Affinage

GLMP

Glycosylated lysosomal membrane protein · UniProt Q8WWB7

Length
406 aa
Mass
43.9 kDa
Annotated
2026-06-10
13 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLMP (NCU-G1/C1orf85) is a heavily N-glycosylated integral lysosomal membrane protein that functions as an obligate accessory subunit of the major facilitator superfamily transporter MFSD1, together constituting a lysosomal dipeptide transport machine (PMID:19489740, PMID:31661432, PMID:38839979). Its lysosomal localization depends on a tyrosine-based sorting motif at position 400 in its C-terminal tail, and extensive N-glycosylation accounts for its apparent mass of ~70–80 kDa well above the ~39 kDa predicted from sequence (PMID:19489740). GLMP and MFSD1 physically interact and each is required to maintain normal lysosomal levels of the other, and the MFSD1–GLMP heterodimer operates as a general dipeptide uniporter transporting cationic, neutral, and anionic dipeptides, with a cryo-EM structure of the dipeptide-bound complex in an outward-open state defining the heterodimer interface and the structural basis for substrate selectivity (PMID:31661432, PMID:38839979). The complex additionally associates with GIMAP5 and is required to maintain its expression, supporting lymphocyte survival and liver homeostasis (PMID:38055739). Consistent with these roles, loss of GLMP in mice produces progressive liver fibrosis with hepatocyte death, oxidative stress, and lysosomal pigment accumulation, along with hepatic and muscle metabolic dysregulation and lymphopenia (PMID:24487409, PMID:26047317, PMID:26707125, PMID:38055739). GLMP expression is controlled by chromatin and epitranscriptomic regulators, being repressed by BRG1 at its promoter and stabilized by NAT10-mediated ac4C mRNA modification, and elevated GLMP has been linked to signaling changes in several cancer contexts (PMID:34158256, PMID:37914704, PMID:41298761).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2007 Medium

    Initial characterization assigned GLMP a nuclear transcriptional role, the first functional hypothesis for an uncharacterized gene.

    Evidence EMSA and reporter assays in Drosophila S2 cells testing DNA binding and PPARα co-activation

    PMID:18021396

    Open questions at the time
    • Conflicts with later evidence for a lysosomal membrane localization
    • No in vivo confirmation of transcriptional or co-activator activity
    • Single lab, single study
  2. 2009 High

    Established GLMP as an integral lysosomal membrane glycoprotein, redefining its cellular compartment and identifying the determinant of its targeting.

    Evidence Immunofluorescence co-localization with LAMP-1, density-shift fractionation, sorting-motif mutagenesis, and N-glycosidase F digestion

    PMID:19489740

    Open questions at the time
    • Molecular function at the lysosome not yet identified
    • Binding partners unknown at this stage
  3. 2014 High

    Demonstrated GLMP is required for lysosomal homeostasis in vivo, linking its loss to organ pathology.

    Evidence Gene-trap knockout mouse with histological and biochemical analysis of liver fibrosis and oxidative stress

    PMID:24487409

    Open questions at the time
    • Molecular cause of fibrosis at the lysosome unresolved
    • Did not identify a transport or enzymatic activity
  4. 2015 Medium

    Extended the knockout phenotype to systemic metabolism, showing hepatic glucose and lipid dysregulation downstream of GLMP loss.

    Evidence Metabolic flux assays in primary hepatocytes and gene expression analysis from Glmp knockout mice

    PMID:26047317

    Open questions at the time
    • Mechanistic link between lysosomal dysfunction and metabolic shifts not established
    • Single lab
  5. 2016 Medium

    Showed the metabolic role extends to skeletal muscle, with a glycolytic shift and reduced fatty acid handling.

    Evidence Radiotracer metabolic assays and gene expression in primary myotubes from Glmp knockout mice

    PMID:26707125

    Open questions at the time
    • Causal mechanism connecting GLMP to PPAR-axis gene expression unknown
    • Single study
  6. 2019 High

    Identified GLMP's primary molecular partner, defining it as an obligate accessory subunit of the lysosomal transporter MFSD1.

