NLRP3_MACMU
ID NLRP3_MACMU Reviewed; 1035 AA.
AC B0FPE9;
DT 03-NOV-2009, integrated into UniProtKB/Swiss-Prot.
DT 26-FEB-2008, sequence version 1.
DT 03-AUG-2022, entry version 87.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 3;
GN Name=NLRP3;
OS Macaca mulatta (Rhesus macaque).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9544;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Oocyte;
RX PubMed=18509866; DOI=10.1002/mrd.20937;
RA McDaniel P., Wu X.;
RT "Identification of oocyte-selective NLRP genes in rhesus macaque monkeys
RT (Macaca mulatta).";
RL Mol. Reprod. Dev. 76:151-159(2009).
CC -!- FUNCTION: As the sensor component of the NLRP3 inflammasome, plays a
CC crucial role in innate immunity and inflammation. In response to
CC pathogens and other damage-associated signals, initiates the formation
CC of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1
CC (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the
CC inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18
CC maturation and secretion in the extracellular milieu. Activation of
CC NLRP3 inflammasome is also required for HMGB1 secretion. The active
CC cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can
CC also induce pyroptosis, an inflammatory form of programmed cell death.
CC Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation
CC stimuli include extracellular ATP, reactive oxygen species, K(+)
CC efflux, crystals of monosodium urate or cholesterol, amyloid-beta
CC fibers, environmental or industrial particles and nanoparticles,
CC cytosolic dsRNA, etc (By similarity). Activation upon, at least, K(+)
CC efflux is mediated by the interaction wit NEK7 (By similarity).
CC Activation in presence of cytosolic dsRNA is mediated by DHX33 (By
CC similarity). Independently of inflammasome activation, regulates the
CC differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-
CC dependent asthma and tumor growth (By similarity). During Th2
CC differentiation, required for optimal IRF4 binding to IL4 promoter and
CC for IRF4-dependent IL4 transcription. Binds to the consensus DNA
CC sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of
CC IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity).
CC {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.
CC -!- ACTIVITY REGULATION: Under resting conditions, NLRP3 is autoinhibited.
CC NLRP3 activation stimuli include extracellular ATP, reactive oxygen
CC species, K(+) efflux, crystals of monosodium urate or cholesterol,
CC amyloid-beta fibers, environmental or industrial particles and
CC nanoparticles, cytosolic dsRNA, etc. However, it is unclear what
CC constitutes the direct NLRP3 activator. Activation in presence of
CC cytosolic dsRNA is mediated by DHX33. {ECO:0000250|UniProtKB:Q96P20}.
CC -!- SUBUNIT: Sensor component of NLRP3 inflammasomes. Inflammasomes are
CC supramolecular complexes that assemble in the cytosol in response to
CC pathogens and other damage-associated signals and play critical roles
CC in innate immunity and inflammation. The core of NLRP3 inflammasomes
CC consists of a signal sensor component (NLRP3), an adapter (ASC/PYCARD),
CC which recruits an effector pro-inflammatory caspase (CASP1 and,
CC possibly, CASP4 and CASP5). Within the complex, NLRP3 and PYCARD
CC interact via their respective DAPIN/pyrin domains. This interaction
CC initiates speck formation (nucleation) which greatly enhances further
CC addition of soluble PYCARD molecules to the speck in a prion-like
CC polymerization process. NLRP3 localizes at the end of each PYCARD
CC filament. Clustered PYCARD nucleates the formation of CASP1 filaments
CC through the interaction of their respective CARD domains, acting as a
CC platform for CASP1 polymerization. CASP1 filament formation increases
CC local enzyme concentration, resulting in trans-autocleavage and
CC activation. Active CASP1 then processes IL1B and IL18 precursors,
CC leading to the release of mature cytokines in the extracellular milieu
CC and inflammatory response. Reconstituted ternary inflammasomes show
CC star-shaped structures, in which multiple filaments, containing CASP1,
CC protrude radially from a single central hub, containing the sensor
CC protein and PYCARD. In this complex, the sensor protein is sub-
CC stoichiometric to PYCARD, and PYCARD is further substoichiometric to
CC CASP1, suggesting amplifications of signal transduction from the
CC sensor, via the adapter, to the effector. Interacts with MEFV; this
CC interaction targets NLRP3 to degradation by autophagy, hence preventing
CC excessive IL1B- and IL18-mediated inflammation. Interacts with GBP5
CC (via DAPIN domain); this interaction promotes inflammasome assembly in
CC response to microbial and soluble, but not crystalline, agents.
