SPNS2 exports sphingosine-1-phosphate and imports glucose, 2026, Weigel et al.

[SNT Gatchaman]

SPNS2 exports sphingosine-1-phosphate and imports glucose

Spoiler: Authors

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

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.

Web | DOI | PDF | Nature Communications | Open Access

 

[SNT Gatchaman]

S1P has come up previously (see tag).

Cellular levels of sphingosine exceed those of S1P by one to two orders of magnitude and can be rapidly replenished through the degradation of complex sphingolipids.

Our findings raised an intriguing question of the biological functions for coupling S1P export to glucose import. It is well accepted that in response to various stimuli (growth factors, hormones, cytokines, chemokines), S1P synthesized intracellularly by activation of sphingosine kinase, is exported out of cells by SPNS2, and activates the ubiquitously expressed S1PRs on the cell surface in an autocrine or paracrine manner to regulate numerous essential physiological processes important in health and diseases.

In addition to EC, lymphendothelial cells, epithelial and cancer cells, a variety of other cell types including pericytes, monocytes, macrophages, smooth muscle cells and microglia 58 have been reported to express SPNS2 which is a central component of the inside-out signaling by S1P.

Consistent with previous reports, we also confirmed that SPNS2 is expressed in multiple tissues, and as an example, demonstrated its distribution in the kidney. Together, these findings indicate that SPNS2 is not restricted to a specific cell type or tissue but is broadly expressed and functionally active across diverse cell populations. This broad expression supports its physiological relevance for inside-out signaling by S1P. The bidirectional coupling provides a mechanistic framework linking metabolic regulation and S1P signaling, a connection not previously established in eukaryotic transport biology.

The mechanistic insight that SPNS2 couples glucose import to S1P signaling has broad implications not only to endothelial biology and glucose homeostasis, but also for the understanding of the inside-out signaling by S1P which plays a vital role in both normal physiology and disease pathology. We have shown here that the autocrine action of inside-out signaling by S1P depends on glucose import by SPNS2. Thus, this autocrine loop uptake of glucose by SPNS2 is crucial for promoting cell growth, facilitating cell migration during wound healing, and as suggested previously, may also contribute to vascular barrier function.

Simultaneous uptake of glucose is needed to provide cells with metabolic energy required for these biological processes. The additional function of SPNS2 described here may provide a mechanism to rapidly obtain glucose during S1P release and S1P/S1PR signaling so cells are bioenergetically prepared for responses to environmental stimuli.