Spns1/SPNS1 was experimentally deorphanized as a proton-dependent lysosomal transporter selective for the lysophospholipids LPC and LPE, defining a lysosomal phospholipid salvage pathway.

Spns1 deficiency causes lysosomal accumulation of LPC and LPE with pathological consequences on lysosomal function across cells, zebrafish embryos, and mouse liver.

Spns1 was described as a lysosomal transporter functioning at a late stage of autophagy.

Beclin 1 suppression ameliorates senescence caused by Spns1 deficiency.

In zebrafish, spns1 acts cell-autonomously in the endocardium; spns1 mutants show abnormal endocardial organization, impaired valve formation and retrograde blood flow, with endocardial-specific differences in lysosome-related genes and altered Notch signalling.

Endocardial-specific overexpression rescues valve formation, revealing a cell-autonomous role for lysosomal processing in cardiac valve morphogenesis upstream of the molecular transporter core.

SPNS1 is required for release of LPC and sphingosine from lysosomes; Spns1 loss causes accumulation of sphingosine, LPC and LPE and produces lysosomal storage disease phenotypes in mouse models.

The sphingosine substrate assignment is reported alongside lysoglycerophospholipids, but is a lower-confidence secondary claim relative to the directly demonstrated LPC/LPE transport.

UniProt describes Spns1 as a proton-dependent lysosomal lysophospholipid efflux transporter.

The transported substrate class is lysophospholipids.

Falcon synthesizes that zebrafish Spns1 was experimentally deorphanized as a proton-dependent lysophospholipid transporter, the best-supported primary molecular function.

The demonstrated substrate specificity is for the zwitterionic lysophospholipids lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE).

The integrated best-supported function is a lysosomal proton-coupled exporter of LPC and LPE enabling lysosomal phospholipid salvage.

Transport is pH-dependent with an acidic optimum (~5-6), consistent with proton coupling for an MFS transporter operating at the lysosome; conserved residues R76, E164, and H427 are required for activity.

Conserved residues R76, E164, and H427 are experimentally implicated in transport activity.

Spns1 is primarily a lysosomal/late-endosomal membrane protein, colocalizing with LAMP1 and Rab7 in mammalian systems.

In zebrafish, spns1 (nrs) is required cell-autonomously in endocardial cells for lysosomal/autophagic processing enabling cardiac valve morphogenesis through notch1 signaling.

A mammalian genetics study additionally argues SPNS1 is required for lysosomal sphingosine release, but this is less certain than LPC/LPE export; the highest-confidence substrate assignment remains LPC/LPE.

The highest-confidence substrate assignment across studies remains LPC/LPE.

Falcon confirms the target zebrafish spns1/nrs matches UniProt Q7ZU13 as a spinster-family MFS transporter.