Deletion of Mfsd2b impairs thrombotic functions of platelets

• Published in: Nature communications Vol. 12; no. 1; p. 2286
• Main Authors: Chandrakanthan, Madhuvanthi, Nguyen, Toan Quoc, Hasan, Zafrul, Muralidharan, Sneha, Vu, Thiet Minh, Li, Aaron Wei Liang, Le, Uyen Thanh Nha, Thi Thuy Ha, Hoa, Baik, Sang-Ha, Tan, Sock Hwee, Foo, Juat Chin, Wenk, Markus R., Cazenave-Gassiot, Amaury, Torta, Federico, Ong, Wei Yi, Chan, Mark Yan Yee, Nguyen, Long N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-04-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 631/45/287/1196; 631/80/2023; 64/60; 692/4019/592/1339; 82/29; 82/58; 82/80; Accumulation; Animals; Biosynthesis; Blood; Blood cells; Blood platelets; Blood Platelets - cytology; Blood Platelets - drug effects; Blood Platelets - metabolism; Cloning; Cytoplasm; Cytoplasm - metabolism; Deletion; Disease Models, Animal; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Humanities and Social Sciences; Humans; Kinases; Life sciences; Lipids; Lymphocytes; Lysophospholipids - metabolism; Male; Medicine; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Morphology; multidisciplinary; Physiology; Plasma; Platelet Function Tests; Platelets; Proteins; Roles; Science; Science (multidisciplinary); Sphingolipids; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine 1-phosphate; Thrombosis; Venous Thrombosis - blood; Venous Thrombosis - diagnosis; Venous Thrombosis - drug therapy; Venous Thrombosis - pathology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22642-x

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.
The mechanisms by which platelets release sphingosine-1-phosphate (S1P) is not well characterized. Here the authors show that Mfsd2b is required for S1P release from both resting and activated platelets and that deletion of Mfsd2b impairs thrombotic functions of platelets.