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The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity

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...

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Autores principales: Heinz, Leonhard X., Baumann, Christoph L., Köberlin, Marielle S., Snijder, Berend, Gawish, Riem, Shui, Guanghou, Sharif, Omar, Aspalter, Irene M., Müller, André C., Kandasamy, Richard K., Breitwieser, Florian P., Pichlmair, Andreas, Bruckner, Manuela, Rebsamen, Manuele, Blüml, Stephan, Karonitsch, Thomas, Fauster, Astrid, Colinge, Jacques, Bennett, Keiryn L., Knapp, Sylvia, Wenk, Markus R., Superti-Furga, Giulio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508342/
https://www.ncbi.nlm.nih.gov/pubmed/26095358
http://dx.doi.org/10.1016/j.celrep.2015.05.006
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author Heinz, Leonhard X.
Baumann, Christoph L.
Köberlin, Marielle S.
Snijder, Berend
Gawish, Riem
Shui, Guanghou
Sharif, Omar
Aspalter, Irene M.
Müller, André C.
Kandasamy, Richard K.
Breitwieser, Florian P.
Pichlmair, Andreas
Bruckner, Manuela
Rebsamen, Manuele
Blüml, Stephan
Karonitsch, Thomas
Fauster, Astrid
Colinge, Jacques
Bennett, Keiryn L.
Knapp, Sylvia
Wenk, Markus R.
Superti-Furga, Giulio
author_facet Heinz, Leonhard X.
Baumann, Christoph L.
Köberlin, Marielle S.
Snijder, Berend
Gawish, Riem
Shui, Guanghou
Sharif, Omar
Aspalter, Irene M.
Müller, André C.
Kandasamy, Richard K.
Breitwieser, Florian P.
Pichlmair, Andreas
Bruckner, Manuela
Rebsamen, Manuele
Blüml, Stephan
Karonitsch, Thomas
Fauster, Astrid
Colinge, Jacques
Bennett, Keiryn L.
Knapp, Sylvia
Wenk, Markus R.
Superti-Furga, Giulio
author_sort Heinz, Leonhard X.
collection PubMed
description 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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spelling pubmed-45083422015-08-01 The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity Heinz, Leonhard X. Baumann, Christoph L. Köberlin, Marielle S. Snijder, Berend Gawish, Riem Shui, Guanghou Sharif, Omar Aspalter, Irene M. Müller, André C. Kandasamy, Richard K. Breitwieser, Florian P. Pichlmair, Andreas Bruckner, Manuela Rebsamen, Manuele Blüml, Stephan Karonitsch, Thomas Fauster, Astrid Colinge, Jacques Bennett, Keiryn L. Knapp, Sylvia Wenk, Markus R. Superti-Furga, Giulio Cell Rep Article 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. Cell Press 2015-06-18 /pmc/articles/PMC4508342/ /pubmed/26095358 http://dx.doi.org/10.1016/j.celrep.2015.05.006 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Heinz, Leonhard X.
Baumann, Christoph L.
Köberlin, Marielle S.
Snijder, Berend
Gawish, Riem
Shui, Guanghou
Sharif, Omar
Aspalter, Irene M.
Müller, André C.
Kandasamy, Richard K.
Breitwieser, Florian P.
Pichlmair, Andreas
Bruckner, Manuela
Rebsamen, Manuele
Blüml, Stephan
Karonitsch, Thomas
Fauster, Astrid
Colinge, Jacques
Bennett, Keiryn L.
Knapp, Sylvia
Wenk, Markus R.
Superti-Furga, Giulio
The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
title The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
title_full The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
title_fullStr The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
title_full_unstemmed The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
title_short The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity
title_sort lipid-modifying enzyme smpdl3b negatively regulates innate immunity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508342/
https://www.ncbi.nlm.nih.gov/pubmed/26095358
http://dx.doi.org/10.1016/j.celrep.2015.05.006
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