| 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
SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950 has established the structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation and the mechanism of action of the NLRP3 specific inhibitor. The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. Visualization of the inhibitor binding mode will enable optimization of the activity of NLRP3 inflammasome inhibitor drugs.
Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation.,Ohto U, Kamitsukasa Y, Ishida H, Zhang Z, Murakami K, Hirama C, Maekawa S, Shimizu T Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2121353119. doi:, 10.1073/pnas.2121353119. Epub 2022 Mar 7. PMID:35254907[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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:http://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:http://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:http://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:http://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:http://dx.doi.org/10.1038/ni.3202
- ↑ Wolf AJ, Reyes CN, Liang W, Becker C, Shimada K, Wheeler ML, Cho HC, Popescu NI, Coggeshall KM, Arditi M, Underhill DM. Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell. 2016 Jul 28;166(3):624-636. doi: 10.1016/j.cell.2016.05.076. Epub 2016 Jun , 30. PMID:27374331 doi:http://dx.doi.org/10.1016/j.cell.2016.05.076
- ↑ 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:http://dx.doi.org/10.1073/pnas.1702946114
- ↑ Ohto U, Kamitsukasa Y, Ishida H, Zhang Z, Murakami K, Hirama C, Maekawa S, Shimizu T. Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation. Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2121353119. doi:, 10.1073/pnas.2121353119. Epub 2022 Mar 7. PMID:35254907 doi:http://dx.doi.org/10.1073/pnas.2121353119
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