Implication of the LRR Domain in the Regulation and Activation of the NLRP3 Inflammasome

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2024 Aug 28

PMID 39195255

Authors

Margaux Cescato

Yixiang Y J Zhu

Laurent Le Corre

Benedicte F Py

Sophie Georgin-Lavialle

Mathieu P Rodero

Affiliations

Soon will be listed here.

Abstract

The NLRP3 inflammasome is a critical component of the innate immune response. NLRP3 activation is a tightly controlled process involving an initial priming to express NLRP3, pro-IL-1 β, and pro-IL-18, followed by an activation signal. The precise mechanism of activation is not fully understood due to the diverse range of activators, yet it effectively orchestrates the activation of caspase-1, which subsequently triggers the release of proinflammatory cytokines IL-1β and IL-18. NLRP3 dysregulation can lead to a variety of inflammatory diseases, highlighting its significant role in immune response and disease pathogenesis. NLRP3 is divided into three domains: the PYD, the NACHT, and the LRR domains. This review focuses on the LRR domain of NLRP3, detailing its structural characteristics, its function in pathogen sensing, its role in the degradation process, and its involvement in inflammasome auto-inhibition and activation. Additionally, we discuss the impact of mutations within the LRR domain found in atypical Cryopyrin-Associated Periodic Syndromes (CAPS), highlighting the clinical relevance of this domain.

Citing Articles

Genome-wide identification of F-box-LRR gene family and the functional analysis of CsFBXL13 transcription factor in tea plants.

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PMID: 40063120 DOI: 10.1007/s10142-025-01569-2.

References

Hafner-Bratkovic I, Susjan P, Lainscek D, Tapia-Abellan A, Cerovic K, Kadunc L . NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway. Nat Commun. 2018; 9(1):5182. PMC: 6281599. DOI: 10.1038/s41467-018-07573-4. View

Ogawa B, Aoki M, Ohnishi H, Ohashi T, Hayashi H, Kuze B . The Long-Term Efficacy of Cochlear Implantation for Hearing Loss in Muckel-Wells Syndrome. J Int Adv Otol. 2019; 15(3):454-458. PMC: 6937186. DOI: 10.5152/iao.2019.6871. View

Pohlentz M, Muller P, Cases-Cunillera S, Opitz T, Surges R, Hamed M . Characterisation of NLRP3 pathway-related neuroinflammation in temporal lobe epilepsy. PLoS One. 2022; 17(8):e0271995. PMC: 9380933. DOI: 10.1371/journal.pone.0271995. View

Chu L, Gangopadhyay A, Dorfleutner A, Stehlik C . An updated view on the structure and function of PYRIN domains. Apoptosis. 2014; 20(2):157-73. PMC: 4297229. DOI: 10.1007/s10495-014-1065-1. View

Colomar A, Marty V, Medina C, Combe C, Parnet P, Amedee T . Maturation and release of interleukin-1beta by lipopolysaccharide-primed mouse Schwann cells require the stimulation of P2X7 receptors. J Biol Chem. 2003; 278(33):30732-40. DOI: 10.1074/jbc.M304534200. View

Zheng D, Mohapatra G, Kern L, He Y, Shmueli M, Valdes-Mas R . Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation. Nat Immunol. 2023; 24(4):585-594. DOI: 10.1038/s41590-023-01450-z. View

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

Rojas-Lopez M, Gil-Marques M, Kharbanda V, Zajac A, Miller K, Wood T . NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages. Sci Immunol. 2023; 8(85):eabo4767. PMC: 10443087. DOI: 10.1126/sciimmunol.abo4767. View

Kastbom A, Verma D, Eriksson P, Skogh T, Wingren G, Soderkvist P . Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project). Rheumatology (Oxford). 2008; 47(4):415-7. DOI: 10.1093/rheumatology/kem372. View

10.

Hornung V, Bauernfeind F, Halle A, Samstad E, Kono H, Rock K . Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008; 9(8):847-56. PMC: 2834784. DOI: 10.1038/ni.1631. View

11.

Labrousse M, Kevorkian-Verguet C, Boursier G, Rowczenio D, Maurier F, Lazaro E . Mosaicism in autoinflammatory diseases: Cryopyrin-associated periodic syndromes (CAPS) and beyond. A systematic review. Crit Rev Clin Lab Sci. 2018; 55(6):432-442. DOI: 10.1080/10408363.2018.1488805. View

12.

Kumar H, Kawai T, Akira S . Pathogen recognition by the innate immune system. Int Rev Immunol. 2011; 30(1):16-34. DOI: 10.3109/08830185.2010.529976. View

13.

Yu X, Matico R, Miller R, Chauhan D, Van Schoubroeck B, Grauwen K . Structural basis for the oligomerization-facilitated NLRP3 activation. Nat Commun. 2024; 15(1):1164. PMC: 10850481. DOI: 10.1038/s41467-024-45396-8. View

14.

Nguyen L, Nguyen H, Kim Y, Nguyen T, Thi Lai T, Lee Y . Role of NLRP3 Inflammasome in Parkinson's Disease and Therapeutic Considerations. J Parkinsons Dis. 2022; 12(7):2117-2133. PMC: 9661339. DOI: 10.3233/JPD-223290. View

15.

Wang L, Cai J, Zhao X, Ma L, Zeng P, Zhou L . Palmitoylation prevents sustained inflammation by limiting NLRP3 inflammasome activation through chaperone-mediated autophagy. Mol Cell. 2022; 83(2):281-297.e10. DOI: 10.1016/j.molcel.2022.12.002. View

16.

Saito M, Nishikomori R, Kambe N, Fujisawa A, Tanizaki H, Takeichi K . Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood. 2007; 111(4):2132-41. DOI: 10.1182/blood-2007-06-094201. View

17.

Caseley E, Lara-Reyna S, Poulter J, Topping J, Carter C, Nadat F . An Atypical Autoinflammatory Disease Due to an LRR Domain NLRP3 Mutation Enhancing Binding to NEK7. J Clin Immunol. 2021; 42(1):158-170. PMC: 8528658. DOI: 10.1007/s10875-021-01161-w. View

18.

Cassel S, Eisenbarth S, Iyer S, Sadler J, Colegio O, Tephly L . The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A. 2008; 105(26):9035-40. PMC: 2449360. DOI: 10.1073/pnas.0803933105. View

19.

Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J . Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006; 440(7081):237-41. DOI: 10.1038/nature04516. View

20.

Wang Y, Hasegawa M, Imamura R, Kinoshita T, Kondo C, Konaka K . PYNOD, a novel Apaf-1/CED4-like protein is an inhibitor of ASC and caspase-1. Int Immunol. 2004; 16(6):777-86. DOI: 10.1093/intimm/dxh081. View