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Nature. 2017 Oct 26;550(7677):524-528. doi: 10.1038/nature24053. Epub 2017 Oct 18.

Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets.

Author information

1
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 5 Medical Drive, Singapore 117545.
2
Cancer Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore 117599.
3
Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456.
4
Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Singapore 117583.
5
Biomedical Institute for Global Health Research and Technology, National University of Singapore, 14 Medical Drive, Singapore 117599.
6
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456.
7
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599.
8
Signature Research Program in Cardiovascular & Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857.

Abstract

Sphingosine-1-phosphate (S1P), a potent signalling lipid secreted by red blood cells and platelets, plays numerous biologically significant roles. However, the identity of its long-sought exporter is enigmatic. Here we show that the major facilitator superfamily transporter 2b (Mfsd2b), an orphan transporter, is essential for S1P export from red blood cells and platelets. Comprehensive lipidomic analysis indicates a dramatic and specific accumulation of S1P species in Mfsd2b knockout red blood cells and platelets compared with that of wild-type controls. Consistently, biochemical assays from knockout red blood cells, platelets, and cell lines overexpressing human and mouse Mfsd2b proteins demonstrate that Mfsd2b actively exports S1P. Plasma S1P level in knockout mice is significantly reduced by 42-54% of that of wild-type level, indicating that Mfsd2b pathway contributes approximately half of the plasma S1P pool. The reduction of plasma S1P in knockout mice is insufficient to cause blood vessel leakiness, but it does render the mice more sensitive to anaphylactic shock. Stress-induced erythropoiesis significantly increased plasma S1P levels and knockout mice were sensitive to these treatments. Surprisingly, knockout mice exhibited haemolysis associated with red blood cell stomatocytes, and the haemolytic phenotype was severely increased with signs of membrane fragility under stress erythropoiesis. We show that S1P secretion by Mfsd2b is critical for red blood cell morphology. Our data reveal an unexpected physiological role of red blood cells in sphingolipid metabolism in circulation. These findings open new avenues for investigating the signalling roles of S1P derived from red blood cells and platelets.

PMID:
29045386
DOI:
10.1038/nature24053
[Indexed for MEDLINE]

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