Genome-wide screen based on 2DG activated NLRP3 inflammasome reveals the priming signal of TLR2/4 to IKKβ but not IKKα.

Autor: Gao H; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road 2#, Haidian District, Beijing 100193, China., Sun M; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road 2#, Haidian District, Beijing 100193, China., Gao H; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road 2#, Haidian District, Beijing 100193, China., Sun Y; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road 2#, Haidian District, Beijing 100193, China., Chen W; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road 2#, Haidian District, Beijing 100193, China., Dong N; State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road 2#, Haidian District, Beijing 100193, China. Electronic address: dongna@cau.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2025 Jan 03; Vol. 145, pp. 113781. Date of Electronic Publication: 2024 Dec 09.
DOI: 10.1016/j.intimp.2024.113781
Abstrakt: NLRP3 inflammasome activation is a pivotal area of research in innate immunity, yet the precise priming and activation signal remain unclear. In this study, we demonstrate that glycolysis inhibitor 2-Deoxy-D-glucose (2DG) triggers NLRP3-driven pyroptosis in human leukemia monocyte THP-1 cells by interfering glycosylation rather than glycolysis, which occurs independent of potassium efflux but requires the involvement of glycolysis rate-limiting enzyme PFKP. Using a CRISPR-Cas9 mediated large-scale screen, with 2DG as a new tool for probing NLRP3 activation, we identified that TLR2, rather than TLR4, initiates a rapid and robust priming signal for NLRP3 inflammasome activation. Importantly, both TLR2 and TLR4 depend entirely on MyD88, but not TRIF, for signal transduction. Furthermore, we discovered that TAK1, IKKβ and NEMO, but not IKKα, are essential for the priming signal. Additionally, we observed that deficiency in the linear ubiquitin assembly complex (LUBAC) subunits HOIP and HOIL-1, but not SHARPIN, is sufficient to inhibit 2DG-induced pyroptotic cell death. Collectively, our study reveals some common mechanism in the NLRP3 priming signals, as well as specific mechanisms upstream of NLRP3 triggered by 2DG, and underscores the potential of 2DG as a trigger to facilitate further detailed analysis of the underlying mechanisms of NLRP3 inflammasome activation. One Sentence Summary: Priming signal by IKKβ is essential for NLRP3 activation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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