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Protein

NACHT, LRR and PYD domains-containing protein 6

Gene

NLRP6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

As the sensor component of the NLRP6 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP6, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitement of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. The precise NLRP6 activation stimulus has not been identified yet (By similarity) (PubMed:12387869). Essential for gut mucosal self-renewal and proliferation. Maintains intestinal homeostasis and a healthy intestinal microbiota. This function is, at least partially, mediated by IL18, and not IL1B, produced by nonhematopoietic cells. Influences intestinal barrier function and microbial homeostasis through the regulation of goblet cell mucus secretion. Acts by promoting autophagy in goblet cells, an essential step for mucus granule exocytosis. Its role in goblet cell physiology is inflammasome-dependent, but IL1B- and IL18-independent. During systemic bacterial infections, may negatively regulate inflammatory signaling and inhibit the influx of monocytes and neutrophils to the circulation and to the peritoneum. May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism (By similarity).By similarity1 Publication

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi202 – 2098ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
NACHT, LRR and PYD domains-containing protein 6
Alternative name(s):
Angiotensin II/vasopressin receptor
PYRIN-containing APAF1-like protein 5
Gene namesi
Name:NLRP6
Synonyms:NALP6, PYPAF5
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:22944. NLRP6.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Inflammasome, Membrane, Nucleus

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA162398002.

Polymorphism and mutation databases

DMDMi259016285.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 892892NACHT, LRR and PYD domains-containing protein 6PRO_0000080892Add
BLAST

Proteomic databases

PaxDbiP59044.
PRIDEiP59044.

PTM databases

iPTMnetiP59044.
PhosphoSiteiP59044.

Expressioni

Tissue specificityi

Expressed in peripheral blood leukocytes, predominantly in granulocytes and, at lower levels, in CD4+ and CD8+ T-cells. Expressed in colonic myofibroblasts (at protein level) (PubMed:21593405).2 Publications

Inductioni

Up-regulated by rosiglitazone, a PPARG agonist, in Caco2 and HCT116 colorectal carcinoma cells (PubMed:21088234, PubMed:23470617). Down-regulated by CRH (at protein level) (PubMed:23470617).2 Publications

Gene expression databases

BgeeiP59044.
CleanExiHS_NLRP6.
GenevisibleiP59044. HS.

Organism-specific databases

HPAiHPA043681.
HPA048500.

Interactioni

Subunit structurei

Sensor component of NLRP6 inflammasomes. Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation. The core of NLRP6 inflammasomes consists of a signal sensor component (NLRP6), an adapter (ASC/PYCARD), which recruits an effector proinflammatory caspase (CASP1 and, possibly, CASP4 and CASP5). Within the complex, NLRP6 and PYCARD interact via their respective pyrin domains. This interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD molecules to the speck in a prion-like polymerization process. NLRP6 localizes at the end of each PYCARD filament. Clustered PYCARD nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization. CASP1 filament formation increases local enzyme concentration, resulting in trans-autocleavage and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response. In this complex, the sensor protein is sub-stoichiometric to PYCARD, and PYCARD is further substoichiometric to CASP1, suggesting amplifications of signal transduction from the sensor, via the adapter, to the effector.By similarity1 Publication

Protein-protein interaction databases

STRINGi9606.ENSP00000309767.

Structurei

3D structure databases

ProteinModelPortaliP59044.
SMRiP59044. Positions 193-218, 670-873.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 103103PyrinPROSITE-ProRule annotationAdd
BLAST
Domaini196 – 513318NACHTPROSITE-ProRule annotationAdd
BLAST
Repeati462 – 48726LRR 1Add
BLAST
Repeati727 – 74721LRR 2Add
BLAST
Repeati755 – 77824LRR 3Add
BLAST
Repeati811 – 83424LRR 4Add
BLAST
Repeati845 – 86824LRR 5Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi604 – 61411Poly-GluAdd
BLAST

Sequence similaritiesi

Belongs to the NLRP family.Curated
Contains 5 LRR (leucine-rich) repeats.Curated
Contains 1 NACHT domain.PROSITE-ProRule annotation
Contains 1 pyrin domain.PROSITE-ProRule annotation

