Affinage

MFSD1

Lysosomal dipeptide transporter MFSD1 · UniProt Q9H3U5

Length
465 aa
Mass
51.2 kDa
Annotated
2026-06-10
15 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MFSD1 is a non-glycosylated lysosomal membrane protein of the major facilitator superfamily that functions as a general uniporter exporting dipeptides—the products of lysosomal proteolysis—from the lysosomal lumen to the cytoplasm (PMID:31661432, PMID:38839979). It is delivered to lysosomes via a dileucine-based sorting motif and forms a tightly linked, mutually stabilizing complex with the accessory subunit GLMP, each protein being required to maintain the other's lysosomal levels (PMID:31661432); the complex additionally associates with GIMAP5, whose stability depends on MFSD1/GLMP and which is critical for lymphocyte development and liver homeostasis (PMID:38055739). A cryo-EM structure of the dipeptide-bound MFSD1-GLMP heterodimer in an outward-open conformation, together with proteoliposome reconstitution and electrophysiology, defines the heterodimer interface and a selectivity for cationic, neutral, and anionic dipeptides, with strongest transport of dipeptides containing lysine, arginine, or histidine and exclusion of single amino acids and tripeptides (PMID:38839979, PMID:38507452). Loss of MFSD1 causes lysosomal accumulation of cationic dipeptides and produces splenomegaly, severe liver disease, lymphopenia, and extramedullary hematopoiesis in mice (PMID:31661432, PMID:38055739, PMID:38507452). Beyond its lysosomal transport role, MFSD1 also promotes recycling of endocytosed inactive β1 integrin to suppress integrin activation and tumor cell migration (PMID:35211397).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2019 High

    Establishing where MFSD1 resides and with whom it partners was the first step toward assigning function; this showed MFSD1 is a lysosomal MFS protein in an obligate complex with GLMP whose loss causes organ disease.

    Evidence Knockout mice, lysosome proteomics, Co-IP, and sorting-motif mutagenesis

    PMID:31661432

    Open questions at the time
    • Did not identify the transported substrate
    • Mechanism linking complex loss to liver disease unresolved
  2. 2023 High

    Extending the complex membership clarified why MFSD1 loss causes immune and hepatic pathology by showing MFSD1 and GLMP stabilize GIMAP5, linking the transporter to lymphocyte development.

    Evidence ENU mutagenesis screen, germline knockouts of Mfsd1/Glmp/Gimap5, and proteomics of MFSD1-associated proteins

    PMID:38055739

    Open questions at the time
    • Does not explain how GIMAP5 stabilization mechanistically requires transport activity
    • Direct binding topology of the tripartite complex not resolved
  3. 2024 High

    The long-standing question of MFSD1's substrate and transport mechanism was answered by defining the MFSD1-GLMP complex as a dipeptide uniporter with a structurally resolved selectivity filter.

    Evidence Untargeted/targeted lysosomal metabolomics, proteoliposome transport assays, Xenopus oocyte and HEK293 patch-clamp electrophysiology, and cryo-EM of the dipeptide-bound outward-open complex with MD simulations

    PMID:38507452 PMID:38839979

    Open questions at the time
    • Conformational cycle beyond the outward-open state not captured
    • Physiological consequence of dipeptide export for downstream metabolism not traced
  4. 2022 Medium

    A distinct cellular role was uncovered, implicating MFSD1 in membrane trafficking by showing it recycles inactive β1 integrin and thereby restrains tumor cell migration.

    Evidence MFSD1 knockout tumor cells, integrin recycling and focal-adhesion turnover assays, and mouse metastasis models

    PMID:35211397

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Relationship between lysosomal dipeptide transport and integrin recycling not established
  5. 2019 Medium

    A conserved organismal role was indicated by demonstrating that the Drosophila ortholog regulates protein O-glycosylation for macrophage tissue invasion, with human MFSD1 rescuing the defect.

    Evidence Drosophila mutant rescue with human MFSD1, O-glycoproteomics, and macrophage migration phenotyping

