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Cell Rep. 2015 Jun 30;11(12):1919-28. doi: 10.1016/j.celrep.2015.05.006. Epub 2015 Jun 18.

The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
2
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.
3
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
4
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.
5
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.
6
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.

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.

PMID:
26095358
PMCID:
PMC4508342
DOI:
10.1016/j.celrep.2015.05.006
[Indexed for MEDLINE]
Free PMC Article

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