NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development
Abstract
:1. Introduction
2. Plant Guard Hypothesis
2.1. Pyrin Inflammasome
2.2. NLRP3 Inflammasome
3. Negative Regulation of NLRP3
3.1. Molecular Inhibitors
3.1.1. Heat Shock Protein 70 (HSP70)
3.1.2. HSP90 and Suppressor of G2 Allele of SKP1 (SGT1)
3.1.3. Caspase Recruitment Domain-Containing Protein 8 (CARD8) [9]
3.2. Structural Insights into NLRP3 Inactivation and Activation Mechanisms
3.2.1. Closed Form
3.2.2. Cage Model
3.3. The Membrane Association of NLRP3 Inflammasome
3.4. Post-Translational Modifications (PTMs)
3.4.1. SUMOylation
3.4.2. Ubiquitination
3.4.3. cAMP
3.4.4. Phosphorylation
3.4.5. Nucleotide Exchange
3.4.6. Palmitoylation
3.5. Spatial Separation
3.6. Inhibitors Associated with Resting State (Table 1)
3.6.1. MCC950
3.6.2. CY-09 (Glitazone) [72]
3.6.3. Tranilast
3.6.4. OLT1177
Name | Compound | Target Site | Mechanism of Action | Association with Resting State | Ref. |
---|---|---|---|---|---|
MCC950 (CRID3) | Diarylsulfonylurea-containing compound | Walker B motif in NACHT domain | Reducing the ATPase activity of NLRP3 | Forces the NLRP3 “open” structure into a “closed” conformation | [56] |
HD1, HD2, WHD, NBD, and trLRR | [66] | ||||
CY-09 | Glitazone derivate | Cysteine 172 of Walker A motif in NACHT domain | Disrupting the ATPase activity of NLRP3 | Possibility of maintaining a closed, inactive form | [67] |
Tranilast | Tryptophan metabolite analog | NACHT domain | Blocking NLRP3-NLRP3 interaction | Possibility of blocking cage formation | [70] |
OLT1177 | β-sulfonyl nitrile compound | NACHT domain | Blocking ATPase activity | Possibility of stabilizing a closed, inactive form | [71] |
Oridonin | Bioactive constituent of the medical plant Rabdosia rubescens | Cysteine 279 in NACHT domain | Blocking NLRP3-NEK7 interaction | Possibility of affecting cage structure and migration | [77] |
MNS | SYK inhibitor group | NACHT and LRR domain | Reducing the ATPase activity of NLRP3 | Possibility of stabilizing a cage structure | [78] |
IFN58 | Acylate and Acrylamide Derivatives | Cys319 in NACHT domain | Reducing the ATPase activity of NLRP3 | Possibility of affecting cage structure | [79] |
IFN39 | Acylate and Acrylamide Derivatives | Unknown | Reducing the ATPase activity of NLRP3 | Affecting conformational change and possibility of influencing closed form | [80] |
3.6.5. Oridonin
3.6.6. MNS (3,4-Methylenedioxy-β-nitrostyrene) [83]
3.6.7. Acrylate and Acrylamide Derivatives
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Burdett, H.; Kobe, B.; Anderson, P.A. Animal NLRs continue to inform plant NLR structure and function. Arch. Biochem. Biophys. 2019, 670, 58–68. [Google Scholar] [CrossRef]
- Hou, S.; Liu, Z.; Shen, H.; Wu, D. Damage-Associated Molecular Pattern-Triggered Immunity in Plants. Front. Plant Sci. 2019, 10, 646. [Google Scholar] [CrossRef]
- Dangl, J.L.; Jones, J.D. Plant pathogens and integrated defence responses to infection. Nature 2001, 411, 826–833. [Google Scholar] [CrossRef] [PubMed]
- Gao, W.; Yang, J.; Liu, W.; Wang, Y.; Shao, F. Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. Proc. Natl. Acad. Sci. USA 2016, 113, E4857–E4866. [Google Scholar] [CrossRef] [PubMed]
