Proximity proteomics reveals UCH-L1 as an NLRP3 interactor that modulates IL-1β production in human macrophages and microglia

Liang, Zhu; Damianou, Andreas; Vendrell, Iolanda; Jenkins, Edward; Lassen, Frederik H.; Washer, Sam J; Liu, Guihai; Yi, Gangshun; Lou, Hantao; Cao, Fangyuan; Zheng, Xiaonan; Fernandes, Ricardo A.; Dong, Tao; Tate, Edward W.; Daniel, Elena Di; Kessler, Benedikt M

doi:10.1101/2023.10.09.561576

Cited by 2 publications

(2 citation statements)

References 70 publications

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“…For Nlrp3-APEX2, proximity to Asc and Casp1 increased following stimulation with either agonist, as expected (Figures 7B-C). A recent human NLRP3 interactome study conducted an extensive meta-analysis of additional NLRP3 interactors detected in low and high-throughput studies [152]. From this analysis, we selected several high-confidence interactors validated with biochemical or cellular data.…”

Section: Resultsmentioning

confidence: 99%

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Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists

Hollingsworth,

Veeraraghavan,

Paulo

et al. 2024

Preprint

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Nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 3 (NLRP3) is an innate immune sensor that forms an inflammasome in response to various cellular stressors. Gain-of-function mutations in NLRP3 cause autoinflammatory diseases and NLRP3 signalling itself exacerbates the pathogenesis of many other human diseases. Despite considerable therapeutic interest, the primary drivers of NLRP3 activation remain controversial due to the diverse array of signals that are integrated through NLRP3. Here, we mapped subcellular proteome changes to lysosomes, mitochondrion, EEA1-positive endosomes, and Golgi caused by the NLRP3 inflammasome agonists nigericin and CL097. We identified several common disruptions to retrograde trafficking pathways, including COPI and Shiga toxin-related transport, in line with recent studies. We further characterized mouse NLRP3 trafficking throughout its activation using temporal proximity proteomics, which supports a recent model of NLRP3 recruitment to endosomes during inflammasome activation. Collectively, these findings provide additional granularity to our understanding of the molecular events driving NLRP3 activation and serve as a valuable resource for cell biological research. We have made our proteomics data accessible through an open-access Shiny browser to facilitate future research within the community, available at: https://harperlab.connect.hms.harvard.edu/inflame/. We will display anonymous peer review for this manuscript on pubpub.org (https://harperlab.pubpub.org/pub/nlrp3/) rather than a traditional journal. Moreover, we invite community feedback on the pubpub version of this manuscript, and we will address criticisms accordingly.

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Section: Resultsmentioning

confidence: 99%

“…additional NLRP3 interactors detected in low and high-throughput studies [152]. From this analysis, we selected several high-confidence interactors validated with biochemical or cellular data.…”

Section: The Nlrp3 Proximity Network In Response To Inflammasome Agon...mentioning

confidence: 99%

Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists

Hollingsworth,

Veeraraghavan,

Paulo

et al. 2024

Preprint

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Data‐independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis

Dellar,

Vendrell,

Talbot

et al. 2023

Journal of Neurochemistry

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While unbiased proteomics of human cerebrospinal fluid (CSF) has been used successfully to identify biomarkers of amyotrophic lateral sclerosis (ALS), high‐abundance proteins mask the presence of lower abundance proteins that may have diagnostic and prognostic value. However, developments in mass spectrometry (MS) proteomic data acquisition methods offer improved protein depth. In this study, MS with library‐free data‐independent acquisition (DIA) was used to compare the CSF proteome of people with ALS (n = 40), healthy (n = 15) and disease (n = 8) controls. Quantified protein groups were subsequently correlated with clinical variables. Univariate analysis identified 7 proteins, all significantly upregulated in ALS versus healthy controls, and 9 with altered abundance in ALS versus disease controls (FDR < 0.1). Elevated chitotriosidase‐1 (CHIT1) was common to both comparisons and was proportional to ALS disability progression rate (Pearson r = 0.41, FDR‐adjusted p = 0.035) but not overall survival. Ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1; upregulated in ALS versus healthy controls) was proportional to disability progression rate (Pearson r = 0.53, FDR‐adjusted p = 0.003) and survival (Kaplan Meier log‐rank p = 0.013) but not independently in multivariate proportional hazards models. Weighted correlation network analysis was used to identify functionally relevant modules of proteins. One module, enriched for inflammatory functions, was associated with age at symptom onset (Pearson r = 0.58, FDR‐adjusted p = 0.005) and survival (Hazard Ratio = 1.78, FDR = 0.065), and a second module, enriched for endoplasmic reticulum proteins, was negatively correlated with disability progression rate (r = −0.42, FDR‐adjusted p = 0.109). DIA acquisition methodology therefore strengthened the biomarker candidacy of CHIT1 and UCHL1 in ALS, while additionally highlighted inflammatory and endoplasmic reticulum proteins as novel sources of prognostic biomarkers.

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Proximity proteomics reveals UCH-L1 as an NLRP3 interactor that modulates IL-1β production in human macrophages and microglia

Cited by 2 publications

References 70 publications

Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists

Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists

Data‐independent acquisition proteomics of cerebrospinal fluid implicates endoplasmic reticulum and inflammatory mechanisms in amyotrophic lateral sclerosis

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