-containing protein 3;
DE AltName: Full=Nucleotide-binding oligomerization domain protein 3;
GN Name=NLRC3; Synonyms=NOD3;
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=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 [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, AND
RP INDUCTION.
RX PubMed=15705585; DOI=10.1074/jbc.m413169200;
RA Conti B.J., Davis B.K., Zhang J., O'Connor W. Jr., Williams K.L.,
RA Ting J.P.-Y.;
RT "CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively
RT regulates T cell function.";
RL J. Biol. Chem. 280:18375-18385(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Spleen;
RX PubMed=12693554; DOI=10.1093/dnares/10.1.49;
RA Jikuya H., Takano J., Kikuno R., Hirosawa M., Nagase T., Nomura N.,
RA Ohara O.;
RT "Characterization of long cDNA clones from human adult spleen. II. The
RT complete sequences of 81 cDNA clones.";
RL DNA Res. 10:49-57(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 567-1065 (ISOFORM 1).
RC TISSUE=Spleen;
RA Jikuya H., Takano J., Nomura N., Kikuno R., Nagase T., Ohara O.;
RT "The nucleotide sequence of a long cDNA clone isolated from human spleen.";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 701-923 (ISOFORMS 1 AND 4).
RA Huse K., Platzer M., Wen G., Hampe J., Schreiber S.;
RT "Leucine-rich repeat containing protein.";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION, INTERACTION WITH TRAF6, INDUCTION BY LPS, AND MUTAGENESIS OF
RP 457-SER--GLU-460 AND 582-SER--GLU-585.
RX PubMed=22863753; DOI=10.1038/ni.2378;
RA Schneider M., Zimmermann A.G., Roberts R.A., Zhang L., Swanson K.V.,
RA Wen H., Davis B.K., Allen I.C., Holl E.K., Ye Z., Rahman A.H., Conti B.J.,
RA Eitas T.K., Koller B.H., Ting J.P.;
RT "The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via
RT modification of the signaling adaptor TRAF6 and transcription factor NF-
RT kappaB.";
RL Nat. Immunol. 13:823-831(2012).
RN [7]
RP INTERACTION WITH TBK1 AND TMEM173, AND SUBCELLULAR LOCATION.
RX PubMed=24560620; DOI=10.1016/j.immuni.2014.01.010;
RA Zhang L., Mo J., Swanson K.V., Wen H., Petrucelli A., Gregory S.M.,
RA Zhang Z., Schneider M., Jiang Y., Fitzgerald K.A., Ouyang S., Liu Z.J.,
RA Damania B., Shu H.B., Duncan J.A., Ting J.P.;
RT "NLRC3, a member of the NLR family of proteins, is a negative regulator of
RT innate immune signaling induced by the DNA sensor STING.";
RL Immunity 40:329-341(2014).
RN [8]
RP FUNCTION, INTERACTION WITH CASP1; CASP5 AND PYCARD, AND SUBCELLULAR
RP LOCATION.
RX PubMed=25277106; DOI=10.1159/000363602;
RA Gueltekin Y., Eren E., Oezoeren N.;
RT "Overexpressed NLRC3 acts as an anti-inflammatory cytosolic protein.";
RL J. Innate Immun. 7:25-36(2015).
CC -!- FUNCTION: Negative regulator of the innate immune response
CC (PubMed:15705585, PubMed:22863753, PubMed:25277106). Attenuates
CC signaling pathways activated by Toll-like receptors (TLRs) and the DNA
CC sensor STING/TMEM173 in response to pathogen-associated molecular
CC patterns, such as intracellular poly(dA:dT), but not poly(I:C), or in
CC response to DNA virus infection, including that of Herpes simplex virus
CC 1 (HSV1) (By similarity) (PubMed:22863753). May affect TLR4 signaling
CC by acting at the level of TRAF6 ubiquitination, decreasing the
CC activating 'Lys-63'-linked ubiquitination and leaving unchanged the
CC degradative 'Lys-48'-linked ubiquitination (PubMed:22863753). Inhibits
CC the PI3K-AKT-mTOR pathway possibly by directly interacting with the
CC posphatidylinositol 3-kinase regulatory subunit p85 (PIK3R1/PIK3R2) and
CC disrupting the association between PIK3R1/PIK3R2 and the catalytic
CC subunit p110 (PIK3CA/PIK3CB/PIK3CD) and reducing PIK3R1/PIK3R2
CC activation. Via its regulation of the PI3K-AKT-mTOR pathway, controls
CC cell proliferation, predominantly in intestinal epithelial cells (By
CC similarity). May also affect NOD1- or NOD2-mediated NF-kappa-B
CC activation (PubMed:25277106). Might also affect the inflammatory
CC response by preventing NLRP3 inflammasome formation, CASP1 cleavage and
CC IL1B maturation (PubMed:25277106). {ECO:0000250|UniProtKB:Q5DU56,
CC ECO:0000269|PubMed:15705585, ECO:0000269|PubMed:22863753,
CC ECO:0000269|PubMed:25277106}.
