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

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1-s2.0-S2211124724004807-main.pdf (8.82 MB)

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Author(s)

Liang, Zhu

Damianou, Andreas

Vendrell, Iolanda

Jenkins, Edward

Lassen, Frederik H

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Type

Journal Article

Abstract

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.

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Date Issued

2024-05-28

Date Acceptance

2024-04-10

Citation

Cell Reports, 2024, 43 (5)

URI

http://hdl.handle.net/10044/1/111811

URL

https://www.sciencedirect.com/science/article/pii/S2211124724004807?via%3Dihub

DOI

https://www.dx.doi.org/10.1016/j.celrep.2024.114152

ISSN

2211-1247

Publisher

Elsevier

Journal / Book Title

Cell Reports

Volume

43

Issue

5

Copyright Statement

© 2024 The Authors. Published by Elsevier Inc.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

License URL

https://creativecommons.org/licenses/by/4.0/

Identifier

https://www.ncbi.nlm.nih.gov/pubmed/38669140

Subjects

CP: Immunology

deubiquitylase

DUB

IL-1β

inflammasome

macrophages

microglia

monocytes

NLRP3

protease inhibitor

ubiquitin

ubiquitin C-terminal hydrolase

UCH-L1

Publication Status

Published

Coverage Spatial

United States

Article Number

114152

Date Publish Online

2024-04-25