Sphingolipid Signaling in Mammals

Division Of Basic Sciences - Nci

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Abstract

We have demonstrated critical roles of the de novo biosynthetic patway in specification and differentiation of various lineages of the bone marrow stem cells.Recently we reported on the role of SPTLC1 in T helper cells development and differentiation. T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. We demonstrated an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyltransferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases. We are continuing to examine the role of components of SPT complex in cells derived from the hematopoietic system including cells of innate and acquired immunity.