CC -!- SUBUNIT: Directly interacts (via CARD) with TMEM173/STING; this
CC interaction reduces TMEM173 trafficking to the perinuclear region in
CC response to interferon stimulatory DNA. Also interacts, but to a lesser
CC extent, with TBK1 (PubMed:24560620). Interacts with TRAF6; this
CC interaction results in decreased TRAF6 'Lys-63'-linked
CC polyubiquitination, but leaves 'Lys-48'-linked chains unchanged,
CC promoting TRAF6 protein degradation (PubMed:22863753). Interacts with
CC PIK3R1/PIK3R2; this interaction disrupts the association between
CC PIK3R1/PIK3R2 and the p110 catalytic subunit PIK3CA/PIK3CB/PIK3CD and
CC reduces PIK3R1/PIK3R2 activation (By similarity). Weakly interacts with
CC PYCARD/ASC. Interacts with CASP1 and CASP5 (PubMed:25277106).
CC {ECO:0000250|UniProtKB:Q5DU56, ECO:0000269|PubMed:22863753,
CC ECO:0000269|PubMed:24560620, ECO:0000269|PubMed:25277106}.
CC -!- INTERACTION:
CC Q7RTR2; Q9ULZ3: PYCARD; NbExp=3; IntAct=EBI-1042625, EBI-751215;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15705585,
CC ECO:0000269|PubMed:24560620, ECO:0000269|PubMed:25277106}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q7RTR2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7RTR2-2; Sequence=VSP_027135;
CC Name=3;
CC IsoId=Q7RTR2-3; Sequence=VSP_027136, VSP_027137;
CC Name=4;
CC IsoId=Q7RTR2-4; Sequence=VSP_027138;
CC -!- INDUCTION: In primary T-cells, down-regulated upon T-cell receptor
CC activation (PubMed:15705585). Down-regulated in peritoneal macrophages
CC soon after the beginning of LPS stimulation. Levels start increasing
CC again after 3 days of LPS treatment (PubMed:22863753).
CC {ECO:0000269|PubMed:15705585, ECO:0000269|PubMed:22863753}.
CC -!- DOMAIN: The leucine-rich repeat domain may reduce the interaction with
CC TMEM173/STING. {ECO:0000269|PubMed:24560620}.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC03412.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; BK001112; DAA01245.1; -; mRNA.
DR EMBL; AY601811; AAT48367.1; -; mRNA.
DR EMBL; AK090431; BAC03412.1; ALT_INIT; mRNA.
DR EMBL; AK074109; BAB84935.1; -; mRNA.
DR EMBL; AF501291; AAM22459.1; -; mRNA.
DR EMBL; AF501292; AAM22460.1; -; mRNA.
DR CCDS; CCDS73817.1; -. [Q7RTR2-1]
DR RefSeq; NP_849172.2; NM_178844.3. [Q7RTR2-1]
DR AlphaFoldDB; Q7RTR2; -.
DR SMR; Q7RTR2; -.
DR BioGRID; 128254; 5.
DR IntAct; Q7RTR2; 3.
DR STRING; 9606.ENSP00000352039; -.
DR iPTMnet; Q7RTR2; -.
DR PhosphoSitePlus; Q7RTR2; -.
DR BioMuta; NLRC3; -.
DR EPD; Q7RTR2; -.
DR jPOST; Q7RTR2; -.
DR MassIVE; Q7RTR2; -.
DR MaxQB; Q7RTR2; -.
DR PeptideAtlas; Q7RTR2; -.
