A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses

Abstract

SummaryLipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids. This evolutionarily conserved network architecture simultaneously reflected membrane lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in lipid abundance assigned distinct functional roles to individual lipid species organized across the network. This functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from lipid storage disorders, based solely on their altered membrane lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane lipid function in diverse biological systems.

Crystal Structure of the Acid Sphingomyelinase-like Phosphodiesterase SMPDL3B Provides Insights into Determinants of Substrate Specificity

“…A negative regulatory role in innate immune signaling was uncovered in murine macrophages, where the enzyme is found on the cell surface and up-regulated upon inflammatory stimuli (11,12). Its knockdown results in enhanced responsiveness to Toll-like receptor (TLR) stimulation and Smpdl3b-deficient mice display an increased inflammatory response.…”

Lipid Cooperativity as a General Membrane-Recruitment Principle for PH Domains

“…These lipids have a role in virtually all biological processes (van Meer, 2005) through their extensive, regulated association with other lipids and proteins. The significance of these regulatory circuits is evident from the variety of human disorders arising from altered protein-lipid interactions (Bayascas et al, 2008;Lindhurst et al, 2011;Zü chner et al, 2005;Kö berlin et al, 2015), which constitute attractive targets for pharmaceutical drug development (Hussein et al, 2013).…”

Analytical Lipidomics in Metabolic and Clinical Research

“…The results showed that membrane lipids are highly coregulated and revealed a conserved circular lipid network reflecting membrane lipid metabolism, subcellular localization, and adaptation mechanisms [8]. Network-wide functional annotation of lipids downstream of the Toll-like receptor signaling pathway based on genetic perturbations allowed accurate prediction of inflammatory responses in cells from patients with multiple lipidstorage disorders.…”