    PMID:30910009

    Open questions at the time
    • How a lysosomal dipeptide transporter influences glycosylation is undefined
    • Direct versus indirect effect on T-antigen display unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MFSD1's defined dipeptide-export activity mechanistically connects to GIMAP5 stabilization, β1 integrin recycling, and conserved glycosylation effects remains unresolved.
  • No mechanism unifying transport activity with trafficking and immune phenotypes
  • Full transport cycle conformations not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005764 lysosome 3
Pathway
R-HSA-382551 Transport of small molecules 2
Partners
GIMAP5GLMP
Complex memberships
MFSD1-GLMP heterodimerMFSD1-GLMP-GIMAP5 complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 MFSD1 localizes to lysosomes via a dileucine-based sorting motif and is not N-glycosylated. MFSD1 physically interacts with GLMP (glycosylated lysosomal membrane protein), forming a tightly linked lysosomal membrane protein transporter complex. GLMP is essential for maintaining normal MFSD1 levels in lysosomes, and vice versa. Mfsd1 knockout mice develop splenomegaly and severe liver disease. Knockout mouse model, lysosome isolation, proteomics, co-immunoprecipitation, mutational analysis of sorting motif, glycosylation assays eLife High 31661432
2023 MFSD1 forms a protein complex with both GLMP and GIMAP5 (GTPase of immunity-associated protein 5). The interactions of MFSD1 and GLMP with GIMAP5 are essential for maintaining normal GIMAP5 expression, which in turn is critical for lymphocyte development and liver homeostasis. Germline knockout of Mfsd1, Glmp, or Gimap5 each caused lymphopenia, liver pathology, extramedullary hematopoiesis, and lipid deposition. ENU mutagenesis screen, germline knockout mice, proteomic analysis of MFSD1-associated proteins, phenotypic characterization of Mfsd1/Glmp/Gimap5 knockout mice Proceedings of the National Academy of Sciences of the United States of America High 38055739
2024 MFSD1, in complex with GLMP, functions as a general lysosomal dipeptide uniporter that exports cationic, neutral, and anionic dipeptides. Untargeted metabolomics of MFSD1-deficient mouse lysosomes revealed accumulation of cationic dipeptides. Cryo-EM structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and substrate selectivity. Molecular dynamics simulations provided a structural basis for dipeptide selectivity. Untargeted metabolomics of isolated lysosomes, purified protein dipeptide binding assays, electrophysiology in Xenopus oocytes, isotope tracer studies, fluorescence-based transport assays in proteoliposomes, cryo-EM structure determination, molecular dynamics simulations Nature cell biology High 38839979
2024 MFSD1 acts as a highly selective lysosomal uniporter for dipeptides containing lysine, arginine, or histidine residues. Targeted metabolomics showed accumulation of cationic dipeptides in MFSD1-deficient lysosomes. Whole-cell patch-clamp electrophysiology of HEK293 cells expressing MFSD1 at the cell surface showed transport affinities in the lower mM range for positively charged dipeptides. Single amino acids, tripeptides, and negatively charged dipeptides were not transported. Targeted metabolomics of MFSD1-deficient lysosomes, whole-cell patch-clamp electrophysiology in HEK293 cells Proceedings of the National Academy of Sciences of the United States of America High 38507452
2019 The Drosophila MFSD1 ortholog (Minerva) regulates O-glycosylation (specifically T-antigen levels) on a subset of proteins in macrophages to enable tissue invasion. Human MFSD1 rescues the minerva mutant's migration and T-antigen glycosylation defects, establishing functional conservation. Minerva/MFSD1 promotes T-antigen display most strongly on the sulfhydryl oxidase Qsox1, which is required for macrophage tissue entry. Drosophila genetic mutant rescue with human MFSD1, O-glycoproteomics, loss-of-function phenotypic analysis of macrophage migration eLife Medium 30910009
2022 MFSD1 promotes recycling of endocytosed inactive β1 integrin to the cell surface, protecting it from proteolytic degradation and thereby reducing the integrin activation index. Loss of MFSD1 leads to increased focal adhesion turnover, reduced stability of mature inactive β1 integrin, increased integrin activation, and greater tumor cell migration and metastasis in mouse models. MFSD1 knockout tumor cells and mouse metastasis models (experimental and spontaneous), integrin recycling assays, focal adhesion turnover measurements, integrin activation index quantification Frontiers in oncology Medium 35211397
2016 MFSD1 protein localizes along the plasma membrane in neurons, and its expression is upregulated in mouse embryonic primary cortex cells upon amino acid deprivation, suggesting a nutrient-sensing role. Homology modelling predicts 12 transmembrane regions consistent with MFS transporter topology. Immunofluorescence/protein staining in neurons, amino acid starvation of primary cortex cells with mRNA quantification, homology modelling Journal of molecular neuroscience : MN Low 27981419

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Therapeutic regulation of autophagy in hepatic metabolism. Acta pharmaceutica Sinica. B 121 35127371
2017 Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression. Open biology 44 28878041
2010 Long evolutionary conservation and considerable tissue specificity of several atypical solute carrier transporters. Gene 43 21044875
2016 The Novel Membrane-Bound Proteins MFSD1 and MFSD3 are Putative SLC Transporters Affected by Altered Nutrient Intake. Journal of molecular neuroscience : MN 32 27981419
2019 The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP. eLife 26 31661432
2019 A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion. eLife 20 30910009
2021 Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample. Biological psychiatry global open science 10 36324662
2023 Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis. Proceedings of the National Academy of Sciences of the United States of America 9 38055739
2024 MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes. Nature cell biology 8 38839979
2023 Liver sinusoidal endothelial cells show reduced scavenger function and downregulation of Fc gamma receptor IIb, yet maintain a preserved fenestration in the Glmpgt/gt mouse model of slowly progressing liver fibrosis. PloS one 7 37910485
2022 The Solute Carrier MFSD1 Decreases the Activation Status of β1 Integrin and Thus Tumor Metastasis. Frontiers in oncology 6 35211397
2018 Screening of Genetic Factor in the Interaction Between Periodontitis and Metabolic Traits Using Candidate Gene Association Study (CGAS). Biochemical genetics 6 30547318
2024 Orphan lysosomal solute carrier MFSD1 facilitates highly selective dipeptide transport. Proceedings of the National Academy of Sciences of the United States of America 4 38507452
2026 Candidate genes related to growth and milk production in three Anatolian goats revealed by GWAS. Mammalian genome : official journal of the International Mammalian Genome Society 1 41629519
2025 The Role of HbA1c in Parkinson's Disease: An Integrative Analysis by Single-Cell, Bulk Transcriptome and Mendelian Randomization. Molecular neurobiology 0 40397357

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