Spinster homolog 2 (Spns2) is an S1P transporter, with S1P being a crucial signaling sphingolipid involved in regulating the immune system, angiogenesis, auditory function, and epithelial and endothelial barrier integrity. Spns2 exports S1P to initiate lipid signaling cascades, and its activity modulation shows potential in treating cancer, inflammation, and immune diseases [1,3,4].

In macrophages, Spns2 deficiency significantly enhances glycolysis, increasing intracellular lactate production. The overactive lactate-ROS axis then drives lethal hyperinflammation during the early sepsis phase, and diminished Spns2/S1P signaling leads to innate immunosuppression in the late-stage of infection [2]. In T-cell egress, Spns2 supplies the S1P that guides T-cells out of lymph nodes during an immune response, and its deletion is protective in a mouse model of multiple sclerosis [5]. In endothelial cells, Spns2 deficiency drives cell senescence and vascular aging by promoting pyruvate-metabolism-mediated mitochondrial dysfunction [6].

In conclusion, Spns2 plays essential roles in multiple biological processes, mainly through its function in transporting S1P. Studies using gene knockout or conditional knockout mouse models have revealed its significance in diseases such as sepsis, multiple sclerosis, and vascular aging, highlighting its potential as a therapeutic target.

References:

1. Chen, Hongwen, Ahmed, Shahbaz, Zhao, Hongtu, Li, Xiaochun, Lee, Chia-Hsueh. 2023. Structural and functional insights into Spns2-mediated transport of sphingosine-1-phosphate. In Cell, 186, 2644-2655.e16. doi:10.1016/j.cell.2023.04.028. https://pubmed.ncbi.nlm.nih.gov/37224812/

2. Fang, Chao, Ren, Pan, Bian, Ganlan, Li, Mingkai, Hou, Zheng. 2023. Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis. In EMBO reports, 24, e56635. doi:10.15252/embr.202256635. https://pubmed.ncbi.nlm.nih.gov/37358015/

3. Zhu, Xiao, Ren, Kun, Zeng, Yong-Zhi, Zheng, Zhi, Yi, Guang-Hui. 2018. Biological function of SPNS2: From zebrafish to human. In Molecular immunology, 103, 55-62. doi:10.1016/j.molimm.2018.08.025. https://pubmed.ncbi.nlm.nih.gov/30196234/

4. Spiegel, Sarah, Maczis, Melissa A, Maceyka, Michael, Milstien, Sheldon. 2019. New insights into functions of the sphingosine-1-phosphate transporter SPNS2. In Journal of lipid research, 60, 484-489. doi:10.1194/jlr.S091959. https://pubmed.ncbi.nlm.nih.gov/30655317/

5. Okuniewska, Martyna, Fang, Victoria, Baeyens, Audrey, Littman, Dan R, Schwab, Susan R. . SPNS2 enables T cell egress from lymph nodes during an immune response. In Cell reports, 36, 109368. doi:10.1016/j.celrep.2021.109368. https://pubmed.ncbi.nlm.nih.gov/34260944/

6. Tang, Haojun, Gao, Pan, Peng, Weng, Yin, Kai, Zhu, Xiao. 2024. Spinster homolog 2 (SPNS2) deficiency drives endothelial cell senescence and vascular aging via promoting pyruvate metabolism mediated mitochondrial dysfunction. In Cell communication and signaling : CCS, 22, 492. doi:10.1186/s12964-024-01859-5. https://pubmed.ncbi.nlm.nih.gov/39394598/