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The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling

By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR...

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Autores principales: Börtlein, Charlene, Draeger, Annette, Schoenauer, Roman, Kuhlemann, Alexander, Sauer, Markus, Schneider-Schaulies, Sibylle, Avota, Elita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915489/
https://www.ncbi.nlm.nih.gov/pubmed/29720981
http://dx.doi.org/10.3389/fimmu.2018.00815
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author Börtlein, Charlene
Draeger, Annette
Schoenauer, Roman
Kuhlemann, Alexander
Sauer, Markus
Schneider-Schaulies, Sibylle
Avota, Elita
author_facet Börtlein, Charlene
Draeger, Annette
Schoenauer, Roman
Kuhlemann, Alexander
Sauer, Markus
Schneider-Schaulies, Sibylle
Avota, Elita
author_sort Börtlein, Charlene
collection PubMed
description By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca(2+) mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3ζ and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCζ as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCζ membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3ζ, Zap70, and PKCζ, and functional immune synapses are organized and stabilized via MTOC polarization.
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spelling pubmed-59154892018-05-02 The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling Börtlein, Charlene Draeger, Annette Schoenauer, Roman Kuhlemann, Alexander Sauer, Markus Schneider-Schaulies, Sibylle Avota, Elita Front Immunol Immunology By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca(2+) mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3ζ and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCζ as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCζ membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3ζ, Zap70, and PKCζ, and functional immune synapses are organized and stabilized via MTOC polarization. Frontiers Media S.A. 2018-04-18 /pmc/articles/PMC5915489/ /pubmed/29720981 http://dx.doi.org/10.3389/fimmu.2018.00815 Text en Copyright © 2018 Börtlein, Draeger, Schoenauer, Kuhlemann, Sauer, Schneider-Schaulies and Avota. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Börtlein, Charlene
Draeger, Annette
Schoenauer, Roman
Kuhlemann, Alexander
Sauer, Markus
Schneider-Schaulies, Sibylle
Avota, Elita
The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling
title The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling
title_full The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling
title_fullStr The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling
title_full_unstemmed The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling
title_short The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling
title_sort neutral sphingomyelinase 2 is required to polarize and sustain t cell receptor signaling
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915489/
https://www.ncbi.nlm.nih.gov/pubmed/29720981
http://dx.doi.org/10.3389/fimmu.2018.00815
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