SPNS2 exports sphingosine-1-phosphate and imports glucose

Spinster homolog 2 (SPNS2) exports the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) out of cells to regulate processes important for health and diseases. However, the molecular mechanism underlying SPNS2 transport functions and its precise physiological roles are not fully understood. Here, through a series of complementary approaches in mice, cellular assays, and particularly with in vitro cell-free binding and transport assays, we show that SPNS2 has antiporter-like activity, transporting S1P out of cells and glucose in. We demonstrate that SPNS2 directly binds glucose and transports it and identify key amino acid residues of SPNS2 involved in glucose engagement and import. Our data reveal that S1P, which enters from the cytosolic side of SPNS2 facilitates conformational changes, enabling extracellular glucose to move inward through the central cavity. Thus, we identify a mechanism that dynamically contributes to glucose homeostasis in response to metabolic and sphingolipid cues with clinical and pathophysiological implications.

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Publication Details

Journal
Nature Communications
Published
2026-04-20
DOI
https://doi.org/10.1038/s41467-026-71659-7
Primary Topic
Sphingolipid Metabolism and Signaling
Type
article
Field-Weighted Citation Impact
0.00

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article

SPNS2 exports sphingosine-1-phosphate and imports glucose

Frank Corwin, Cynthia Weigel, Sarah Spiegel, Can E. Senkal et al.
Nature Communications
Sphingolipid Metabolism and Signaling
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SPNS2 exports sphingosine-1-phosphate and imports glucose

Frank Corwin, Cynthia Weigel, Sarah Spiegel, Can E. Senkal, Huanyu Li, Francesco S. Celi, Elisa N.D. Palladino, Md Lokman Hossen, Sumit Saha, David B. Sauer, Christopher D. Green, Prem P. Chapagain, Bin Ni, Ryan D. R. Brown, Xianjun Fang, Jason Newton
article en

Abstract

Spinster homolog 2 (SPNS2) exports the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) out of cells to regulate processes important for health and diseases. However, the molecular mechanism underlying SPNS2 transport functions and its precise physiological roles are not fully understood. Here, through a series of complementary approaches in mice, cellular assays, and particularly with in vitro cell-free binding and transport assays, we show that SPNS2 has antiporter-like activity, transporting S1P out of cells and glucose in. We demonstrate that SPNS2 directly binds glucose and transports it and identify key amino acid residues of SPNS2 involved in glucose engagement and import. Our data reveal that S1P, which enters from the cytosolic side of SPNS2 facilitates conformational changes, enabling extracellular glucose to move inward through the central cavity. Thus, we identify a mechanism that dynamically contributes to glucose homeostasis in response to metabolic and sphingolipid cues with clinical and pathophysiological implications.

Nature CommunicationsVol. 17(1)
Virginia Commonwealth University (US), Florida International University (US), University of Barishal (BD), University of Oxford (GB), Keele University (GB), UConn Health (US)
Virginia Commonwealth University, National Institutes of Health, School of Medicine, Virginia Commonwealth University, National Cancer Institute, National Institute of General Medical Sciences
Zero hunger
Openalex Percentile: Top 21%
Sphingolipid Metabolism and Signaling
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