Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport

Abstract

Orphan solute carrier (SLC) represents a group of membrane transporters whose exact functions and substrate specificities are not known. Elucidating the function and regulation of orphan SLC transporters is not only crucial for advancing our knowledge of cellular and molecular biology but can potentially lead to the development of new therapeutic strategies. Here, we provide evidence for the biological function of a ubiquitous orphan lysosomal SLC, the Major Facilitator Superfamily Domain-containing Protein 1 (MFSD1), which has remained phylogenetically unassigned. Targeted metabolomics revealed that dipeptides containing either lysine or arginine residues accumulate in lysosomes of cells lacking MFSD1. Whole-cell patch-clamp electrophysiological recordings of HEK293-cells expressing MFSD1 on the cell surface displayed transport affinities for positively charged dipeptides in the lower mM range, while dipeptides that carry a negative net charge were not transported. This was also true for single amino acids and tripeptides, which MFSD1 failed to transport. Our results identify MFSD1 as a highly selective lysosomal lysine/arginine/histidine-containing dipeptide exporter, which functions as a uniporter.

MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes

“…During the revision of our manuscript, another study identified MFSD1 as a lysosomal dipeptide uniporter based on the accumulation of dipeptides with at least one cationic residue in MFSD1-defective lysosomes and the electrogenic transport of such dipeptides 65 . The authors concluded that MFSD1 is highly specific for this subset of dipeptides.…”