Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid metabolite that is now emerging as an important regulator of many physiological and pathological processes in health and diseases. S1P is produced intracellularly by two closely related sphingosine kinases, SphK1 and SphK2. Although much has been learned about SphK1 and its functions, those of SphK2 remained enigmatic. We recently found that SphK2, which is present in the nucleus, produces S1P that specifically binds to histone deacetylases HDAC1/2 and inhibits their enzymatic activities, linking sphingolipid metabolism and S1P in the nucleus to epigenetic regulation of gene expression. Hence, we suggested that S1P is an endogenous small molecule regulator of these enzymes, which opens a fascinating scenario for sphingolipid signaling in the nucleus and for HDAC regulation. HDAC1/2 belong to a large family of zinc-dependent HDACs, and HDAC inhibitors have long been used in psychiatry and various neurological disorders. However, despite the widespread interest in HDACs, the environmental cues and signal transduction pathways that regulate their activity, as well as endogenous regulators remain largely unknown.
In Aim 1 of this proposal, we will examine the role of S1P produced by SphK2 in the nucleus as an endogenous regulator of HDACs, histone acetylations, and gene expression, independently of S1P receptor signaling. The discovery that the immunomodulator FTY720, which opened new approaches for the treatment of multiple sclerosis, is a pro-drug that is phosphorylated in vivo by SphK2 to a mimetic of S1P, raised the intriguing possibility that it also mimics the nuclear actions of S1P. Therefore, in Aim 2 we will analyze the potential of FTY720 and other S1P receptor modulators as regulators of HDACs and histone acetylations. As HDACs have emerged as key targets to reverse aberrant epigenetic changes associated with memory deficits, we will use genetic, molecular, and pharmacological approaches in Aim 3 to decipher the in vivo role of the SphK2/S1P axis and FTY720 in histone acetylation, gene regulation, and contextual memory in mice. Our proposal will uncover new actions of FTY720, and potentially other S1P mimetics, as specific HDAC inhibitors and constitute an initial test of the capacity of manipulating the epigenome to potentially reverse memory dysfunction associated with aging, multiple sclerosis, and other neurological diseases. Understanding how the SphK2/S1P axis regulates functions of HDACs should provide fundamental insights into the molecular and cellular basis of chromatin modifications and their involvement in memory and may pave the way for effective therapies aimed at cognitive disorders.
|Lima, Santiago; Milstien, Sheldon; Spiegel, Sarah (2017) Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking. J Biol Chem 292:3074-3088|
|Grenald, Shaness A; Doyle, Timothy M; Zhang, Hong et al. (2017) Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain 158:1733-1742|
|Newton, Jason; Hait, Nitai C; Maceyka, Michael et al. (2017) FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. FASEB J 31:1719-1730|
|Cai, Lin; Oyeniran, Clement; Biswas, Debolina D et al. (2016) ORMDL proteins regulate ceramide levels during sterile inflammation. J Lipid Res 57:1412-22|
|Liakath-Ali, Kifayathullah; Vancollie, Valerie E; Lelliott, Christopher J et al. (2016) Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure. J Pathol 239:374-83|
|Huang, Wei-Ching; Liang, Jie; Nagahashi, Masayuki et al. (2016) Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. FASEB J 30:2945-58|
|Newton, Jason; Lima, Santiago; Maceyka, Michael et al. (2015) Revisiting the sphingolipid rheostat: Evolving concepts in cancer therapy. Exp Cell Res 333:195-200|
|Nagahashi, Masayuki; Takabe, Kazuaki; Liu, Runping et al. (2015) Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology 61:1216-26|
|Campos, Ludmila S; Rodriguez, Yamila I; Leopoldino, Andreia M et al. (2015) Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-?B Activation in Melanoma Cells by Inhibition of Akt Signaling. Mol Cell Biol 36:320-9|
|Yester, Jessie W; Bryan, Lauren; Waters, Michael R et al. (2015) Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-? amplification loop. FASEB J 29:4853-65|
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