DR PRIDE; Q7RTR2; -.
DR ProteomicsDB; 68886; -. [Q7RTR2-1]
DR ProteomicsDB; 68887; -. [Q7RTR2-2]
DR ProteomicsDB; 68888; -. [Q7RTR2-3]
DR ProteomicsDB; 68889; -. [Q7RTR2-4]
DR TopDownProteomics; Q7RTR2-3; -. [Q7RTR2-3]
DR Antibodypedia; 56241; 52 antibodies from 20 providers.
DR DNASU; 197358; -.
DR Ensembl; ENST00000359128.10; ENSP00000352039.6; ENSG00000167984.18. [Q7RTR2-1]
DR Ensembl; ENST00000615877.4; ENSP00000482989.1; ENSG00000167984.18. [Q7RTR2-3]
DR GeneID; 197358; -.
DR KEGG; hsa:197358; -.
DR MANE-Select; ENST00000359128.10; ENSP00000352039.6; NM_178844.4; NP_849172.2.
DR UCSC; uc032dpc.2; human. [Q7RTR2-1]
DR CTD; 197358; -.
DR DisGeNET; 197358; -.
DR GeneCards; NLRC3; -.
DR HGNC; HGNC:29889; NLRC3.
DR HPA; ENSG00000167984; Tissue enhanced (intestine, lymphoid tissue).
DR MIM; 615648; gene.
DR neXtProt; NX_Q7RTR2; -.
DR OpenTargets; ENSG00000167984; -.
DR PharmGKB; PA162397626; -.
DR VEuPathDB; HostDB:ENSG00000167984; -.
DR eggNOG; KOG4308; Eukaryota.
DR GeneTree; ENSGT00940000159861; -.
DR HOGENOM; CLU_002274_3_0_1; -.
DR InParanoid; Q7RTR2; -.
DR OMA; DFTQVET; -.
DR OrthoDB; 259987at2759; -.
DR PhylomeDB; Q7RTR2; -.
DR PathwayCommons; Q7RTR2; -.
DR Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN.
DR SignaLink; Q7RTR2; -.
DR BioGRID-ORCS; 197358; 9 hits in 261 CRISPR screens.
DR ChiTaRS; NLRC3; human.
DR GeneWiki; NLRC3; -.
DR GenomeRNAi; 197358; -.
DR Pharos; Q7RTR2; Tbio.
DR PRO; PR:Q7RTR2; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q7RTR2; protein.
DR Bgee; ENSG00000167984; Expressed in thymus and 121 other tissues.
DR ExpressionAtlas; Q7RTR2; baseline and differential.
DR Genevisible; Q7RTR2; HS.
DR GO; GO:0034451; C:centriolar satellite; IDA:HPA.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0036312; F:phosphatidylinositol 3-kinase regulatory subunit binding; ISS:UniProtKB.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; ISS:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IMP:MGI.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:0045824; P:negative regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:0032687; P:negative regulation of interferon-alpha production; ISS:UniProtKB.
DR GO; GO:0032688; P:negative regulation of interferon-beta production; ISS:UniProtKB.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:CACAO.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase signaling; ISS:UniProtKB.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IDA:CACAO.
DR GO; GO:0042110; P:T cell activation; IEP:UniProtKB.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 4.
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; 12.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cytoplasm; Leucine-rich repeat;
KW Nucleotide-binding; Reference proteome; Repeat.
