| Structural highlights
Function
[NLRP3_MOUSE] As the sensor component of the NLRP3 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 NLRP3, 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 (PubMed:28847925, PubMed:27374331). Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is unclear what constitutes the direct NLRP3 activator. Activation in presence of cytosolic dsRNA is mediated by DHX33 (By similarity). Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth. During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (PubMed:26098997).[UniProtKB:Q96P20][1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here, we report that an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to 16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for many NLRP3-activating stimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutants abolish inflammasome punctum formation, caspase-1 processing, and cell death. Thus, our data uncover a physiological NLRP3 oligomer on the membrane that is poised to sense diverse signals to induce inflammasome activation.
NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation.,Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, Wu H Cell. 2021 Nov 30. pii: S0092-8674(21)01326-X. doi: 10.1016/j.cell.2021.11.011. PMID:34861190[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006 Mar 9;440(7081):228-32. Epub 2006 Jan 11. PMID:16407890 doi:https://dx.doi.org/nature04515
- ↑ Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity. 2006 Mar;24(3):317-27. doi: 10.1016/j.immuni.2006.02.004. PMID:16546100 doi:https://dx.doi.org/10.1016/j.immuni.2006.02.004
- ↑ Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Nunez G. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem. 2006 Dec 1;281(48):36560-8. doi: 10.1074/jbc.M607594200. Epub 2006, Sep 28. PMID:17008311 doi:https://dx.doi.org/10.1074/jbc.M607594200
- ↑ Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundback P, Valdes-Ferrer SI, Olofsson PS, Kalb T, Roth J, Zou Y, Erlandsson-Harris H, Yang H, Ting JP, Wang H, Andersson U, Antoine DJ, Chavan SS, Hotamisligil GS, Tracey KJ. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012 Aug 30;488(7413):670-4. doi: 10.1038/nature11290. PMID:22801494 doi:https://dx.doi.org/10.1038/nature11290
- ↑ Bruchard M, Rebe C, Derangere V, Togbe D, Ryffel B, Boidot R, Humblin E, Hamman A, Chalmin F, Berger H, Chevriaux A, Limagne E, Apetoh L, Vegran F, Ghiringhelli F. The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat Immunol. 2015 Aug;16(8):859-70. doi: 10.1038/ni.3202. Epub 2015 Jun 22. PMID:26098997 doi:https://dx.doi.org/10.1038/ni.3202
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- ↑ Nakanishi H, Kawashima Y, Kurima K, Chae JJ, Ross AM, Pinto-Patarroyo G, Patel SK, Muskett JA, Ratay JS, Chattaraj P, Park YH, Grevich S, Brewer CC, Hoa M, Kim HJ, Butman JA, Broderick L, Hoffman HM, Aksentijevich I, Kastner DL, Goldbach-Mansky R, Griffith AJ. NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7766-E7775. doi:, 10.1073/pnas.1702946114. Epub 2017 Aug 28. PMID:28847925 doi:https://dx.doi.org/10.1073/pnas.1702946114
- ↑ Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, Wu H. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell. 2021 Nov 30. pii: S0092-8674(21)01326-X. doi: 10.1016/j.cell.2021.11.011. PMID:34861190 doi:https://dx.doi.org/10.1016/j.cell.2021.11.011
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