- Park, Y.H.; Wood, G.; Kastner, D.L.; Chae, J.J. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 2016, 17, 914–921. [Google Scholar] [CrossRef] [PubMed]
- Song, C.; Zhang, Y.; Pei, Q.; Zheng, L.; Wang, M.; Shi, Y.; Wu, S.; Ni, W.; Fu, X.; Peng, Y.; et al. HSP70 alleviates sepsis-induced cardiomyopathy by attenuating mitochondrial dysfunction-initiated NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes. Burns Trauma 2022, 10, tkac043. [Google Scholar] [CrossRef]
- Mayor, A.; Martinon, F.; De Smedt, T.; Petrilli, V.; Tschopp, J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat. Immunol. 2007, 8, 497–503. [Google Scholar] [CrossRef]
- Piippo, N.; Korhonen, E.; Hytti, M.; Skottman, H.; Kinnunen, K.; Josifovska, N.; Petrovski, G.; Kaarniranta, K.; Kauppinen, A. Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome. Sci. Rep. 2018, 8, 6720. [Google Scholar] [CrossRef]
- Ito, S.; Hara, Y.; Kubota, T. CARD8 is a negative regulator for NLRP3 inflammasome, but mutant NLRP3 in cryopyrin-associated periodic syndromes escapes the restriction. Arthritis Res. Ther. 2014, 16, R52. [Google Scholar] [CrossRef]
- Hofmann, K.; Bucher, P.; Tschopp, J. The CARD domain: A new apoptotic signalling motif. Trends Biochem. Sci. 1997, 22, 155–156. [Google Scholar] [CrossRef]
- Blonska, M.; Lin, X. NF-kappaB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res. 2011, 21, 55–70. [Google Scholar] [CrossRef]
- Jiang, C.; Lin, X. Regulation of NF-kappaB by the CARD proteins. Immunol. Rev. 2012, 246, 141–153. [Google Scholar] [CrossRef] [PubMed]
- Mao, L.; Kitani, A.; Similuk, M.; Oler, A.J.; Albenberg, L.; Kelsen, J.; Aktay, A.; Quezado, M.; Yao, M.; Montgomery-Recht, K.; et al. Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease. J. Clin. Investig. 2018, 128, 1793–1806. [Google Scholar] [CrossRef]
- Compan, V.; Baroja-Mazo, A.; Lopez-Castejon, G.; Gomez, A.I.; Martinez, C.M.; Angosto, D.; Montero, M.T.; Herranz, A.S.; Bazan, E.; Reimers, D.; et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity 2012, 37, 487–500. [Google Scholar] [CrossRef]
- 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, 184, 6299–6312.e22. [Google Scholar] [CrossRef] [PubMed]
- Fu, J.; Schroder, K.; Wu, H. Mechanistic insights from inflammasome structures. Nat. Rev. Immunol. 2024, 24, 518–535. [Google Scholar] [CrossRef]
- Guo, C.; Chi, Z.; Jiang, D.; Xu, T.; Yu, W.; Wang, Z.; Chen, S.; Zhang, L.; Liu, Q.; Guo, X.; et al. Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages. Immunity 2018, 49, 842–856.e7. [Google Scholar] [CrossRef]
- Misawa, T.; Takahama, M.; Kozaki, T.; Lee, H.; Zou, J.; Saitoh, T.; Akira, S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 2013, 14, 454–460. [Google Scholar] [CrossRef] [PubMed]
- Subramanian, N.; Natarajan, K.; Clatworthy, M.R.; Wang, Z.; Germain, R.N. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 2013, 153, 348–361. [Google Scholar] [CrossRef]
- Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011, 469, 221–225. [Google Scholar] [CrossRef]