    Evidence Lysosomal proteomics, co-immunoprecipitation, and parallel Glmp/Mfsd1 knockout phenotyping in mice

    PMID:31661432

    Open questions at the time
    • Transport substrate of the complex not yet identified
    • Stoichiometry and structure undefined
  7. 2021 Medium

    Revealed upstream chromatin control, showing BRG1 represses GLMP and that GLMP influences PI3K/AKT signaling and lipid storage in liver cancer cells.

    Evidence ChIP, siRNA knockdown, lipid staining, and pathway western blots in HCC cells

    PMID:34158256

    Open questions at the time
    • Whether signaling effects reflect lysosomal transport function unclear
    • Single lab
  8. 2023 Medium

    Defined a second regulatory layer (epitranscriptomic) and a cancer-promoting signaling output for GLMP.

    Evidence ac4C-seq, mRNA stability assays, and gain/loss-of-function with in vivo metastasis models in HNSCC

    PMID:37914704

    Open questions at the time
    • Mechanism linking GLMP levels to MAPK/ERK activation not resolved
    • Single lab
  9. 2023 High

    Connected the MFSD1–GLMP complex to immune homeostasis by identifying GIMAP5 as an associated client whose stability depends on the complex.

    Evidence ENU screen, proteomics, and parallel germline knockouts of Mfsd1, Glmp, and Gimap5 with flow cytometry and histology

    PMID:38055739

    Open questions at the time
    • Direct versus indirect nature of the GIMAP5 interaction not fully resolved
    • Mechanism by which the complex stabilizes GIMAP5 unknown
  10. 2024 High

    Resolved the molecular function of the complex as a general dipeptide uniporter and provided its structure, closing the long-standing question of what GLMP–MFSD1 transports.

    Evidence Cryo-EM of the dipeptide-bound complex, lysosomal metabolomics, and reconstituted transport in oocytes and proteoliposomes

    PMID:38839979

    Open questions at the time
    • Precise catalytic contribution of GLMP versus MFSD1 to transport not dissected
    • Physiological consequences of dipeptide accumulation in disease models not directly tested
  11. 2025 Medium

    Linked elevated GLMP to drug resistance, implicating RhoA ubiquitination, EMT, and lysosomal/autophagy hyperactivity in cancer.

    Evidence Overexpression/knockdown models, ubiquitination and autophagy flux assays, and RhoA pathway inhibition in NSCLC

    PMID:41298761

    Open questions at the time
    • Mechanism connecting GLMP transport function to RhoA ubiquitination unclear
    • Single lab, single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GLMP's defined lysosomal dipeptide transport function mechanistically produces the diverse downstream phenotypes — metabolic dysregulation, GIMAP5/lymphocyte effects, and cancer signaling outputs — remains unresolved.
  • No mechanistic bridge between dipeptide transport and hepatic/muscle metabolic shifts
  • Whether cancer signaling roles depend on transport activity untested
  • Direct substrate-level link to GIMAP5 stabilization unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0005215 transporter activity 1
Pathway
R-HSA-382551 Transport of small molecules 1
Partners
Complex memberships
MFSD1-GLMP lysosomal dipeptide uniporter

