Structural basis of Sphingosine-1-phosphate transport via human SPNS2
Yaning Duan, Nancy C.P. Leong, Jing Zhao, Yu Zhang, Dat T. Nguyen, Hoa T. T. Ha, Na Wang, Ruixue Xia, Zhenmei Xu, Zhengxiong Ma, Yu Qian, Han Yin, Xinyan Zhu, Anqi Zhang, Changyou Guo, Yu Xia, Long N. Nguyen, Yuanzheng He
Abstract
Sphingosine 1-phosphate (S1P) plays crucial roles in various physiological processes, including immune response, vascular development, and neural system homeostasis 1 through activating S1P receptors (S1PRs). Notably, a desirable concentration gradient of S1P which is achieved by S1P transporters, including spinster homolog 2 protein (SPNS2) and MFSD2B that transport S1P from the intracellular side to the extracellular side of cells, 2 , 3 is essential for proper S1P signaling. SPNS2 and MFSD2B belong to the major facilitator superfamily (MFS), and specifically, SPNS2 belongs to the endosomal spinster subfamily. 4 S1PR modulators, such as Fingolimod (FTY720), have been approved for treating multiple sclerosis. 1 Nevertheless, S1PR modulators often exert undesirable effects on the patients, highlighting the need for a better target. Recent findings suggested that targeting SPNS2 has shown promise in reducing disease severity of autoimmune diseases. 5 , 6 Together with the fact that the reported lysolipid transporter MFSD2A 7 , 8 and a bacterial homolog of spinster Hyphomonas neptunium ( Hn SPNS) structures 9 can only offer limited insights into the S1P transport mechanism due to their low sequence homology (Supplementary information, Fig. S1 ), suggesting an imminent need for the structural determination of SPNS2.