title: The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity.
abstract: Lipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis. Activation of Toll-like receptors (TLRs) leads to a complex cellular response, orchestrating a diverse range of inflammatory events that need to be tightly controlled. Here, we identified the GPI-anchored Sphingomyelin Phosphodiesterase, Acid-Like 3B (SMPDL3B) in a mass spectrometry screening campaign for membrane proteins co-purifying with TLRs. Deficiency of Smpdl3b in macrophages enhanced responsiveness to TLR stimulation and profoundly changed the cellular lipid composition and membrane fluidity. Increased cellular responses could be reverted by re-introducing affected ceramides, functionally linking membrane lipid composition and innate immune signaling. Finally, Smpdl3b-deficient mice displayed an intensified inflammatory response in TLR-dependent peritonitis models, establishing its negative regulatory role in vivo. Taken together, our results identify the membrane-modulating enzyme SMPDL3B as a negative regulator of TLR signaling that functions at the interface of membrane biology and innate immunity.
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: 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; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Riem
authors.initials: R
authors.lastname: Gawish
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Omar
authors.initials: O
authors.lastname: Sharif
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Aspalter
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: André C
authors.initials: AC
authors.lastname: Müller
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Kandasamy
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Florian P
authors.initials: FP
authors.lastname: Breitwieser
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pichlmair
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bruckner
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Manuele
authors.initials: M
authors.lastname: Rebsamen
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Division of Rheumatology, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karonitsch
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: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Department of Biochemistry and Department of Biological Sciences, National University of Singapore, Singapore 117456, Singapore; Swiss Tropical and Public Health Institute, University of Basel, 4003 Basel, Switzerland.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
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; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008055:Lipids / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D010538:Peritonitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: D008055:Lipids; D051193:Toll-Like Receptors; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C000595964:sphingomyelinase-like phosphodiesterase 3b, mouse