@article{BoertleinDraegerSchoenaueretal.2018,
  author    = {B{\"o}rtlein, Charlene and Draeger, Annette and Schoenauer, Roman and Kuhlemann, Alexander and Sauer, Markus and Schneider-Schaulies, Sybille and Avota, Elita},
  title     = {The neutral sphingomyelinase 2 is required to polarize and sustain T Cell receptor signaling},
  series = {Frontiers in Immunology},
  volume    = {9},
  journal   = {Frontiers in Immunology},
  number    = {815},
  doi       = {10.3389/fimmu.2018.00815},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176572},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{BoertleinSchumacherKleuseretal.2019,
  author    = {B{\"o}rtlein, Charlene and Schumacher, Fabian and Kleuser, Burkhard and D{\"o}lken, Lars and Avota, Elita},
  title     = {Role of neutral sphingomyelinase-2 (NSM 2) in the control of T cell plasma membrane lipid composition and cholesterol homeostasis},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {7},
  journal   = {Frontiers in Cell and Developmental Biology},
  number    = {226},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2019.00226},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190596},
  year      = {2019},
  abstract  = {The activity of neutral sphingomyelinase-2 (NSM2) to catalyze the conversion of sphingomyelin (SM) to ceramide and phosphocholine at the cytosolic leaflet of plasma membrane (PM) is important in T cell receptor (TCR) signaling. We recently identified PKCζ as a major NSM2 downstream effector which regulates microtubular polarization. It remained, however, unclear to what extent NSM2 activity affected overall composition of PM lipids and downstream effector lipids in antigen stimulated T cells. Here, we provide a detailed lipidomics analyses on PM fractions isolated from TCR stimulated wild type and NSM2 deficient (ΔNSM) Jurkat T cells. This revealed that in addition to that of sphingolipids, NSM2 depletion also affected concentrations of many other lipids. In particular, NSM2 ablation resulted in increase of lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) which both govern PM biophysical properties. Crucially, TCR dependent upregulation of the important T cell signaling lipid diacylglycerol (DAG), which is fundamental for activation of conventional and novel PKCs, was abolished in ΔNSM cells. Moreover, NSM2 activity was found to play an important role in PM cholesterol transport to the endoplasmic reticulum (ER) and production of cholesteryl esters (CE) there. Most importantly, CE accumulation was essential to sustain human T cell proliferation. Accordingly, inhibition of CE generating enzymes, the cholesterol acetyltransferases ACAT1/SOAT1 and ACAT2/SOAT2, impaired TCR driven expansion of both CD4\(^+\) and CD8\(^+\) T cells. In summary, our study reveals an important role of NSM2 in regulating T cell functions by its multiple effects on PM lipids and cholesterol homeostasis.},
  language  = {en}
}