- Xiao, L.; Magupalli, V.G.; Wu, H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature 2023, 613, 595–600. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Venditti, R.; Ran, L.; Liu, Z.; Vivot, K.; Schurmann, A.; Bonifacino, J.S.; De Matteis, M.A.; Ricci, R. Distinct changes in endosomal composition promote NLRP3 inflammasome activation. Nat. Immunol. 2023, 24, 30–41. [Google Scholar] [CrossRef]
- Lee, B.; Hoyle, C.; Wellens, R.; Green, J.P.; Martin-Sanchez, F.; Williams, D.M.; Matchett, B.J.; Seoane, P.I.; Bennett, H.; Adamson, A.; et al. Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome. Sci. Signal. 2023, 16, eabm7134. [Google Scholar] [CrossRef]
- Lee, G.S.; Subramanian, N.; Kim, A.I.; Aksentijevich, I.; Goldbach-Mansky, R.; Sacks, D.B.; Germain, R.N.; Kastner, D.L.; Chae, J.J. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 2012, 492, 123–127. [Google Scholar] [CrossRef] [PubMed]
- Barry, R.; John, S.W.; Liccardi, G.; Tenev, T.; Jaco, I.; Chen, C.H.; Choi, J.; Kasperkiewicz, P.; Fernandes-Alnemri, T.; Alnemri, E.; et al. SUMO-mediated regulation of NLRP3 modulates inflammasome activity. Nat. Commun. 2018, 9, 3001. [Google Scholar] [CrossRef]
- Shao, L.; Liu, Y.; Wang, W.; Li, A.; Wan, P.; Liu, W.; Shereen, M.A.; Liu, F.; Zhang, W.; Tan, Q.; et al. SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation. FASEB J. 2020, 34, 1497–1515. [Google Scholar] [CrossRef]
- Qin, Y.; Li, Q.; Liang, W.; Yan, R.; Tong, L.; Jia, M.; Zhao, C.; Zhao, W. TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation. Nat. Commun. 2021, 12, 4794. [Google Scholar] [CrossRef]
- Yan, Y.; Jiang, W.; Liu, L.; Wang, X.; Ding, C.; Tian, Z.; Zhou, R. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 2015, 160, 62–73. [Google Scholar] [CrossRef] [PubMed]
- Kawashima, A.; Karasawa, T.; Tago, K.; Kimura, H.; Kamata, R.; Usui-Kawanishi, F.; Watanabe, S.; Ohta, S.; Funakoshi-Tago, M.; Yanagisawa, K.; et al. ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages. J. Immunol. 2017, 199, 3614–3622. [Google Scholar] [CrossRef] [PubMed]
- Kimura, T.; Jain, A.; Choi, S.W.; Mandell, M.A.; Schroder, K.; Johansen, T.; Deretic, V. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J. Cell Biol. 2015, 210, 973–989. [Google Scholar] [CrossRef]
- Song, H.; Liu, B.; Huai, W.; Yu, Z.; Wang, W.; Zhao, J.; Han, L.; Jiang, G.; Zhang, L.; Gao, C.; et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat. Commun. 2016, 7, 13727. [Google Scholar] [CrossRef]
- Tang, J.; Tu, S.; Lin, G.; Guo, H.; Yan, C.; Liu, Q.; Huang, L.; Tang, N.; Xiao, Y.; Pope, R.M.; et al. Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia. J. Exp. Med. 2020, 217, e20182091. [Google Scholar] [CrossRef]
- Han, S.; Lear, T.B.; Jerome, J.A.; Rajbhandari, S.; Snavely, C.A.; Gulick, D.L.; Gibson, K.F.; Zou, C.; Chen, B.B.; Mallampalli, R.K. Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase. J. Biol. Chem. 2015, 290, 18124–18133. [Google Scholar] [CrossRef] [PubMed]
- He, J.; Chen, Y.; Xu, M.; Wu, S. USP5 negatively regulates the activation of NLRP3 inflammasomes and participates in the pathological and physiological processes of Sjogren’s syndrome. Int. Immunopharmacol. 2024, 135, 112274. [Google Scholar] [CrossRef]
