scholarly journals A Glimpse of the Structural Biology of the Metabolism of Sphingosine-1-Phosphate

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642199560
Author(s):  
Ruobing Ren ◽  
Bin Pang ◽  
Yufei Han ◽  
Yihao Li
Keyword(s):  
Structural Biology ◽  
Metabolic Pathways ◽  
Therapeutic Effects ◽  
Lymphocyte Trafficking ◽  
Vascular Integrity ◽  
S1p Receptors ◽  
Biochemical Studies ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Therapeutic Molecules

As a key sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays crucial roles in vascular and immune systems. It regulates angiogenesis, vascular integrity and homeostasis, allergic responses, and lymphocyte trafficking. S1P is interconverted with sphingosine, which is also derived from the deacylation of ceramide. S1P levels and the ratio to ceramide in cells are tightly regulated by its metabolic pathways. Abnormal S1P production causes the occurrence and progression of numerous severe diseases, such as metabolic syndrome, cancers, autoimmune disorders such as multiple sclerosis, and kidney and cardiovascular diseases. In recent years, huge advances on the structure of S1P metabolic pathways have been accomplished. In this review, we have got a glimpse of S1P metabolism through structural and biochemical studies of: sphingosine kinases, S1P transporters and S1P receptors, and the development of therapeutics targeting S1P signaling. The progress we summarize here could provide fresh perspectives to further the exploration of S1P functions and facilitate the development of therapeutic molecules targeting S1P signaling with improved specificity and therapeutic effects.

scholarly journals Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

2004 ◽  
Vol 279 (50) ◽  
pp. 52487-52492 ◽  
Author(s):  
Maria L. Allende ◽  
Teiji Sasaki ◽  
Hiromichi Kawai ◽  
Ana Olivera ◽  
Yide Mi ◽  
...  
Keyword(s):  
Vascular Development ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Cellular Functions ◽  
Lymphocyte Trafficking ◽  
Signaling Molecule ◽  
Physiological Functions ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

scholarly journals FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

2022 ◽  
Author(s):  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Aran Groves ◽  
Manisha Ray ◽  
Arjun Saha ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Metabolic Pathways ◽  
Type I ◽  
Rna Seq ◽  
Autoimmune Encephalomyelitis ◽  
Altered Expression ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P1. Vitamin B12 (B12) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B12 receptor, by S1P1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B12 worsened EAE and eliminated FTY720 efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.

scholarly journals Characterizing Sphingosine Kinases and Sphingosine 1-Phosphate Receptors in the Mammalian Eye and Retina

2018 ◽  
Vol 19 (12) ◽  
pp. 3885 ◽  
Author(s):  
Hunter Porter ◽  
Hui Qi ◽  
Nicole Prabhu ◽  
Richard Grambergs ◽  
Joel McRae ◽  
...  
Keyword(s):  
Stress Responses ◽  
Expression Profiles ◽  
Receptor Gene ◽  
Light Stress ◽  
Rat Tissues ◽  
Light Damage ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases

Sphingosine 1-phosphate (S1P) signaling regulates numerous biological processes including neurogenesis, inflammation and neovascularization. However, little is known about the role of S1P signaling in the eye. In this study, we characterize two sphingosine kinases (SPHK1 and SPHK2), which phosphorylate sphingosine to S1P, and three S1P receptors (S1PR1, S1PR2 and S1PR3) in mouse and rat eyes. We evaluated sphingosine kinase and S1P receptor gene expression at the mRNA level in various rat tissues and rat retinas exposed to light-damage, whole mouse eyes, specific eye structures, and in developing retinas. Furthermore, we determined the localization of sphingosine kinases and S1P receptors in whole rat eyes by immunohistochemistry. Our results unveiled unique expression profiles for both sphingosine kinases and each receptor in ocular tissues. Furthermore, these kinases and S1P receptors are expressed in mammalian retinal cells and the expression of SPHK1, S1PR2 and S1PR3 increased immediately after light damage, which suggests a function in apoptosis and/or light stress responses in the eye. These findings have numerous implications for understanding the role of S1P signaling in the mechanisms of ocular diseases such as retinal inflammatory and degenerative diseases, neovascular eye diseases, glaucoma and corneal diseases.

scholarly journals Sphingosine-1-phosphate receptor modulator FTY720 attenuates experimental myeloperoxidase-ANCA vasculitis in a T cell-dependent manner

2020 ◽  
Vol 134 (12) ◽  
pp. 1475-1489
Author(s):  
Luo-Yi Wang ◽  
Xiao-Jing Sun ◽  
Chen Wang ◽  
Su-Fang Chen ◽  
Zhi-Ying Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pulmonary Hemorrhage ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Crescent Formation ◽  
S1p Receptors ◽  
Anca Associated Vasculitis ◽  
Sphingosine 1 Phosphate

Abstract Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1β in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.

scholarly journals The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Melissa R. Pitman ◽  
Alexander C. Lewis ◽  
Lorena T. Davies ◽  
Paul A. B. Moretti ◽  
Dovile Anderson ◽  
...  
Keyword(s):  
Sphingolipid Metabolism ◽  
Protein Targets ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Dihydroceramide Desaturase ◽  
Dihydroceramide Desaturase 1 ◽  
G Protein Coupled ◽  
Potential Therapeutics ◽  
Target Effects

