SPNS2 beyond sphingosine-1-phosphate transport: Emerging roles in glucose uptake and transcriptional regulation in endothelial cells.

Abstract

Spinster homolog 2 (SPNS2), a member of the major facilitator superfamily transporter, is best known for exporting sphingosine-1-phosphate (S1P), thereby regulating vascular signaling, lymphocyte trafficking, and immune responses. We recently identified SPNS2 as a glucose importer that couples extracellular glucose uptake to intracellular S1P export, revealing a new link between cellular metabolism and S1P pathways. Here, we examined the functional and transcriptional consequences of SPNS2 activity in endothelial cells. SPNS2 overexpression enhances S1P export, glucose uptake, and endothelial cell proliferation. RNA sequencing of these SPNS2-overexpressing endothelial cells revealed extensive transcriptional reprogramming. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed enrichment of oxidative phosphorylation, cell-cycle progression, PPAR signaling, lysosomal and vesicular trafficking, cytoskeletal remodeling, and biosynthetic processes. In contrast, pathways associated with apoptosis, antigen processing and presentation, interferon responses, cell adhesion, and inflammatory signaling were reduced. These findings suggest that SPNS2 coordinates S1P export with glucose import to promote a metabolically active, proliferative, and remodeling endothelial phenotype while limiting inflammatory activation. The dual transport activity of SPNS2 expands its physiological significance and suggests a potential new mechanistic and therapeutic link between S1P signaling, glucose homeostasis, vascular function, immunity, and disease.