- Juliana, C.; Fernandes-Alnemri, T.; Kang, S.; Farias, A.; Qin, F.; Alnemri, E.S. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J. Biol. Chem. 2012, 287, 36617–36622. [Google Scholar] [CrossRef] [PubMed]
- Py, B.F.; Kim, M.S.; Vakifahmetoglu-Norberg, H.; Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 2013, 49, 331–338. [Google Scholar] [CrossRef] [PubMed]
- Ren, G.M.; Li, J.; Zhang, X.C.; Wang, Y.; Xiao, Y.; Zhang, X.Y.; Liu, X.; Zhang, W.; Ma, W.B.; Zhang, J.; et al. Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases. Sci. Immunol. 2021, 6, eabe2933. [Google Scholar] [CrossRef]
- Xu, T.; Yu, W.; Fang, H.; Wang, Z.; Chi, Z.; Guo, X.; Jiang, D.; Zhang, K.; Chen, S.; Li, M.; et al. Ubiquitination of NLRP3 by gp78/Insig-1 restrains NLRP3 inflammasome activation. Cell Death Differ. 2022, 29, 1582–1595. [Google Scholar] [CrossRef]
- Tang, T.; Li, P.; Zhou, X.; Wang, R.; Fan, X.; Yang, M.; Qi, K. The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3. Front. Immunol. 2021, 12, 741839. [Google Scholar] [CrossRef]
- Palazon-Riquelme, P.; Worboys, J.D.; Green, J.; Valera, A.; Martin-Sanchez, F.; Pellegrini, C.; Brough, D.; Lopez-Castejon, G. USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation. EMBO Rep. 2018, 19, e44766. [Google Scholar] [CrossRef]
- Wu, Z.; Li, W.; Wang, S.; Zheng, Z. Role of deubiquitinase USP47 in cardiac function alleviation and anti-inflammatory immunity after myocardial infarction by regulating NLRP3 inflammasome-mediated pyroptotic signal pathways. Int. Immunopharmacol. 2024, 136, 112346. [Google Scholar] [CrossRef] [PubMed]
- Liu, C.; Fan, C.; Liu, J.; Zhang, S.; Tang, H.; Liu, Y.; Zhang, S.; Wu, Q.; Zhang, J.; Qi, Z.; et al. YOD1 protects against MRSA sepsis-induced DIC through Lys33-linked deubiquitination of NLRP3. Cell Death Dis. 2024, 15, 360. [Google Scholar] [CrossRef] [PubMed]
- Gross, O.; Poeck, H.; Bscheider, M.; Dostert, C.; Hannesschlager, N.; Endres, S.; Hartmann, G.; Tardivel, A.; Schweighoffer, E.; Tybulewicz, V.; et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 2009, 459, 433–436. [Google Scholar] [CrossRef]
- Said-Sadier, N.; Padilla, E.; Langsley, G.; Ojcius, D.M. Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS ONE 2010, 5, e10008. [Google Scholar] [CrossRef]
- Shio, M.T.; Eisenbarth, S.C.; Savaria, M.; Vinet, A.F.; Bellemare, M.J.; Harder, K.W.; Sutterwala, F.S.; Bohle, D.S.; Descoteaux, A.; Flavell, R.A.; et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog. 2009, 5, e1000559. [Google Scholar] [CrossRef]
- Chuang, Y.T.; Lin, Y.C.; Lin, K.H.; Chou, T.F.; Kuo, W.C.; Yang, K.T.; Wu, P.R.; Chen, R.H.; Kimchi, A.; Lai, M.Z. Tumor suppressor death-associated protein kinase is required for full IL-1beta production. Blood 2011, 117, 960–970. [Google Scholar] [CrossRef] [PubMed]
- Gong, Y.N.; Wang, X.; Wang, J.; Yang, Z.; Li, S.; Yang, J.; Liu, L.; Lei, X.; Shao, F. Chemical probing reveals insights into the signaling mechanism of inflammasome activation. Cell Res. 2010, 20, 1289–1305. [Google Scholar] [CrossRef]
- Ghonime, M.G.; Shamaa, O.R.; Das, S.; Eldomany, R.A.; Fernandes-Alnemri, T.; Alnemri, E.S.; Gavrilin, M.A.; Wewers, M.D. Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J. Immunol. 2014, 192, 3881–3888. [Google Scholar] [CrossRef]
