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Protein

NACHT, LRR and PYD domains-containing protein 6

Gene

Nlrp6

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

As the sensor component of the NLRP6 inflammasome, plays a crucial role in innate immunity and inflammation. In response to yet unidentified signals, initiates the formation of the inflammasome polymeric complex, made of NLRP6, PYCARD and CASP1 (or possibly CASP4/CASP11). Recruitment 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:21593405). Essential for gut mucosal self-renewal and proliferation (PubMed:21593405, PubMed:21565393, PubMed:21543645). Maintains intestinal homeostasis and a healthy intestinal microbiota (PubMed:21565393, PubMed:22763455). This function is, at least partially, mediated by IL18, and not IL1B, produced by nonhematopoietic cells (PubMed:21565393). 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 (PubMed:24581500). During systemic bacterial infections, may negatively regulate inflammatory signaling and inhibit the influx of monocytes and neutrophils to the circulation and to the peritoneum (PubMed:22763455). May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism (PubMed:26253422).By similarity6 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi200 – 2078ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • negative regulation of ERK1 and ERK2 cascade Source: CACAO
  • negative regulation of I-kappaB kinase/NF-kappaB signaling Source: CACAO
  • negative regulation of immune response Source: MGI
  • negative regulation of inflammatory response to antigenic stimulus Source: CACAO
  • negative regulation of MAPK cascade Source: MGI
  • negative regulation of toll-like receptor signaling pathway Source: MGI
  • regulation of autophagy Source: MGI
  • regulation of inflammatory response Source: UniProtKB
  • regulation of mucus secretion Source: MGI
  • response to bacterium Source: MGI
  • wound healing Source: MGI
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
Non-angiotensin-vasopressin receptor1 Publication
Short name:
Non-AVR1 Publication
PYRIN-containing APAF1-like protein 5-like
Gene namesi
Name:Nlrp6
Synonyms:Nalp6, Navr, Pypaf5
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:2141990. Nlrp6.

Subcellular locationi

Isoform 1 :
  • Cytoplasm By similarity
  • Inflammasome By similarity
  • Cell membrane By similarity
  • Nucleus membrane By similarity
Isoform 2 :
  • Cytoplasm By similarity
  • Cell membrane By similarity

  • Note: Predominantly expressed in the cell membrane.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Inflammasome, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

Knockout mice are born at the expected Mendelian rate with no morphological abnormalities (PubMed:20923861, PubMed:21593405). They are characterized by spontaneous intestinal hyperplasia, inflammatory cell recruitment, exacerbation of chemical colitis induced by exposure to dextran sodium sulfate (DSS) and develop higher tumor loads in response to a combined treatment with the alkylating procarcinogen azoxymethane (AOM) and DSS (PubMed:21593405, PubMed:21565393, PubMed:21543645). The colitogenic phenotype is associated with altered microbiota and is transmissible to cohoused wild-type mice, both early in postnatal life and during adulthood (PubMed:21565393, PubMed:22763455). Mice infected with an enteric pathogen, such as Citrobacter rodentium, show impaired clearance of the bacteria from colon. Their intestinal epithelium lack a thick continuous overlaying inner mucus layer and exhibit a marked goblet cell hyperplasia along with abrogated mucus secretion (PubMed:24581500). When injected intraperitoneally or intravenously, knockout mice show increased resistance to Salmonella typhimurium, Listeria monocytogenes or Escherichia coli (PubMed:22763455). After crushing the sciatic nerve, mutant mice have a more dramatic drop in sciatic function index immediately upon surgery compared to the control group and need more time to recover fully (PubMed:26253422). Mutant animals show reduced systolic blood pressure without affecting heart rate. Males, but not females, exhibit increased urine flow and decreased ability to reduce urinary flow under water restriction conditions compared to wild type littermates. Mutant males may show somewhat lowered cognitive performance (PubMed:20923861).7 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 869869NACHT, LRR and PYD domains-containing protein 6PRO_0000080893Add
BLAST

Proteomic databases

MaxQBiQ91WS2.
PaxDbiQ91WS2.
PeptideAtlasiQ91WS2.
PRIDEiQ91WS2.

PTM databases

PhosphoSiteiQ91WS2.

Expressioni

Tissue specificityi

Highly expressed in the gastrointestinal tract, predominantly in colonic myofibroblasts and in colonic epithelial and endothelial cells. Within the intestinal mucosa, highly expressed by goblet cells. Also expressed in hepatocytes and in immune cells, including CD4+ and CD8+ T-cells, dendritic cells, mastocytes and peritoneal macrophages, as well as in lung, kidney, bladder and gonads.5 Publications

Developmental stagei

Up-regulated transiently following sterile or LPS-induced sciatic nerve injury with a peak after 4 hours.1 Publication

Inductioni

Up-regulated by rosiglitazone, a PPARG agonist, in CT26 cells. Down-regulated by CRH during water-avoidance stress.1 Publication

Gene expression databases

BgeeiENSMUSG00000038745.
CleanExiMM_NLRP6.
ExpressionAtlasiQ91WS2. baseline and differential.
GenevisibleiQ91WS2. MM.

