Journal
CELL REPORTS
Volume 11, Issue 12, Pages 1919-1928Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.05.006
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Funding
- Austrian Academy of Sciences
- Medical University of Vienna
- European Research Council under the European Union [250179]
- Marie Curie Fellowship [220596, 301663]
- EMBO [ATLF 2008-463, ALTF 1346-2011, ATLF 314-2012]
- Austrian Science Fund [FWFI291B09, FWF1205B09]
- Austrian Federal Ministry for Science and Research GEN-AU/BIN
- Austrian Federal Ministry for Science and Research GEN-AU/APP
- Swiss National Science Foundation [P300P3_147897]
- National University of Singapore via the Life Sciences Institute (LSI)
- Singapore National Research Foundation under CRP [2007-04]
- SystemsX.ch RTD project LipidX
- Swiss National Science Foundation (SNF) [P300P3_147897] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [250179] Funding Source: European Research Council (ERC)
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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.
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