NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Aug 29

PMID 39201704

Authors

Yeji Kim

Sumin Lee

Yong Hwan Park

Affiliations

Soon will be listed here.

Abstract

The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular sensor of the innate immune system that detects various pathogen- and danger-associated molecular patterns, leading to the assembly of the NLRP3 inflammasome and release of interleukin (IL) 1β and IL-18. However, the abnormal activation of the NLRP3 inflammasome has been implicated in the pathogenesis of autoinflammatory diseases such as cryopyrin-associated autoinflammatory syndromes (CAPS) and common diseases such as Alzheimer's disease and asthma. Recent studies have revealed that pyrin functions as an indirect sensor, similar to the plant guard system, and is regulated by binding to inhibitory 14-3-3 proteins. Upon activation, pyrin transitions to its active form. NLRP3 is predicted to follow a similar regulatory mechanism and maintain its inactive form in the cage model, as it also acts as an indirect sensor. Additionally, newly developed NLRP3 inhibitors have been found to inhibit NLRP3 activity by stabilizing its inactive form. Most studies and reviews on NLRP3 have focused on the activation of the NLRP3 inflammasome. This review highlights the molecular mechanisms that regulate NLRP3 in its resting state, and discusses how targeting this inhibitory mechanism can lead to novel therapeutic strategies for NLRP3-related diseases.

Citing Articles

p16INK4a Deletion Alleviated Obesity-Associated Kidney Fibrosis by Regulating Metabolic Reprogramming and the Inflammasome Pathway.

Liu Q, Wang F, Du Y, Liu Y, Zhang Z, Zhang X J Cell Mol Med. 2025; 29(5):e70444.

PMID: 40079088 PMC: 11904428. DOI: 10.1111/jcmm.70444.

References

Tang T, Li P, Zhou X, Wang R, Fan X, Yang M . The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3. Front Immunol. 2021; 12:741839. PMC: 8427430. DOI: 10.3389/fimmu.2021.741839. View

Wang S, Zhang Y, Saas P, Wang H, Xu Y, Chen K . Oridonin's therapeutic effect: suppressing Th1/Th17 simultaneously in a mouse model of Crohn's disease. J Gastroenterol Hepatol. 2014; 30(3):504-12. DOI: 10.1111/jgh.12710. View

Xu T, Yu W, Fang H, Wang Z, Chi Z, Guo X . Ubiquitination of NLRP3 by gp78/Insig-1 restrains NLRP3 inflammasome activation. Cell Death Differ. 2022; 29(8):1582-1595. PMC: 9345978. DOI: 10.1038/s41418-022-00947-8. View

Mortimer L, Moreau F, MacDonald J, Chadee K . NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat Immunol. 2016; 17(10):1176-86. DOI: 10.1038/ni.3538. View

Py B, Kim M, Vakifahmetoglu-Norberg H, Yuan J . Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell. 2012; 49(2):331-8. DOI: 10.1016/j.molcel.2012.11.009. View

Magupalli V, Negro R, Tian Y, Hauenstein A, Di Caprio G, Skillern W . HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science. 2020; 369(6510). PMC: 7814939. DOI: 10.1126/science.aas8995. View

Chuang Y, Lin Y, Lin K, Chou T, Kuo W, Yang K . Tumor suppressor death-associated protein kinase is required for full IL-1β production. Blood. 2010; 117(3):960-70. DOI: 10.1182/blood-2010-08-303115. View

Palazon-Riquelme P, Worboys J, Green J, Valera A, Martin-Sanchez F, Pellegrini C . USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation. EMBO Rep. 2018; 19(10). PMC: 6172458. DOI: 10.15252/embr.201744766. View

Piippo N, Korhonen E, Hytti M, Skottman H, Kinnunen K, Josifovska N . Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome. Sci Rep. 2018; 8(1):6720. PMC: 5928092. DOI: 10.1038/s41598-018-25123-2. View

10.

Gross O, Poeck H, Bscheider M, Dostert C, Hannesschlager N, Endres S . Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009; 459(7245):433-6. DOI: 10.1038/nature07965. View

11.

Jiang C, Lin X . Regulation of NF-κB by the CARD proteins. Immunol Rev. 2012; 246(1):141-53. PMC: 3339759. DOI: 10.1111/j.1600-065X.2012.01110.x. View

12.

Hochheiser I, Pilsl M, Hagelueken G, Moecking J, Marleaux M, Brinkschulte R . Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3. Nature. 2022; 604(7904):184-189. DOI: 10.1038/s41586-022-04467-w. View

13.

Park Y, Wood G, Kastner D, Chae J . Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016; 17(8):914-21. PMC: 4955684. DOI: 10.1038/ni.3457. View

14.

Burdett H, Kobe B, Anderson P . Animal NLRs continue to inform plant NLR structure and function. Arch Biochem Biophys. 2019; 670:58-68. DOI: 10.1016/j.abb.2019.05.001. View

15.

Riedl S, Li W, Chao Y, Schwarzenbacher R, Shi Y . Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature. 2005; 434(7035):926-33. DOI: 10.1038/nature03465. View

16.

Cocco M, Pellegrini C, Martinez-Banaclocha H, Giorgis M, Marini E, Costale A . Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease. J Med Chem. 2017; 60(9):3656-3671. DOI: 10.1021/acs.jmedchem.6b01624. View

17.

Sharif H, Wang L, Wang W, Magupalli V, Andreeva L, Qiao Q . Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 2019; 570(7761):338-343. PMC: 6774351. DOI: 10.1038/s41586-019-1295-z. View

18.

Song H, Liu B, Huai W, Yu Z, Wang W, Zhao J . The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat Commun. 2016; 7:13727. PMC: 5155141. DOI: 10.1038/ncomms13727. View

19.

Spalinger M, Lang S, Gottier C, Dai X, Rawlings D, Chan A . PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner. Autophagy. 2017; 13(9):1590-1601. PMC: 5612532. DOI: 10.1080/15548627.2017.1341453. View

20.

Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri E . Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012; 287(43):36617-22. PMC: 3476327. DOI: 10.1074/jbc.M112.407130. View