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/CASP11). 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 similarity

Protein-protein interaction databases

DIPiDIP-61874N.
STRINGi10090.ENSMUSP00000101660.

Structurei

3D structure databases

ProteinModelPortaliQ91WS2.
SMRiQ91WS2. Positions 16-96, 191-216, 654-869.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini37 – 12892PyrinPROSITE-ProRule annotationAdd
BLAST
Domaini194 – 511318NACHTPROSITE-ProRule annotationAdd
BLAST
Repeati460 – 48526LRR 1Add
BLAST
Repeati635 – 65824LRR 2Add
BLAST
Repeati837 – 86024LRR 3Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi595 – 61117Asp/Glu-richAdd
BLAST
Compositional biasi680 – 6878Poly-Lys

Sequence similaritiesi

Belongs to the NLRP family.Curated
Contains 3 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.
InParanoidiQ91WS2.
OMAiFRDERKA.
OrthoDBiEOG091G01CG.
PhylomeDBiQ91WS2.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 1 hit.
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 (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative promoter usage and alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q91WS2-1) [UniParc]FASTAAdd to basket
Also known as: NAVR1 Publication

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
MDAAGASCSS VDAVARELLM ATLEELSQEQ LKRFRHKLRD APLDGRSIPW
60 70 80 90 100
GRLERSDAVD LVDKLIEFYE PVPAVEMTRQ VLKRSDIRDV ASRLKQQQLQ
110 120 130 140 150
KLGPTSVLLS VSAFKKKYRE HVLRQHAKVK ERNARSVKIN KRFTKLLIAP
160 170 180 190 200
GTGAVEDELL GPLGEPEPER ARRSDTHTFN RLFRGNDEES SQPLTVVLQG
210 220 230 240 250
PAGIGKTMAA KKILYDWAAG KLYHSQVDFA FFMPCGELLE RPGKRSLADL
260 270 280 290 300
VLDQCPDRAW PVKRILAQPN RLLFILDGAD ELPTLPSSEA TPCKDPLEAT
310 320 330 340 350
SGLRVLSGLL SQELLPGARL LVTTRHAATG RLQGRLCSPQ CAEIRGFSDK
360 370 380 390 400
DKKKYFFKFF RDERKAERAY RFVKENETLF ALCFVPFVCW IVCTVLQQQL
410 420 430 440 450
ELGRDLSRTS KTTTSVYLLF ITSMLKSAGT NGPRVQGELR TLCRLAREGI
460 470 480 490 500
LDHHKAQFSE EDLEKLKLRG SQVQTIFLNK KEIPGVLKTE VTYQFIDQSF
510 520 530 540 550
QEFLAALSYL LEAERTPGTP AGGVQKLLNS DAELRGHLAL TTRFLFGLLN
560 570 580 590 600
TEGLRDIGNH FGCVVPDHVK KDTLRWVQGQ SHPKGPPVGA KKTAELEDIE
610 620 630 640 650
DAEEEEEEEE DLNFGLELLY CLYETQEEDF VRQALSSLPE IVLERVRLTR
660 670 680 690 700
MDLEVLNYCV QCCPDGQALR LVSCGLVAAK EKKKKKKSLV KRLKGSQSTK
710 720 730 740 750
KQPPVSLLRP LCETMTTPKC HLSVLILSHC RLPDAVCRDL SEALKVAPAL
760 770 780 790 800
RELGLLQSRL TNTGLRLLCE GLAWPKCQVK TLRMQLPDLQ EVINYLVIVL
810 820 830 840 850
QQSPVLTTLD LSGCQLPGVI VEPLCAALKH PKCSLKTLSL TSVELSENSL
860
RDLQAVKTSK PDLSIIYSK
Length:869
Mass (Da):97,402
Last modified:August 21, 2007 - v3
Checksum:i801498F67872969F
GO
Isoform 2 (identifier: Q91WS2-2) [UniParc]FASTAAdd to basket
Also known as: Angiotensin-vasopressin receptor, AVR1 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     1-423: Missing.

