We recently discovered that Mfsd2b, which is the S1P exporter found in blood cells. Here, we report that Mfsd2b is critical for the release of all S1P species in both resting and activated platelets. We show that resting platelets store S1P in the cytoplasm. After activation, this S1P pool is delivered to the plasma membrane, where Mfsd2b is predominantly localized for export. Employing knockout mice of Mfsd2b, we reveal that platelets contribute a minor amount of plasma S1P. Nevertheless, Mfsd2b deletion in whole body or platelets impairs platelet morphology and functions. In particular, Mfsd2b knockout mice show significantly reduced thrombus formation. We show that loss of Mfsd2b affects intrinsic platelet functions as part of remarkable sphingolipid accumulation. These findings indicate that accumulation of sphingolipids including S1P by deletion of Mfsd2b strongly impairs platelet functions, which suggests that the transporter may be a target for the prevention of thrombotic disorders.
Accumulation of sphingolipids, especially sphingosines, in the lysosomes is attributed to the pathogenesis of several lysosomal storage diseases. In search for a lysosomal protein that mediates the release of sphingosines, we identified SPNS1 which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter. We generated knockout cells and mice for Spns1 and employed lipidomics and metabolomics to identify SPNS1 ligands. We found that knockouts of Spns1 resulted in the accumulation of sphingolipids, including sphingosines in embryonic brains and cell lines. These results suggest that deficiency of SPNS1 affects the clearance of sphingolipids in lysosomes. Biochemical assays demonstrated that sphingosines released from lysosomes required SPNS1. Furthermore, by performing a comprehensive analysis of metabolites from livers of postnatal Spns1 knockout mice (gSpns1-cKO), we detected a striking accumulation of lysoglycerophospholipids including LPC, LPE, LPG, and lysoplasmalogens. Interestingly, the release of these lysoglycerophospholipids also required SPNS1. Global knockout of Spns1 (gSpns1-KO) resulted in embryonic lethality between E12.5-E13.5 with developmental defects. Postnatal deletion of Spns1 in mice caused lipid accumulation in the lysosomes and pathological conditions reminiscent of lysosomal storage diseases. These results reveal a critical molecular role of SPNS1 as a transporter for lysosphingolipids and lysoglyerophospholipids from the lysosomes and link its physiological functions with lysosomal storage diseases.
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