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiENOG410IIC5. Eukaryota.
ENOG41115SU. LUCA.
GeneTreeiENSGT00840000129675.
HOGENOMiHOG000169726.
HOVERGENiHBG108172.
InParanoidiP59044.
OMAiPEAAPCT.
OrthoDBiEOG7P5T07.
PhylomeDBiP59044.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 2 hits.
InterProiIPR004020. DAPIN.
IPR011029. DEATH-like_dom.
IPR032675. L_dom-like.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF02758. PYRIN. 1 hit.
[Graphical view]
SMARTiSM01289. PYRIN. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiPS50824. DAPIN. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P59044-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MDQPEAPCSS TGPRLAVARE LLLAALEELS QEQLKRFRHK LRDVGPDGRS
60 70 80 90 100
IPWGRLERAD AVDLAEQLAQ FYGPEPALEV ARKTLKRADA RDVAAQLQER
110 120 130 140 150
RLQRLGLGSG TLLSVSEYKK KYREHVLQLH ARVKERNARS VKITKRFTKL
160 170 180 190 200
LIAPESAAPE EAMGPAEEPE PGRARRSDTH TFNRLFRRDE EGRRPLTVVL
210 220 230 240 250
QGPAGIGKTM AAKKILYDWA AGKLYQGQVD FAFFMPCGEL LERPGTRSLA
260 270 280 290 300
DLILDQCPDR GAPVPQMLAQ PQRLLFILDG ADELPALGGP EAAPCTDPFE
310 320 330 340 350
AASGARVLGG LLSKALLPTA LLLVTTRAAA PGRLQGRLCS PQCAEVRGFS
360 370 380 390 400
DKDKKKYFYK YFRDERRAER AYRFVKENET LFALCFVPFV CWIVCTVLRQ
410 420 430 440 450
QLELGRDLSR TSKTTTSVYL LFITSVLSSA PVADGPRLQG DLRNLCRLAR
460 470 480 490 500
EGVLGRRAQF AEKELEQLEL RGSKVQTLFL SKKELPGVLE TEVTYQFIDQ
510 520 530 540 550
SFQEFLAALS YLLEDGGVPR TAAGGVGTLL RGDAQPHSHL VLTTRFLFGL
560 570 580 590 600
LSAERMRDIE RHFGCMVSER VKQEALRWVQ GQGQGCPGVA PEVTEGAKGL
610 620 630 640 650
EDTEEPEEEE EGEEPNYPLE LLYCLYETQE DAFVRQALCR FPELALQRVR
660 670 680 690 700
FCRMDVAVLS YCVRCCPAGQ ALRLISCRLV AAQEKKKKSL GKRLQASLGG
710 720 730 740 750
GSSSQGTTKQ LPASLLHPLF QAMTDPLCHL SSLTLSHCKL PDAVCRDLSE
760 770 780 790 800
ALRAAPALTE LGLLHNRLSE AGLRMLSEGL AWPQCRVQTV RVQLPDPQRG
810 820 830 840 850
LQYLVGMLRQ SPALTTLDLS GCQLPAPMVT YLCAVLQHQG CGLQTLSLAS
860 870 880 890
VELSEQSLQE LQAVKRAKPD LVITHPALDG HPQPPKELIS TF
Length:892
Mass (Da):98,768
Last modified:September 22, 2009 - v2
Checksum:iA987FDACE6448C6A
GO
Isoform 2 (identifier: P59044-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     702-702: Missing.

Note: No experimental confirmation available.
Show »
Length:891
Mass (Da):98,681
Checksum:iF3AA5228E297E935
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti163 – 1631M → L.3 Publications
Corresponds to variant rs6421985 [ dbSNP | Ensembl ].
VAR_058968
Natural varianti361 – 3611Y → F.3 Publications
Corresponds to variant rs56159585 [ dbSNP | Ensembl ].
VAR_058969

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei702 – 7021Missing in isoform 2. 1 PublicationVSP_054400

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF479748 mRNA. Translation: AAL87105.1.
AY154461 mRNA. Translation: AAO18157.1.
AK292668 mRNA. Translation: BAF85357.1.
AC136475 mRNA. No translation available.
CCDSiCCDS60680.1. [P59044-2]
CCDS7693.1. [P59044-1]
RefSeqiNP_001263629.1. NM_001276700.1. [P59044-2]
NP_612202.2. NM_138329.2. [P59044-1]
UniGeneiHs.352611.