CC Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity,
CC is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome
CC assembly in response to specific stimuli. Interacts with PML (isoform
CC PML-1) (via the leucine-rich repeat (LRR) domain); PML-mediated
CC increase in NLRP3 inflammasome activation does not depend upon this
CC interaction (By similarity). Directly interacts with IRF4 (via the LRR
CC domain); this interaction is required for optimal IRF4 binding to IL4
CC promoter and efficient IL4 transactivation during differentiation of
CC Th2 helper T-cells (By similarity). Interacts (via NACHT domain) with
CC DHX33 (via DEAH box). Interacts with PYDC5 (By similarity). Interacts
CC (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-
CC activating conditions (By similarity) Interacts (via NACHT and LRR
CC domains) with ARRB2; this interaction is direct and inducible by
CC polyunsaturated fatty acids (PUFAs). Interacts with CARD8; leading to
CC inhibit formation of the NLRP3 inflammasome (By similarity). Interacts
CC (via LRR repeat domain) with NEK7 (via N-terminus); the interaction is
CC required for the formation of the complex NLRP3:PYCARD, oligomerization
CC of PYCARD and activation of CASP1 (By similarity).
CC {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q96P20}. Inflammasome
CC {ECO:0000250|UniProtKB:Q96P20}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:Q8R4B8}. Secreted
CC {ECO:0000250|UniProtKB:Q96P20}. Nucleus {ECO:0000250|UniProtKB:Q8R4B8}.
CC Note=In macrophages, under resting conditions, mainly located in the
CC cytosol, on the endoplasmic reticulum. After stimulation with inducers
CC of the NLRP3 inflammasome, mitochondria redistribute in the vicinity of
CC the endoplasmic reticulum in the perinuclear region, which results in
CC colocalization of NLRP3 on the endoplasmic reticulum and PYCARD on
CC mitochondria, allowing the activation of inflammasome assembly. After
CC the induction of pyroptosis, inflammasome specks are released into the
CC extracellular space where they can further promote IL1B processing and
CC where they can be engulfed by macrophages. Phagocytosis induces
CC lysosomal damage and inflammasome activation in the recipient cells (By
CC similarity). In the Th2 subset of CD4(+) helper T-cells, mainly located
CC in the nucleus. Nuclear localization depends upon KPNA2. In the Th1
CC subset of CD4(+) helper T-cells, mainly cytoplasmic (By similarity).
CC {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.
CC -!- TISSUE SPECIFICITY: Highly expressed in oocyte, testis, spleen, thymus
CC and kidney. {ECO:0000269|PubMed:18509866}.
CC -!- DOMAIN: The pyrin domain (also called DAPIN domain or PYD) is involved
CC in PYCARD-binding. {ECO:0000250|UniProtKB:Q96P20}.
CC -!- DOMAIN: The LRR domain mediates the interaction with IRF4 and PML.
CC {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.
CC -!- DOMAIN: Intramolecular interactions between NACHT and leucine-rich
CC repeat (LRR) domains may be important for autoinhibition in the absence
CC of activating signal. {ECO:0000250|UniProtKB:Q96P20,
CC ECO:0000250|UniProtKB:Q9EPB4}.
CC -!- PTM: The disulfide bond in the pyrin domain might play a role in
CC reactive oxygen species-mediated activation.
CC {ECO:0000250|UniProtKB:Q96P20}.
CC -!- PTM: Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked
CC polyubiquitination. Ubiquitination does not lead to degradation, but
CC inhibits inflammasome activation (By similarity). Deubiquitination is
CC catalyzed by BRCC3 and associated with NLRP3 activation and
CC inflammasome assembly. This process can be induced by the activation of
CC Toll-like receptors (by LPS), through a non-transcriptional pathway
CC dependent on the mitochondrial production of reactive oxygen species,
CC and by ATP (By similarity). {ECO:0000250|UniProtKB:Q8R4B8,
CC ECO:0000250|UniProtKB:Q96P20}.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; EU344966; ABY58962.1; -; mRNA.
DR RefSeq; NP_001107823.1; NM_001114351.1.
DR RefSeq; XP_014983267.1; XM_015127781.1.
DR AlphaFoldDB; B0FPE9; -.
DR SMR; B0FPE9; -.
DR STRING; 9544.ENSMMUP00000007829; -.
DR GeneID; 701278; -.
DR KEGG; mcc:701278; -.
DR CTD; 114548; -.
DR eggNOG; ENOG502SBIG; Eukaryota.
DR HOGENOM; CLU_002274_2_3_1; -.
DR InParanoid; B0FPE9; -.
DR OrthoDB; 114368at2759; -.
