The neutral sphingomyelinase 2 is required to polarize and sustain T Cell receptor signaling
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-176572
- 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 TBy 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.…
Autor(en): | Charlene Börtlein, Annette Draeger, Roman Schoenauer, Alexander Kuhlemann, Markus Sauer, Sybille Schneider-Schaulies, Elita Avota |
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URN: | urn:nbn:de:bvb:20-opus-176572 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Institut für Virologie und Immunbiologie |
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften | |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Frontiers in Immunology |
Erscheinungsjahr: | 2018 |
Band / Jahrgang: | 9 |
Heft / Ausgabe: | 815 |
Originalveröffentlichung / Quelle: | Frontiers in Immunology 2018, Volume 9, Article 815. DOI: 10.3389/fimmu.2018.00815 |
DOI: | https://doi.org/10.3389/fimmu.2018.00815 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | PKCζ,; T cells; ceramides; neutral sphingomyelinase 2; the microtubule-organizing center |
Datum der Freischaltung: | 26.02.2019 |
Sammlungen: | Open-Access-Publikationsfonds / Förderzeitraum 2018 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |