TY  - JOUR
A1  - Börtlein, Charlene
A1  - Draeger, Annette
A1  - Schoenauer, Roman
A1  - Kuhlemann, Alexander
A1  - Sauer, Markus
A1  - Schneider-Schaulies, Sybille
A1  - Avota, Elita
T1  - The neutral sphingomyelinase 2 is required to polarize and sustain T Cell receptor signaling
JF  - Frontiers in Immunology
N2  - 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.
KW  - neutral sphingomyelinase 2
KW  - T cells
KW  - ceramides
KW  - PKCζ,
KW  - the microtubule-organizing center
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176572
VL  - 9
IS  - 815
ER  -