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

Börtlein, Charlene; Draeger, Annette; Schönauer, Roman; Kuhlemann, Alexander; Sauer, Markus; Schneider-Schaulies, Sibylle; Avota, Elita (2018). The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling. Frontiers in immunology, 9, p. 815. Frontiers Research Foundation 10.3389/fimmu.2018.00815

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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 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 MTOC polarization.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Cell Biology

UniBE Contributor:

Draeger, Annette and Schönauer, Roman

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1664-3224

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Annette Draeger

Date Deposited:

12 Feb 2019 12:54

Last Modified:

28 Oct 2019 02:49

Publisher DOI:

10.3389/fimmu.2018.00815

PubMed ID:

29720981

Uncontrolled Keywords:

PKCζ T cells ceramides neutral sphingomyelinase 2 the microtubule-organizing center

BORIS DOI:

10.7892/boris.125163

URI:

https://boris.unibe.ch/id/eprint/125163

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