Protein: NACHT, LRR and PYD domains-containing protein 3 (EC 3.6.4.-) (D4A523)
Organism: Rattus norvegicus (Rat)
Function: Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis. In response to pathogens and other damage-associated signals that affect the integrity of membranes, initiates the formation of the inflammasome polymeric complex composed of NLRP3, CASP1 and PYCARD/ASC. Recruitment of pro-caspase-1 (proCASP1) to the NLRP3 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion and pyroptosis. Activation of NLRP3 inflammasome is also required for HMGB1 secretion; stimulating inflammatory responses (By similarity). Under resting conditions, ADP-bound NLRP3 is autoinhibited (By similarity). NLRP3 activation stimuli include extracellular ATP, nigericin, reactive oxygen species, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, such as asbestos, silica, aluminum salts, cytosolic dsRNA, etc. Almost all stimuli trigger intracellular K(+) efflux (By similarity). These stimuli lead to membrane perturbation and activation of NLRP3 (By similarity). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes and formation of an active inflammasome complex. Associates with dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P). Shows ATPase activity (By similarity).
Subcellular location: Cytoplasm, cytosol {ECO:0000250|UniProtKB:Q8R4B8}. Inflammasome {ECO:0000250|UniProtKB:Q8R4B8}. Cytoplasm, cytoskeleton, microtubule organizing center {ECO:0000250|UniProtKB:Q8R4B8}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q8R4B8}. Endoplasmic reticulum {ECO:0000250|UniProtKB:Q8R4B8}. Mitochondrion {ECO:0000250|UniProtKB:Q8R4B8}. Secreted {ECO:0000250|UniProtKB:Q8R4B8}. Nucleus {ECO:0000250|UniProtKB:Q8R4B8}. Note=In macrophages, under resting conditions, mainly located in the cytosol and on membranes of various organelles, such as endoplasmic reticulum, mitochondria and Golgi: forms an inactive double-ring cage that is primarily localized on membranes. Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes for the formation of an active inflammasome complex. Recruited to dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P). After the induction of pyroptosis, inflammasome specks are released into the extracellular space where they can further promote IL1B processing and where they can be engulfed by macrophages. Phagocytosis induces lysosomal damage and inflammasome activation in the recipient cells. In the Th2 subset of CD4(+) helper T-cells, mainly located in the nucleus. Nuclear localization depends upon KPNA2. In the Th1 subset of CD4(+) helper T-cells, mainly cytoplasmic. {ECO:0000250|UniProtKB:Q8R4B8}.
Interaction partners:
- Caspase-1
- Apoptosis-associated speck-like protein containing a CARD
- Thioredoxin-interacting protein
- NLR family CARD domain-containing protein 4
- Absent in melanoma 2
- Serine/threonine-protein kinase Nek7
- Interleukin-1 beta
- Mitochondrial antiviral-signaling protein
- Pyrin
- NLR family, pyrin domain-containing 1A.
Sequence:
MKMMSVRCKLAQYLEDLEDVDLKKFKMHLEDYPPEKGCVPIPRGQMEKADHLDLATLMIDFNGEEKAWGMAVWIFAAINRRDLWEKAKKDQPEWNDACTSNLSMVCQEDSLEEEWIGLLGYLSRISICKKKKDYCKIYRRHVRSRFYSIKDRNARLGESVDLNRRYTQLQLVKEHPSKQEREHELLTIGRTKMWDRPMSSLKLELLFEPEDEHLEPVHTVVFQGAAGIGKTILARKIMLDWALGKLFKDKFDYLFFIHCREVSLRAPKSLADLIISCWPDPNPPVCKILCKPSRILFLMDGFDELQGAFDEHIEEVCTDWQKAVRGDILLSSLIRKKLLPKASLLITTRPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSNELQAREAFRLIQENEILFTMCFIPLVCWIVCTGLKQQMETGKSLAQTSKTTTAVYVFFLSSLLQSRGGIEEHLFSAYLPGLCSLAADGIWNQKILFEECDLRKHGLQKTDVSAFLRMNVFQKEVDCERFYSFSHMTFQEFFAAMYYLLEEEEEGVTVRKGPEGCSDLLNRDVKVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKISQQVRLELLKWIEVKAKAKKLQRQPSQLELFYCLYEMQEEDFVQSAMGHFPKIEINLSTRMDHVVSSFCIKNCHRVKTLSLGFLHNSPKEEEEEKRGSQPLDQVQCVFPDPHVACSSRLVNCCLTSSFCRGLFSSLSTNQSLTELDLSDNTLGDPGMRVLCEALQHPGCNIQRLWLGRCGLTHQCCFNISSVLSSSQKLVELDLSDNALGDFGVRLLCVGLKHLLCNLQKLWLVSCCLTSACCQDLALVLSSNHSLTRLYIGENALGDSGVQVLCEKMKDPQCNLQKLGLVNSGLTSLCCSALTSVLKTNQNLTHLYLRSNALGDMGLKLLCEGLLHPDCKLQMLELDNCSLTSHSCWDLSTILTHNQSLRKLNLSNNDLGDLCVVTLCEVLKQQGCLLQSLQLGEMYLNCETKRTLEALQEEKPELTVVFEISW