Note: Produced by alternative promoter usage.
Show »
Length:446
Mass (Da):49,706
Checksum:iE88403A1F46F597B
GO
Isoform 3 (identifier: Q91WS2-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-9: MDAAGASCS → MYCPGAPCGECAMCDPGCFGGSGTGPIQVASVMITLLIP

Note: Produced by alternative splicing.
Show »
Length:899
Mass (Da):100,439
Checksum:iC12DB9DF6BE7A8BC
GO

Sequence cautioni

The sequence ACN32212 differs from that shown. Reason: Frameshift at position 869. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti429 – 4291G → F in ACN32212 (PubMed:20923861).Curated
Sequence conflicti454 – 4541Missing in ACN32212 (PubMed:20923861).Curated
Sequence conflicti733 – 7331P → R in ACN32212 (PubMed:20923861).Curated
Sequence conflicti869 – 8691K → KIRHTSPASEG in ACN32212 (PubMed:20923861).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 423423Missing in isoform 2. 2 PublicationsVSP_042301Add
BLAST
Alternative sequencei1 – 99MDAAGASCS → MYCPGAPCGECAMCDPGCFG GSGTGPIQVASVMITLLIP in isoform 3. VSP_057971

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
JF810536 mRNA. Translation: AEI54131.1.
AC107815 Genomic DNA. No translation available.
AC162287 Genomic DNA. No translation available.
BC013519 mRNA. Translation: AAH13519.1.
BC031139 mRNA. Translation: AAH31139.1.
FJ222825 mRNA. Translation: ACN32212.1. Frameshift.
AY355343 mRNA. Translation: AAR14740.1.
CCDSiCCDS40178.2. [Q91WS2-1]
RefSeqiNP_598707.2. NM_133946.2. [Q91WS2-1]
XP_006536212.1. XM_006536149.2. [Q91WS2-3]
UniGeneiMm.386833.

Genome annotation databases

EnsembliENSMUST00000183845; ENSMUSP00000139357; ENSMUSG00000038745. [Q91WS2-1]
ENSMUST00000184560; ENSMUSP00000139170; ENSMUSG00000038745. [Q91WS2-3]
GeneIDi101613.
KEGGimmu:101613.
UCSCiuc009kiv.3. mouse. [Q91WS2-1]
uc029wpm.2. mouse.

Keywords - Coding sequence diversityi

Alternative promoter usage, Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
JF810536 mRNA. Translation: AEI54131.1.
AC107815 Genomic DNA. No translation available.
AC162287 Genomic DNA. No translation available.
BC013519 mRNA. Translation: AAH13519.1.
BC031139 mRNA. Translation: AAH31139.1.
FJ222825 mRNA. Translation: ACN32212.1. Frameshift.
AY355343 mRNA. Translation: AAR14740.1.
CCDSiCCDS40178.2. [Q91WS2-1]
RefSeqiNP_598707.2. NM_133946.2. [Q91WS2-1]
XP_006536212.1. XM_006536149.2. [Q91WS2-3]
UniGeneiMm.386833.

3D structure databases

ProteinModelPortaliQ91WS2.
SMRiQ91WS2. Positions 16-96, 191-216, 654-869.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-61874N.
STRINGi10090.ENSMUSP00000101660.

PTM databases

PhosphoSiteiQ91WS2.

Proteomic databases

MaxQBiQ91WS2.
PaxDbiQ91WS2.
PeptideAtlasiQ91WS2.
PRIDEiQ91WS2.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000183845; ENSMUSP00000139357; ENSMUSG00000038745. [Q91WS2-1]
ENSMUST00000184560; ENSMUSP00000139170; ENSMUSG00000038745. [Q91WS2-3]
GeneIDi101613.
KEGGimmu:101613.
UCSCiuc009kiv.3. mouse. [Q91WS2-1]
uc029wpm.2. mouse.

Organism-specific databases

CTDi171389.
MGIiMGI:2141990. Nlrp6.

Phylogenomic databases

eggNOGiENOG410IIC5. Eukaryota.
ENOG41115SU. LUCA.
GeneTreeiENSGT00840000129675.
HOGENOMiHOG000169726.
HOVERGENiHBG108172.
InParanoidiQ91WS2.
OMAiFRDERKA.
OrthoDBiEOG091G01CG.
PhylomeDBiQ91WS2.

Miscellaneous databases

PROiQ91WS2.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000038745.
CleanExiMM_NLRP6.
ExpressionAtlasiQ91WS2. baseline and differential.
GenevisibleiQ91WS2. MM.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
3.80.10.10. 1 hit.
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...

Entry informationi

Entry nameiNLRP6_MOUSE
AccessioniPrimary (citable) accession number: Q91WS2
Secondary accession number(s): C9W978
, F8UKQ6, Q67EY0, Q8K0L4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: August 21, 2007
Last modified: September 7, 2016
This is version 128 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. 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.