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Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex is an essential innate immune signaling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labeling, affinity purification, and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-interleukin-1β (IL-1β) levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1β cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1β production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

Competing Interests: Declaration of interests E.W.T. is a founder and shareholder in Myricx Pharma Ltd. and receives consultancy or research funding from Kura Oncology, Pfizer Ltd., Samsara Therapeutics, Myricx Pharma Ltd., MSD, Exscientia, and Daiichi Sankyo.

Titel:	Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia.
Autor/in / Beteiligte Person:	Liang, Z ; Damianou, A ; Vendrell, I ; Jenkins, E ; Lassen, FH ; Washer, SJ ; Grigoriou, A ; Liu, G ; Yi, G ; Lou, H ; Cao, F ; Zheng, X ; Fernandes, RA ; Dong, T ; Tate, EW ; Di Daniel, E ; Kessler, BM
Zeitschrift:	Cell reports, Jg. 43 (2024-05-28), Heft 5, S. 114152
Veröffentlichung:	[Cambridge, MA] : Cell Press, c 2012-, 2024
Medientyp:	academicJournal
ISSN:	2211-1247 (electronic)
DOI:	10.1016/j.celrep.2024.114152
Schlagwort:	Humans Inflammasomes metabolism Interleukin-1beta metabolism Macrophages metabolism Microglia metabolism NLR Family, Pyrin Domain-Containing 3 Protein metabolism Proteomics methods Ubiquitin Thiolesterase metabolism Ubiquitin Thiolesterase genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Cell Rep] 2024 May 28; Vol. 43 (5), pp. 114152. <i>Date of Electronic Publication: </i>2024 Apr 25. MeSH Terms: Inflammasomes* / metabolism ; Interleukin-1beta* / metabolism ; Macrophages* / metabolism ; Microglia* / metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism ; Proteomics* / methods ; Ubiquitin Thiolesterase* / metabolism ; Ubiquitin Thiolesterase* / genetics ; Humans Contributed Indexing: Keywords: CP: Immunology; DUB; IL-1β; NLRP3; UCH-L1; deubiquitylase; inflammasome; macrophages; microglia; monocytes; protease inhibitor; ubiquitin; ubiquitin C-terminal hydrolase Substance Nomenclature: 0 (Inflammasomes) ; 0 (Interleukin-1beta) ; 0 (NLR Family, Pyrin Domain-Containing 3 Protein) ; 0 (NLRP3 protein, human) ; EC 3.4.19.12 (Ubiquitin Thiolesterase) ; 0 (UCHL1 protein, human) ; 0 (IL1B protein, human) Entry Date(s): Date Created: 20240426 Date Completed: 20240531 Latest Revision: 20240613 Update Code: 20240614

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Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia.