title: A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.
abstract: Lipid 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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Marielle S
authors.initials: MS
authors.lastname: Köberlin
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Berend
authors.initials: B
authors.lastname: Snijder
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Leonhard X
authors.initials: LX
authors.lastname: Heinz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Christoph L
authors.initials: CL
authors.lastname: Baumann
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Astrid
authors.initials: A
authors.lastname: Fauster
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Vladimer
authors.affiliation: European Molecular Biology Laboratory, EMBL, 69117 Heidelberg, Germany.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gavin
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address: gsuperti@cemm.oeaw.ac.at.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005776:Gaucher Disease / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000276:immunology; D007965:Leukodystrophy, Globoid Cell / Q000276:immunology; D008055:Lipids / Q000276:immunology*; D053858:Metabolic Networks and Pathways; D051379:Mice; D013107:Sphingolipids / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D015850:Interleukin-6; D008055:Lipids; D013107:Sphingolipids; D051193:Toll-Like Receptors