- Spalinger, M.R.; Kasper, S.; Gottier, C.; Lang, S.; Atrott, K.; Vavricka, S.R.; Scharl, S.; Raselli, T.; Frey-Wagner, I.; Gutte, P.M.; et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J. Clin. Invest. 2016, 126, 1783–1800. [Google Scholar] [CrossRef] [PubMed]
- Spalinger, M.R.; Lang, S.; Gottier, C.; Dai, X.; Rawlings, D.J.; Chan, A.C.; Rogler, G.; Scharl, M. PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner. Autophagy 2017, 13, 1590–1601. [Google Scholar] [CrossRef]
- Zhang, Z.; Meszaros, G.; He, W.T.; Xu, Y.; de Fatima Magliarelli, H.; Mailly, L.; Mihlan, M.; Liu, Y.; Puig Gamez, M.; Goginashvili, A.; et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J. Exp. Med. 2017, 214, 2671–2693. [Google Scholar] [CrossRef]
- Mortimer, L.; Moreau, F.; MacDonald, J.A.; Chadee, K. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat. Immunol. 2016, 17, 1176–1186. [Google Scholar] [CrossRef]
- Dekker, C.; Mattes, H.; Wright, M.; Boettcher, A.; Hinniger, A.; Hughes, N.; Kapps-Fouthier, S.; Eder, J.; Erbel, P.; Stiefl, N.; et al. Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition. J. Mol. Biol. 2021, 433, 167309. [Google Scholar] [CrossRef]
- Riedl, S.J.; Li, W.; Chao, Y.; Schwarzenbacher, R.; Shi, Y. Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature 2005, 434, 926–933. [Google Scholar] [CrossRef]
- Faustin, B.; Lartigue, L.; Bruey, J.M.; Luciano, F.; Sergienko, E.; Bailly-Maitre, B.; Volkmann, N.; Hanein, D.; Rouiller, I.; Reed, J.C. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell 2007, 25, 713–724. [Google Scholar] [CrossRef]
- Harris, P.A.; Duraiswami, C.; Fisher, D.T.; Fornwald, J.; Hoffman, S.J.; Hofmann, G.; Jiang, M.; Lehr, R.; McCormick, P.M.; Nickels, L.; et al. High throughput screening identifies ATP-competitive inhibitors of the NLRP1 inflammasome. Bioorganic Med. Chem. Lett. 2015, 25, 2739–2743. [Google Scholar] [CrossRef] [PubMed]
- Bauernfried, S.; Scherr, M.J.; Pichlmair, A.; Duderstadt, K.E.; Hornung, V. Human NLRP1 is a sensor for double-stranded RNA. Science 2021, 371, eabd0811. [Google Scholar] [CrossRef]
- Radian, A.D.; Khare, S.; Chu, L.H.; Dorfleutner, A.; Stehlik, C. ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides. Mol. Immunol. 2015, 67, 294–302. [Google Scholar] [CrossRef] [PubMed]
- Su, M.Y.; Kuo, C.I.; Chang, C.F.; Chang, C.I. Three-dimensional structure of human NLRP10/PYNOD pyrin domain reveals a homotypic interaction site distinct from its mouse homologue. PLoS ONE 2013, 8, e67843. [Google Scholar] [CrossRef]
- Ye, Z.; Lich, J.D.; Moore, C.B.; Duncan, J.A.; Williams, K.L.; Ting, J.P. ATP binding by monarch-1/NLRP12 is critical for its inhibitory function. Mol. Cell Biol. 2008, 28, 1841–1850. [Google Scholar] [CrossRef] [PubMed]
- Coll, R.C.; Hill, J.R.; Day, C.J.; Zamoshnikova, A.; Boucher, D.; Massey, N.L.; Chitty, J.L.; Fraser, J.A.; Jennings, M.P.; Robertson, A.A.B.; et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol. 2019, 15, 556–559. [Google Scholar] [CrossRef]
