Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport

• 成果类型: Article
• 署名作者: Boytsov, Danila; Madej, Gregor M.; Horn, Georg; Blaha, Nadine; Koecher, Thomas; Sitte, Harald H.; Siekhaus, Daria; Ziegler, Christine; Sandtner, Walter; Roblek, Marko
• 署名单位: University of California System; University of California Los Angeles; Medical University of Vienna; University of Regensburg; Vienna Biocenter (VBC); Al-Ahliyya Amman University; Medical University of Vienna; Institute of Science & Technology - Austria
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11180
• DOI: 10.1073/pnas.2319686121
• 发表日期: 2024-03-26
• 关键词: leucine methyl-ester; pot family; oligopeptide transporter; cytotoxic lymphocytes; peptide transporters; slc transporters; cloning; mechanism; expression; proteins

摘要

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.