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Neutral Sphingomyelinase-2 (NSM 2) Controls T Cell Metabolic Homeostasis and Reprogramming During Activation
Please always quote using this URN: urn:nbn:de:bvb:20-opus-211311
- Neutral sphingomyelinase-2 (NSM2) is a member of a superfamily of enzymes responsible for conversion of sphingomyelin into phosphocholine and ceramide at the cytosolic leaflet of the plasma membrane. Upon specific ablation of NSM2, T cells proved to be hyper-responsive to CD3/CD28 co-stimulation, indicating that the enzyme acts to dampen early overshooting activation of these cells. It remained unclear whether hyper-reactivity of NSM2-deficient T cells is supported by a deregulated metabolic activity in these cells. Here, we demonstrate thatNeutral sphingomyelinase-2 (NSM2) is a member of a superfamily of enzymes responsible for conversion of sphingomyelin into phosphocholine and ceramide at the cytosolic leaflet of the plasma membrane. Upon specific ablation of NSM2, T cells proved to be hyper-responsive to CD3/CD28 co-stimulation, indicating that the enzyme acts to dampen early overshooting activation of these cells. It remained unclear whether hyper-reactivity of NSM2-deficient T cells is supported by a deregulated metabolic activity in these cells. Here, we demonstrate that ablation of NSM2 activity affects metabolism of the quiescent CD4\(^+\) T cells which accumulate ATP in mitochondria and increase basal glycolytic activity. This supports enhanced production of total ATP and metabolic switch early after TCR/CD28 stimulation. Most interestingly, increased metabolic activity in resting NSM2-deficient T cells does not support sustained response upon stimulation. While elevated under steady-state conditions in NSM2-deficient CD4\(^+\) T cells, the mTORC1 pathway regulating mitochondria size, oxidative phosphorylation, and ATP production is impaired after 24 h of stimulation. Taken together, the absence of NSM2 promotes a hyperactive metabolic state in unstimulated CD4\(^+\) T cells yet fails to support sustained T cell responses upon antigenic stimulation.…
Author: | Maria Nathalia De Lira, Sudha Janaki Raman, Almut Schulze, Sibylle Schneider-Schaulies, Elita Avota |
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URN: | urn:nbn:de:bvb:20-opus-211311 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Institut für Virologie und Immunbiologie |
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften | |
Language: | English |
Parent Title (English): | Frontiers in Molecular Biosciences |
ISSN: | 2296-889X |
Year of Completion: | 2020 |
Volume: | 7 |
Article Number: | 217 |
Source: | Frontiers in Molecular Biosciences 2020, 7:217.doi: 10.3389/fmolb.2020.00217 |
DOI: | https://doi.org/10.3389/fmolb.2020.00217 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | ATP-adenosine triphosphate; Mitochondria; Seahorse XF; T cell receptor; neutral sphingomyelinase-2; oxidative phosphorylation |
Release Date: | 2021/04/22 |
Date of first Publication: | 2020/09/04 |
Open-Access-Publikationsfonds / Förderzeitraum 2020 | |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |