Many lysosomal transporters use the pH gradient to transport a diverse array of substances, thus maintaining the internal environment of lysosomes. Spns1 has recently been identified to export lysophospholipids across lysosomal membranes to the cytosol. Patients with a homozygous mutation in Spns1 develop symptoms reminiscent of lysosomal storage diseases, highlighting its physiological significance. Our structure of human Spns1 in complex with an LPC substrate, along with functional analysis and molecular dynamics simulations, uncovers the transport mechanism of Spns1-mediated lysophospholipid export from the lysosome. It also highlights that the ability of lysosomal transporters to sense protons might not rely solely on one acidic residue, but rather on an interaction network of several residues to control transporter dynamics.<\/p>\n