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

• Published in: Nature (London) Vol. 550; no. 7677; pp. 524 - 528
• Main Authors: Vu, Thiet M., Ishizu, Ayako-Nakamura, Foo, Juat Chin, Toh, Xiu Ru, Zhang, Fangyu, Whee, Ding Ming, Torta, Federico, Cazenave-Gassiot, Amaury, Matsumura, Takayoshi, Kim, Sangho, Toh, Sue-Anne E. S., Suda, Toshio, Silver, David L., Wenk, Markus R., Nguyen, Long N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.10.2017; Nature Publishing Group
• Subjects: 13/106; 13/31; 13/51; 14/19; 14/28; 631/45/287/1196; 631/80/2023; 64/60; 82/1; 82/29; Anaphylaxis; Blood; Blood circulation; Blood platelets; Bone marrow; Cell lines; Cell morphology; Cytology; Erythrocytes; Erythropoiesis; Fragility; Humanities and Social Sciences; Kinases; letter; Lipid metabolism; Lipids; Metabolism; Mice; multidisciplinary; Phosphates; Physiological aspects; Plasmas (physics); Platelets; Proteins; Red blood cells; Science; Secretion; Signal transduction; Signaling; Sphingosine 1-phosphate
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature24053

Identification of a transmembrane protein, Mfsd2b, that is essential for the export of the signalling molecule sphingosine-1-phosphate (S1P) from red blood cells and platelets. Protein assists escape from blood cells Sphingosine-1-phosphate (S1P) is a signalling molecule that is secreted by red blood cells and platelets and performs a broad range of biological functions, including influencing lymphocyte egress and maintaining blood vessel integrity. How it is exported from these cells has been unclear. Long Nguyen and colleagues now identify a transmembrane protein, Mfsd2b, which is essential for the export of S1P from red blood cells, and for maintaining the numbers and morphology of red blood cells. Their findings could provide new ways of exploring the signalling roles of S1P derived from red blood cells and platelets. Sphingosine-1-phosphate (S1P), a potent signalling lipid secreted by red blood cells and platelets 1 , 2 , plays numerous biologically significant roles 3 , 4 , 5 , 6 . 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.