DR Proteomes; UP000006718; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IBA:GO_Central.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002674; P:negative regulation of acute inflammatory response; IBA:GO_Central.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; ISS:UniProtKB.
DR GO; GO:2000553; P:positive regulation of T-helper 2 cell cytokine production; ISS:UniProtKB.
DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0002830; P:positive regulation of type 2 immune response; 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; -; 1.
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; IPR029495; NACHT-assoc.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR041267; NLRP_HD2.
DR InterPro; IPR041075; NOD2_WH.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF14484; FISNA; 1.
DR Pfam; PF13516; LRR_6; 5.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR Pfam; PF02758; PYRIN; 1.
DR SMART; SM01288; FISNA; 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 2: Evidence at transcript level;
KW Activator; Amyloidosis; ATP-binding; Cytoplasm; Disulfide bond;
KW Endoplasmic reticulum; Immunity; Inflammasome; Inflammatory response;
KW Innate immunity; Leucine-rich repeat; Nucleotide-binding; Nucleus;
KW Reference proteome; Repeat; Secreted; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..1035
FT /note="NACHT, LRR and PYD domains-containing protein 3"
FT /id="PRO_0000387569"
FT DOMAIN 1..93
FT /note="Pyrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00061"
FT DOMAIN 220..536
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 741..761
FT /note="LRR 1"
FT REPEAT 770..791
FT /note="LRR 2"
FT REPEAT 798..818
FT /note="LRR 3"
FT REPEAT 827..848
FT /note="LRR 4"
FT REPEAT 855..875
FT /note="LRR 5"
FT REPEAT 884..905
FT /note="LRR 6"
FT REPEAT 912..932
FT /note="LRR 7"
FT REPEAT 941..962
FT /note="LRR 8"
FT REPEAT 969..990
FT /note="LRR 9"
FT BINDING 226..233
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT DISULFID 8..108
FT /note="Redox-active"
FT /evidence="ECO:0000250|UniProtKB:Q96P20"
SQ SEQUENCE 1035 AA; 118192 MW; 7EE691EEC6BFCF7C CRC64;
MKMASTRCKL ARYLEDLEDV DLKKFKMHLE DYPPQKGCIS LPRGQTEKAD HVDLATLMID
FNGEEKAWAM AVWIFAAINR RDLYEKAKRD EPKWGSDNAR VSNPTVICQE DSIEEEWMGL
LEYLSRISIC KKKKDYCKKY RKYVRSRFQC IEDRNARLGE SVSLNKRYTR LRLIKEHRSQ
QEREHELLAI GKTKTWESPV SPIKMELLFD PDDEHSEPVH TVVFQGAAGI GKTILARKIM
LDWASGTLYQ DRFDYLFYIH CREVSLVTQR SLGDLIMSCC PDPNPPIRKI VSKPSRILFL
MDGFDELQGA FDEHIGPLCT DWQKAERGDI LLSSLIRKKL LPEASLLITT RPVALEKLQH
LLDHPRHVEI LGFSEAKRKE YFFKYFSDEA QARAAFSLIQ ENEVLFTMCF IPLVCWIVCT
GLKQQMESGK SLAQTSKTTT AVYTFFLSSL LQPRGGSQEH RLCAHLWGLC SLAADGIWNQ
KILFEESDLR NHGLQKADVS AFLRMNLFQK EVDCEKFYSF IHMTFQEFFA AMYYLLEEEK
EGRTNVPGSC LKLPSRDVTV LLENYGKFEK GYLIFVVRFL FGLVNQERTC YLEKKLSCKI
SQQIRLELLK WIEVKAKAKK LQIQPSQLEL FYCLYEMQEE DFVQRAMDYF PKIEINLSTR
MDHVVSSFCI ENCHRVESLS LGFLHNMPKE EEEEEKEGRH LDMVQCVLPG SHAACSHRLV
NSHLTSSFCR GLFSVLSTSQ SLTELDLSDN SLGDPGMRVL CETLQHPDCN IRRLWLGRCG
LSHECCFDIS LVLSSNQKLV ELDLSDNALG DFGIRLLCVG LKHLLCNLKK LWLVSCCLTS
ACCQDLASVL STSRSLTRLY VGENALGDAG VAILCEKAKN PQCNLQKLGL VNSGLTSACC
SALSSVLSTN QNLTHLYLRG NTLGDKGIKL LCEGLLHPDC KLQVLELDNC NLTSHCCWDL
STLLTSSQSL RKLSLGNNDL GDLGVMMFCE VLKQQSCLLQ NLGLSEMYFN YETKSALETL
QEEKPELTIV FEPSW