- Tapia-Abellan, A.; Angosto-Bazarra, D.; Martinez-Banaclocha, H.; de Torre-Minguela, C.; Ceron-Carrasco, J.P.; Perez-Sanchez, H.; Arostegui, J.I.; Pelegrin, P. MCC950 closes the active conformation of NLRP3 to an inactive state. Nat. Chem. Biol. 2019, 15, 560–564. [Google Scholar] [CrossRef]
- Brinkschulte, R.; Fussholler, D.M.; Hoss, F.; Rodriguez-Alcazar, J.F.; Lauterbach, M.A.; Kolbe, C.C.; Rauen, M.; Ince, S.; Herrmann, C.; Latz, E.; et al. ATP-binding and hydrolysis of human NLRP3. Commun. Biol. 2022, 5, 1176. [Google Scholar] [CrossRef]
- He, Y.; Zeng, M.Y.; Yang, D.; Motro, B.; Nunez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 2016, 530, 354–357. [Google Scholar] [CrossRef] [PubMed]
- Schmid-Burgk, J.L.; Chauhan, D.; Schmidt, T.; Ebert, T.S.; Reinhardt, J.; Endl, E.; Hornung, V. A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation. J. Biol. Chem. 2016, 291, 103–109. [Google Scholar] [CrossRef]
- Shi, H.; Wang, Y.; Li, X.; Zhan, X.; Tang, M.; Fina, M.; Su, L.; Pratt, D.; Bu, C.H.; Hildebrand, S.; et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 2016, 17, 250–258. [Google Scholar] [CrossRef] [PubMed]
- Magupalli, V.G.; Negro, R.; Tian, Y.; Hauenstein, A.V.; Di Caprio, G.; Skillern, W.; Deng, Q.; Orning, P.; Alam, H.B.; Maliga, Z.; et al. HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science 2020, 369, eaas8995. [Google Scholar] [CrossRef]
- Perregaux, D.G.; McNiff, P.; Laliberte, R.; Hawryluk, N.; Peurano, H.; Stam, E.; Eggler, J.; Griffiths, R.; Dombroski, M.A.; Gabel, C.A. Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors. J. Pharmacol. Exp. Ther. 2001, 299, 187–197. [Google Scholar] [PubMed]
- Coll, R.C.; Robertson, A.A.; Chae, J.J.; Higgins, S.C.; Munoz-Planillo, R.; Inserra, M.C.; Vetter, I.; Dungan, L.S.; Monks, B.G.; Stutz, A.; et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 2015, 21, 248–255. [Google Scholar] [CrossRef]
- Sharif, H.; Wang, L.; Wang, W.L.; Magupalli, V.G.; Andreeva, L.; Qiao, Q.; Hauenstein, A.V.; Wu, Z.; Nunez, G.; Mao, Y.; et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature 2019, 570, 338–343. [Google Scholar] [CrossRef]
- Hochheiser, I.V.; Pilsl, M.; Hagelueken, G.; Moecking, J.; Marleaux, M.; Brinkschulte, R.; Latz, E.; Engel, C.; Geyer, M. Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3. Nature 2022, 604, 184–189. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; He, H.; Chen, Y.; Huang, W.; Cheng, J.; Ye, J.; Wang, A.; Tao, J.; Wang, C.; Liu, Q.; et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med. 2017, 214, 3219–3238. [Google Scholar] [CrossRef]
- Martin, J.; Kelly, D.J.; Mifsud, S.A.; Zhang, Y.; Cox, A.J.; See, F.; Krum, H.; Wilkinson-Berka, J.; Gilbert, R.E. Tranilast attenuates cardiac matrix deposition in experimental diabetes: Role of transforming growth factor-beta. Cardiovasc. Res. 2005, 65, 694–701. [Google Scholar] [CrossRef] [PubMed]
- Kelly, D.J.; Zhang, Y.; Gow, R.; Gilbert, R.E. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J. Am. Soc. Nephrol. 2004, 15, 2619–2629. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Jiang, H.; Chen, Y.; Wang, X.; Yang, Y.; Tao, J.; Deng, X.; Liang, G.; Zhang, H.; Jiang, W.; et al. Tranilast directly targets NLRP3 to treat inflammasome-driven diseases. EMBO Mol. Med. 2018, 10, e8689. [Google Scholar] [CrossRef]
