Erythrocytes efficiently utilize exogenous sphingosines for S1P synthesis and export via Mfsd2b.

Autor:	Nguyen TQ; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Vu TM; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Tukijan F; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Muralidharan S; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Foo JC; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Li Chin JF; Mechanobiology Institute, National University of Singapore, Singapore., Hasan Z; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Torta F; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Nguyen LN; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; SLING/Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; Immunology Translational and Cardiovascular Disease Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: bchnnl@nus.edu.sg.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100201. Date of Electronic Publication: 2021 Jan 23.
DOI:	10.1074/jbc.RA120.012941
Abstrakt:	Sphingosine-1-phosphate (S1P) is a potent lipid mediator that exerts its activity via activation of five different G protein-coupled receptors, designated as S1P1-5. This potent lipid mediator is synthesized from the sphingosine precursor by two sphingosine kinases (SphK1 and 2) and must be exported to exert extracellular signaling functions. We recently identified Mfsd2b as the S1P transporter in the hematopoietic system. However, the sources of sphingosine for S1P synthesis and the transport mechanism of Mfsd2b in erythrocytes remain to be determined. Here, we show that erythrocytes efficiently take up exogenous sphingosine and that a de novo synthesis pathway in part provides sphingosines to erythrocytes. The uptake of sphingosine in erythrocytes is facilitated by the activity of SphK1. By converting sphingosine into S1P, SphK1 indirectly increases the influx of sphingosine, a process that is irreversible in erythrocytes. Our results explain for the abnormally high amount of sphingosine accumulation in Mfsd2b knockout erythrocytes. Furthermore, we show that Mfsd2b utilizes a proton gradient to facilitate the release of S1P. The negatively charged residues D95 and T157 are essential for Mfsd2b transport activity. Of interest, we also discovered an S1P analog that inhibits S1P export from erythrocytes, providing evidence that sphingosine analogs can be used to inhibit S1P export by Mfsd2b. Collectively, our results highlight that erythrocytes are efficient in sphingosine uptake for S1P production and the release of S1P is dependent on Mfsd2b functions. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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