FT CHAIN 1..1065
FT /note="NLR family CARD domain-containing protein 3"
FT /id="PRO_0000296187"
FT DOMAIN 139..460
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 617..639
FT /note="LRR 1"
FT REPEAT 641..663
FT /note="LRR 2"
FT REPEAT 665..688
FT /note="LRR 3"
FT REPEAT 693..716
FT /note="LRR 4"
FT REPEAT 721..744
FT /note="LRR 5"
FT REPEAT 749..772
FT /note="LRR 6"
FT REPEAT 777..800
FT /note="LRR 7"
FT REPEAT 805..828
FT /note="LRR 8"
FT REPEAT 833..856
FT /note="LRR 9"
FT REPEAT 861..884
FT /note="LRR 10"
FT REPEAT 889..912
FT /note="LRR 11"
FT REPEAT 917..940
FT /note="LRR 12"
FT REPEAT 945..968
FT /note="LRR 13"
FT REPEAT 973..996
FT /note="LRR 14"
FT REPEAT 1001..1029
FT /note="LRR 15"
FT REPEAT 1031..1052
FT /note="LRR 16"
FT REGION 1..62
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 457..460
FT /note="TRAF6-binding"
FT /evidence="ECO:0000269|PubMed:22863753"
FT BINDING 145..152
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT VAR_SEQ 1
FT /note="M -> MEMDAPRPPSLAVPGAASRPGRLLDGGHGRQQVQALSSQLLEVIPDS
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12766759"
FT /id="VSP_027135"
FT VAR_SEQ 728..761
FT /note="SLQGNTVRDDGARSMAEALASNRTLSMLHLQKNS -> RVKFMYHKIDCFRR
FT VPEADACNPSTLGGQGRWIT (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12693554"
FT /id="VSP_027136"
FT VAR_SEQ 762..1065
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12693554"
FT /id="VSP_027137"
FT VAR_SEQ 869..896
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.5"
FT /id="VSP_027138"
FT VARIANT 567
FT /note="V -> M (in dbSNP:rs8057436)"
FT /id="VAR_034606"
FT MUTAGEN 457..460
FT /note="SLQE->AAAA: Strong decrease of TRAF6-binding."
FT /evidence="ECO:0000269|PubMed:22863753"
FT MUTAGEN 582..585
FT /note="SVEE->AAAA: Almost no effect on TRAF6-binding."
FT /evidence="ECO:0000269|PubMed:22863753"
FT CONFLICT 41
FT /note="Q -> H (in Ref. 1; DAA01245)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1065 AA; 114658 MW; 9BFFCB21FD134562 CRC64;
MRKQEVRTGR EAGQGHGTGS PAEQVKALMD LLAGKGSQGS QAPQALDRTP DAPLGPCSND
SRIQRHRKAL LSKVGGGPEL GGPWHRLASL LLVEGLTDLQ LREHDFTQVE ATRGGGHPAR
TVALDRLFLP LSRVSVPPRV SITIGVAGMG KTTLVRHFVR LWAHGQVGKD FSLVLPLTFR
DLNTHEKLCA DRLICSVFPH VGEPSLAVAV PARALLILDG LDECRTPLDF SNTVACTDPK
KEIPVDHLIT NIIRGNLFPE VSIWITSRPS ASGQIPGGLV DRMTEIRGFN EEEIKVCLEQ
MFPEDQALLG WMLSQVQADR ALYLMCTVPA FCRLTGMALG HLWRSRTGPQ DAELWPPRTL
CELYSWYFRM ALSGEGQEKG KASPRIEQVA HGGRKMVGTL GRLAFHGLLK KKYVFYEQDM
KAFGVDLALL QGAPCSCFLQ REETLASSVA YCFTHLSLQE FVAAAYYYGA SRRAIFDLFT
ESGVSWPRLG FLTHFRSAAQ RAMQAEDGRL DVFLRFLSGL LSPRVNALLA GSLLAQGEHQ
AYRTQVAELL QGCLRPDAAV CARAINVLHC LHELQHTELA RSVEEAMESG ALARLTGPAH
RAALAYLLQV SDACAQEANL SLSLSQGVLQ SLLPQLLYCR KLRLDTNQFQ DPVMELLGSV
LSGKDCRIQK ISLAENQISN KGAKALARSL LVNRSLTSLD LRGNSIGPQG AKALADALKI
NRTLTSLSLQ GNTVRDDGAR SMAEALASNR TLSMLHLQKN SIGPMGAQRM ADALKQNRSL
KELMFSSNSI GDGGAKALAE ALKVNQGLES LDLQSNSISD AGVAALMGAL CTNQTLLSLS
LRENSISPEG AQAIAHALCA NSTLKNLDLT ANLLHDQGAR AIAVAVRENR TLTSLHLQWN
FIQAGAAQAL GQALQLNRSL TSLDLQENAI GDDGACAVAR ALKVNTALTA LYLQVASIGA
SGAQVLGEAL AVNRTLEILD LRGNAIGVAG AKALANALKV NSSLRRLNLQ ENSLGMDGAI
CIATALSGNH RLQHINLQGN HIGDSGARMI SEAIKTNAPT CTVEM