- Marchetti, C.; Swartzwelter, B.; Gamboni, F.; Neff, C.P.; Richter, K.; Azam, T.; Carta, S.; Tengesdal, I.; Nemkov, T.; D’Alessandro, A.; et al. OLT1177, a beta-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl. Acad. Sci. USA 2018, 115, E1530–E1539. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Zhu, Z. Oridonin inhibits metastasis of human ovarian cancer cells by suppressing the mTOR pathway. Arch. Med. Sci. 2019, 15, 1017–1027. [Google Scholar] [CrossRef]
- Liu, X.; Xu, J.; Zhou, J.; Shen, Q. Oridonin and its derivatives for cancer treatment and overcoming therapeutic resistance. Genes. Dis. 2021, 8, 448–462. [Google Scholar] [CrossRef] [PubMed]
- Jia, T.; Cai, M.; Ma, X.; Li, M.; Qiao, J.; Chen, T. Oridonin inhibits IL-1beta-induced inflammation in human osteoarthritis chondrocytes by activating PPAR-gamma. Int. Immunopharmacol. 2019, 69, 382–388. [Google Scholar] [CrossRef]
- Wang, S.; Zhang, Y.; Saas, P.; Wang, H.; Xu, Y.; Chen, K.; Zhong, J.; Yuan, Y.; Wang, Y.; Sun, Y. Oridonin’s therapeutic effect: Suppressing Th1/Th17 simultaneously in a mouse model of Crohn’s disease. J. Gastroenterol. Hepatol. 2015, 30, 504–512. [Google Scholar] [CrossRef]
- Wang, S.; Yang, H.; Yu, L.; Jin, J.; Qian, L.; Zhao, H.; Xu, Y.; Zhu, X. Oridonin attenuates Abeta1-42-induced neuroinflammation and inhibits NF-kappaB pathway. PLoS ONE 2014, 9, e104745. [Google Scholar]
- He, H.; Jiang, H.; Chen, Y.; Ye, J.; Wang, A.; Wang, C.; Liu, Q.; Liang, G.; Deng, X.; Jiang, W.; et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat. Commun. 2018, 9, 2550. [Google Scholar] [CrossRef] [PubMed]
- He, Y.; Varadarajan, S.; Munoz-Planillo, R.; Burberry, A.; Nakamura, Y.; Nunez, G. 3,4-methylenedioxy-beta-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J. Biol. Chem. 2014, 289, 1142–1150. [Google Scholar] [CrossRef]
- Cocco, M.; Miglio, G.; Giorgis, M.; Garella, D.; Marini, E.; Costale, A.; Regazzoni, L.; Vistoli, G.; Orioli, M.; Massulaha-Ahmed, R.; et al. Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors. ChemMedChem 2016, 11, 1790–1803. [Google Scholar] [CrossRef] [PubMed]
- Cocco, M.; Pellegrini, C.; Martinez-Banaclocha, H.; Giorgis, M.; Marini, E.; Costale, A.; Miglio, G.; Fornai, M.; Antonioli, L.; Lopez-Castejon, G.; et al. Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease. J. Med. Chem. 2017, 60, 3656–3671. [Google Scholar] [CrossRef]
- Liston, A.; Masters, S.L. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat. Rev. Immunol. 2017, 17, 208–214. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Kim, Y.; Lee, S.; Park, Y.H. NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development. Int. J. Mol. Sci. 2024, 25, 9018. https://doi.org/10.3390/ijms25169018
Kim Y, Lee S, Park YH. NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development. International Journal of Molecular Sciences. 2024; 25(16):9018. https://doi.org/10.3390/ijms25169018
Chicago/Turabian StyleKim, YeJi, Sumin Lee, and Yong Hwan Park. 2024. "NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development" International Journal of Molecular Sciences 25, no. 16: 9018. https://doi.org/10.3390/ijms25169018