Neutral Sphingomyelinase-2 (NSM 2) Controls T Cell Metabolic Homeostasis and Reprogramming During Activation

Abstract

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 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.

Sphingolipids in thyroid eye disease

“…Several studies imply that also neutral sphingomyelinases are important in T cell activation ( 100 , 101 ). These studies demonstrated that inhibition of neutral sphingomyelinases interfered with lymph node homing and adhesion of T cells to activated endothelial cells ( 99 , 100 ).…”

“…Thus, deletion of neutral sphingomyelinase-2 resulted in hyper-responsivity of T cells upon stimulation via CD3/CD28 ( 99 , 100 ). This effect seems to be mediated by an increased metabolic activity with an accumulation of ATP in mitochondria and higher basal glycolytic activity in lymphocytes upon downregulation of neutral sphingomyelinase-2 ( 101 ). Whether down-regulation of neutral sphingomyelinase-2 results in an altered immune response in vivo remains to be determined.…”

Mass versus personalized medicine againstCOVID‐19 in the “system sciences” era

“…While ceramide promoted uptake of SARS-CoV-2 virion into epithelial cells, sphingosine-1-phosphate (S1P) receptor activation inhibited the entry [29]. Neutral and acid sphingomyelinase regulate distribution of voltage gated channels, glucose, and lipid uptake [30], therefore, also regulate SARS-CoV-2 spike protein binding and proteolytic processing. Multiple biochemical pathways produce ceramide, with S1P and ceramide interconversion potentially altering the balance of viral transmission.…”

“Multiomics” Approaches to Understand and Treat COVID-19: Mass Spectrometry and Next-Generation Sequencing

“…While ceramide promoted uptake of SARS-CoV-2 virion into epithelial cells, sphingosine-1-phosphate (S1P) receptor activation inhibited entry [20]. Neutral and acid sphingomyelinase regulate distribution of voltage gated channels, glucose and lipid uptake [21,22] and may, therefore, also regulate SARS-CoV-2 spike protein binding and proteolytic processing. Multiple biochemical pathways produce ceramide, with S1P and ceramide interconversion potentially altering the balance of viral transmission.…”