AbstractSphingosine 1-phosphate (S1P) is a signaling lipid that has broad roles, working either intracellularly through various protein targets, or extracellularly via a family of five G-protein coupled receptors. Agents that selectively and specifically target each of the S1P receptors have been sought as both biological tools and potential therapeutics. JTE-013, a small molecule antagonist of S1P receptors 2 and 4 (S1P2 and S1P4) has been widely used in defining the roles of these receptors in various biological processes. Indeed, our previous studies showed that JTE-013 had anti-acute myeloid leukaemia (AML) activity, supporting a role for S1P2 in the biology and therapeutic targeting of AML. Here we examined this further and describe lipidomic analysis of AML cells that revealed JTE-013 caused alterations in sphingolipid metabolism, increasing cellular ceramides, dihydroceramides, sphingosine and dihydrosphingosine. Further examination of the mechanisms behind these observations showed that JTE-013, at concentrations frequently used in the literature to target S1P2/4, inhibits several sphingolipid metabolic enzymes, including dihydroceramide desaturase 1 and both sphingosine kinases. Collectively, these findings demonstrate that JTE-013 can have broad off-target effects on sphingolipid metabolism and highlight that caution must be employed in interpreting the use of this reagent in defining the roles of S1P2/4.

Real-time differential labeling of blood, interstitium, and lymphatic and single-field analysis of vasculature dynamics in vivo

2012 ◽  
Vol 302 (10) ◽  
pp. C1460-C1468 ◽  
Author(s):  
Gor Sarkisyan ◽  
Stuart M. Cahalan ◽  
Pedro J. Gonzalez-Cabrera ◽  
Nora B. Leaf ◽  
Hugh Rosen
Keyword(s):  
Endothelial Cells ◽  
Real Time ◽  
Multiphoton Microscopy ◽  
Endothelial Permeability ◽  
Field Analysis ◽  
Lymphocyte Trafficking ◽  
Vascular Integrity ◽  
Sphingosine 1 Phosphate ◽  
Single Field

Lymph nodes are highly organized structures specialized for efficient regulation of adaptive immunity. The blood and lymphatic systems within a lymph node play essential roles by providing functionally distinct environments for lymphocyte entry and egress, respectively. Direct imaging and measurement of vascular microenvironments by intravital multiphoton microscopy provide anatomical and mechanistic insights into the essential events of lymphocyte trafficking. Lymphocytes, blood endothelial cells, and lymphatic endothelial cells express sphingosine 1-phosphate receptor 1, a key G protein-coupled receptor regulating cellular egress and a modulator of endothelial permeability. Here we report the development of a differential vascular labeling (DVL) technique in which a single intravenous injection of a fluorescent dextran, in combination with fluorescent semiconductor quantum dot particles, differentially labels multiple blood and lymphatic compartments in a manner dependent on the size of the fluorescent particle used. Thus DVL allows measurement of endothelial integrity in multiple vascular compartments and the affects or pharmacological manipulation in vascular integrity. In addition, this technique allows for real-time observation of lymphocyte trafficking across physiological barriers differentiated by DVL. Last, single-field fluid movement dynamics can be derived, allowing for the simultaneous determination of fluid flow rates in diverse blood and lymphatic compartments.

scholarly journals Interaction of microRNAs with sphingosine kinases, sphingosine-1 phosphate, and sphingosine-1 phosphate receptors in cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guangmeng Xu ◽  
Zecheng Yang ◽  
Yamin Sun ◽  
Hongmei Dong ◽  
Jingru Ma
Keyword(s):  
Cell Proliferation ◽  
G Protein Coupled Receptors ◽  
Lipid Mediator ◽  
Cellular Processes ◽  
S1p Receptors ◽  
Carcinoma Prostate ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Non Coding Rnas ◽  
G Protein Coupled

AbstractSphingosine-1-phosphate (S1P), a pleiotropic lipid mediator, participates in various cellular processes during tumorigenesis, including cell proliferation, survival, drug resistance, metastasis, and angiogenesis. S1P is formed by two sphingosine kinases (SphKs), SphK1 and SphK2. The intracellularly produced S1P is delivered to the extracellular space by ATP-binding cassette (ABC) transporters and spinster homolog 2 (SPNS2), where it binds to five transmembrane G protein-coupled receptors to mediate its oncogenic functions (S1PR1-S1PR5). MicroRNAs (miRNAs) are small non-coding RNAs, 21–25 nucleotides in length, that play numerous crucial roles in cancer, such as tumor initiation, progression, apoptosis, metastasis, and angiogenesis via binding to the 3′‐untranslated region (3′‐UTR) of the target mRNA. There is growing evidence that various miRNAs modulate tumorigenesis by regulating the expression of SphKs, and S1P receptors. We have reviewed various roles of miRNAs, SphKs, S1P, and S1P receptors (S1PRs) in malignancies and how notable miRNAs like miR-101, miR-125b, miR-128, and miR-506, miR-1246, miR-21, miR-126, miR499a, miR20a-5p, miR-140-5p, miR-224, miR-137, miR-183-5p, miR-194, miR181b, miR136, and miR-675-3p, modulate S1P signaling. These tumorigenesis modulating miRNAs are involved in different cancers including breast, gastric, hepatocellular carcinoma, prostate, colorectal, cervical, ovarian, and lung cancer via cell proliferation, invasion, angiogenesis, apoptosis, metastasis, immune evasion, chemoresistance, and chemosensitivity. Therefore, understanding the interaction of SphKs, S1P, and S1P receptors with miRNAs in human malignancies will lead to better insights for miRNA-based cancer therapy.

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