SPNS1 is required for the transport of lysosphingolipids and lysoglycerophospholipids from lysosomes

Abstract

Accumulation of sphingolipids, especially sphingosines, in the lysosomes is attributed to the pathogenesis of several lysosomal storage diseases. In search for a lysosomal protein that mediates the release of sphingosines, we identified SPNS1 which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter. We generated knockout cells and mice for Spns1 and employed lipidomics and metabolomics to identify SPNS1 ligands. We found that knockouts of Spns1 resulted in the accumulation of sphingolipids, including sphingosines in embryonic brains and cell lines. These results suggest that deficiency of SPNS1 affects the clearance of sphingolipids in lysosomes. Biochemical assays demonstrated that sphingosines released from lysosomes required SPNS1. Furthermore, by performing a comprehensive analysis of metabolites from livers of postnatal Spns1 knockout mice (gSpns1-cKO), we detected a striking accumulation of lysoglycerophospholipids including LPC, LPE, LPG, and lysoplasmalogens. Interestingly, the release of these lysoglycerophospholipids also required SPNS1. Global knockout of Spns1 (gSpns1-KO) resulted in embryonic lethality between E12.5-E13.5 with developmental defects. Postnatal deletion of Spns1 in mice caused lipid accumulation in the lysosomes and pathological conditions reminiscent of lysosomal storage diseases. These results reveal a critical molecular role of SPNS1 as a transporter for lysosphingolipids and lysoglyerophospholipids from the lysosomes and link its physiological functions with lysosomal storage diseases.

The sterol transporter STARD3 transports sphingosine at ER-lysosome contact sites

“…Contrary to STARD3 overexpression, the absence of STARD3 resulted only in a mild sphingosine accumulation phenotype, far less pronounced than when lysosomal transporters such as NPC1 36 or Spns1 37 are absent, presuming the export from lysosomal lumen to the lysosomal limiting membrane as the bottle-neck. Considering that sphingosine recycling fulfills a significant portion (50 - 90%) of the demand for long-chain base in the synthesis of cellular sphingolipids 38 , it is likely that other inter-organellar transporters or additional transport mechanisms such as spontaneous diffusion may share the task of transporting lysosomal sphingosine to target organelles.…”