Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport

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 potent...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (13), p.e2319686121-e2319686121
Main Authors: Boytsov, Danila, Madej, Gregor M, Horn, Georg, Blaha, Nadine, Köcher, Thomas, Sitte, Harald H, Siekhaus, Daria, Ziegler, Christine, Sandtner, Walter, Roblek, Marko
Format: Article
Language:English
Subjects:
Amino acids
Arginine - metabolism
Biological Sciences
Biological Transport
Cell surface
Current carriers
Dipeptides - metabolism
HEK293 Cells
Histidine
Humans
Lysine
Lysine - metabolism
Lysosomes
Lysosomes - metabolism
Membrane Transport Proteins - metabolism
Metabolomics
Molecular biology
Phosphoproteins - metabolism
Phylogeny
Substrates
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2319686121