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Phosphatidylinositol Acyl Chains Configure TLR-Dependent Priming and Activation of the NLRP3 Inflammasome
OA Location
Author(s)
Hamilton, C
Larrouy-Maumus, Gerald
Anand, Paras
Type
Working Paper
Abstract
Abstract Lipids are important in establishing cellular homeostasis by conducting varied functions including relay of extracellular signals. Imbalance in lipid homeostasis results in metabolic diseases, and is tightly connected to discrepancies in immune signalling. The phosphorylation status of the lipid second messenger phosphatidylinositol phosphates is implicated in key physiological functions and pathologies. By contrast, little is known as to how phosphatidylinositol (PI) lipid acyl chains contribute to cellular processes. Here, by employing a mass-spectrometry-based method, we show a role for PI acyl group chains in regulating NLRP3 inflammasome activation in cells lacking ABC transporter ABCB1. In response to canonical stimuli, Abcb1 -/- cells revealed defective priming and activation of the NLRP3 inflammasome owing to blunted TLR-dependent signalling. Cellular lipidomics demonstrated that ABC transporter deficiency shifted the total PI balance such that Abcb1 -/- cells exhibited reduced ratio of the short-chain to long-chain acyl chain lipids. Changes in PI acyl chain configuration accompanied diminished levels of ganglioside GM1, a marker of cholesterol-rich membrane microdomains, in deficient cells. Strikingly, this was not due to differences in the expression of enzymes that either synthesize PI or are involved in acyl chain remodelling. Our study thus suggests an important role for PI lipid chains in priming and activation of the NLRP3 inflammasome thereby highlighting the metabolic regulation of immune responses.
Date Issued
2020-01-15
Date Acceptance
2020-01-15
Citation
BioRxiv 2020, 2020
URI
DOI
Publisher
bioRxiv
Journal / Book Title
BioRxiv 2020
Copyright Statement
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Sponsor
Wellcome Trust
Imperial College London
Medical Research Council (MRC)
Grant Number
108248/Z/15/Z
MR/S00968X/1
Date Publish Online
2020-01-15