Genome annotation databases

EnsembliENST00000312165; ENSP00000309767; ENSG00000174885. [P59044-1]
ENST00000534750; ENSP00000433617; ENSG00000174885. [P59044-2]
GeneIDi171389.
KEGGihsa:171389.
UCSCiuc010qvs.4. human. [P59044-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF479748 mRNA. Translation: AAL87105.1.
AY154461 mRNA. Translation: AAO18157.1.
AK292668 mRNA. Translation: BAF85357.1.
AC136475 mRNA. No translation available.
CCDSiCCDS60680.1. [P59044-2]
CCDS7693.1. [P59044-1]
RefSeqiNP_001263629.1. NM_001276700.1. [P59044-2]
NP_612202.2. NM_138329.2. [P59044-1]
UniGeneiHs.352611.

3D structure databases

ProteinModelPortaliP59044.
SMRiP59044. Positions 193-218, 670-873.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9606.ENSP00000309767.

PTM databases

iPTMnetiP59044.
PhosphoSiteiP59044.

Polymorphism and mutation databases

DMDMi259016285.

Proteomic databases

PaxDbiP59044.
PRIDEiP59044.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000312165; ENSP00000309767; ENSG00000174885. [P59044-1]
ENST00000534750; ENSP00000433617; ENSG00000174885. [P59044-2]
GeneIDi171389.
KEGGihsa:171389.
UCSCiuc010qvs.4. human. [P59044-1]

Organism-specific databases

CTDi171389.
GeneCardsiNLRP6.
HGNCiHGNC:22944. NLRP6.
HPAiHPA043681.
HPA048500.
MIMi609650. gene.
neXtProtiNX_P59044.
PharmGKBiPA162398002.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IIC5. Eukaryota.
ENOG41115SU. LUCA.
GeneTreeiENSGT00840000129675.
HOGENOMiHOG000169726.
HOVERGENiHBG108172.
InParanoidiP59044.
OMAiPEAAPCT.
OrthoDBiEOG7P5T07.
PhylomeDBiP59044.

Miscellaneous databases

GeneWikiiNLRP6.
GenomeRNAii171389.
NextBioi35502743.
PROiP59044.
SOURCEiSearch...

Gene expression databases

BgeeiP59044.
CleanExiHS_NLRP6.
GenevisibleiP59044. HS.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 2 hits.
InterProiIPR004020. DAPIN.
IPR011029. DEATH-like_dom.
IPR032675. L_dom-like.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF02758. PYRIN. 1 hit.
[Graphical view]
SMARTiSM01289. PYRIN. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiPS50824. DAPIN. 1 hit.
PS50837. NACHT. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing."
    Wang L., Manji G.A., Grenier J.M., Al-Garawi A., Merriam S., Lora J.M., Geddes B.J., Briskin M., DiStefano P.S., Bertin J.
    J. Biol. Chem. 277:29874-29880(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS LEU-163 AND PHE-361.
  2. "NALPs: a novel protein family involved in inflammation."
    Tschopp J., Martinon F., Burns K.
    Nat. Rev. Mol. Cell Biol. 4:95-104(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS LEU-163 AND PHE-361.
  3. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), VARIANTS LEU-163 AND PHE-361.
    Tissue: Thymus.
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1."
    Grenier J.M., Wang L., Manji G.A., Huang W.-J., Al-Garawi A., Kelly R., Carlson A., Merriam S., Lora J.M., Briskin M., DiStefano P.S., Bertin J.
    FEBS Lett. 530:73-78(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INVOLVEMENT IN INFLAMMASOME COMPLEX, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  6. "Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine."
    Kempster S.L., Belteki G., Forhead A.J., Fowden A.L., Catalano R.D., Lam B.Y., McFarlane I., Charnock-Jones D.S., Smith G.C.
    Am. J. Physiol. 300:G253-G263(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION BY ROSIGLITAZONE.
  7. "Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury."
    Normand S., Delanoye-Crespin A., Bressenot A., Huot L., Grandjean T., Peyrin-Biroulet L., Lemoine Y., Hot D., Chamaillard M.
    Proc. Natl. Acad. Sci. U.S.A. 108:9601-9606(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  8. "Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice."
    Sun Y., Zhang M., Chen C.C., Gillilland M. III, Sun X., El-Zaatari M., Huffnagle G.B., Young V.B., Zhang J., Hong S.C., Chang Y.M., Gumucio D.L., Owyang C., Kao J.Y.
    Gastroenterology 144:1478-1487(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION BY CRH AND ROSIGLITAZONE.

Entry informationi

Entry nameiNLRP6_HUMAN
AccessioniPrimary (citable) accession number: P59044
Secondary accession number(s): A8K9F3, E9PJZ8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 19, 2002
Last sequence update: September 22, 2009
Last modified: May 11, 2016
This is version 126 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.