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 NCU-G1 (GLMP) binds specifically to the footprint 1 element of the human cellular retinol-binding protein 1 gene promoter (shown by EMSA) and activates transcription from this promoter; it also functions as a co-activator for ligand-activated PPARα in transiently transfected Drosophila S2 cells, increasing expression of a CAT reporter under the acyl-CoA oxidase promoter. Electrophoretic mobility shift assay (EMSA), transient transfection reporter assays in Drosophila S2 cells BMC molecular biology Medium 18021396
2009 NCU-G1 (GLMP/C1orf85) is a highly glycosylated integral lysosomal membrane protein; its lysosomal localization depends on a tyrosine-based sorting motif at position 400 in its C-terminal tail (Y→A mutation impairs lysosomal targeting), and its apparent molecular mass (~70–80 kDa) greatly exceeds calculated mass (~39 kDa) due to extensive N-glycosylation (shown by N-glycosidase F digestion). Immunofluorescence co-localization with LAMP-1, subcellular fractionation with density-shift assay, site-directed mutagenesis of sorting motif, N-glycosidase F digestion The Biochemical journal High 19489740
2014 Disruption of Ncu-g1 (Glmp) in mice causes spontaneous liver fibrosis with increased hepatocyte death, oxidative stress, active fibrogenesis, and accumulation of lipofuscin and iron in Kupffer cells, demonstrating GLMP is required for lysosomal homeostasis in liver. Gene-trap knockout mouse model, histological/immunohistochemical analysis, biochemical assays for oxidative stress and fibrogenesis markers Disease models & mechanisms High 24487409
2015 Loss of GLMP in mice (Glmp gt/gt) leads to metabolic dysregulation in liver: increased hepatic glucose flux, elevated de novo lipogenesis, lipid accumulation, and upregulation of genes for fatty acid uptake and lipogenesis, while blood glucose, triacylglycerol, and non-esterified fatty acids are reduced. Glmp knockout mouse model, primary hepatocyte metabolic flux assays, gene expression analysis PloS one Medium 26047317
2016 GLMP ablation in mouse skeletal muscle myotubes shifts metabolism toward glycolysis: Glmp gt/gt myotubes show faster glucose metabolism, larger glycogen pools, and reduced oleic acid uptake, storage, and oxidation, with decreased expression of PPARα, PPARβ/δ, PPARγ, PGC1α, and lipid metabolism genes. Primary myotubes from Glmp knockout mice, radiotracer-based metabolic assays, gene expression analysis Archives of physiology and biochemistry Medium 26707125
2019 GLMP is a critical accessory subunit of the lysosomal transporter MFSD1: MFSD1 and GLMP physically interact (co-immunoprecipitation), and each protein is required for maintenance of normal lysosomal levels of the other. Glmp knockout mice phenocopy Mfsd1 knockout mice (splenomegaly, severe liver disease), identifying a tightly linked MFSD1/GLMP lysosomal membrane protein transporter complex. Proteomics of isolated lysosomes from Mfsd1 knockout mice, co-immunoprecipitation, Glmp and Mfsd1 knockout mouse phenotyping eLife High 31661432
2021 BRG1 transcriptionally represses GLMP expression by binding to the GLMP promoter region (shown by chromatin immunoprecipitation); BRG1 knockdown increases GLMP expression, which in turn alters the PIK3AP1/PI3K/AKT pathway and reduces lipid droplet accumulation in HCC cells, and GLMP knockdown partially restores lipid droplets and pathway changes caused by BRG1 loss. Chromatin immunoprecipitation (ChIP), siRNA knockdown, lipid staining (BODIPY, Oil Red O), western blot for pathway markers Digestive and liver disease Medium 34158256
2023 NAT10 induces ac4C modification of GLMP mRNA, stabilizing it and increasing GLMP protein levels, which triggers activation of the MAPK/ERK signaling pathway to promote HNSCC cell metastasis. Gain- and loss-of-function experiments, ac4C-seq (RNA modification mapping), mRNA stability assays, in vivo mouse metastasis models Cell death & disease Medium 37914704
2023 MFSD1 and GLMP each associate with GIMAP5 (identified by proteomics); GLMP and MFSD1 interactions with GIMAP5 are essential for maintaining normal GIMAP5 expression, which is required for lymphocyte survival and liver homeostasis. Germline knockout of Glmp causes lymphopenia, liver pathology, extramedullary hematopoiesis, and lipid deposition. ENU mutagenesis screen, proteomic analysis, germline knockout mouse models for Mfsd1, Glmp, and Gimap5, flow cytometry, histology Proceedings of the National Academy of Sciences of the United States of America High 38055739
2024 MFSD1 forms a tight complex with GLMP in the lysosomal membrane and together they function as a general dipeptide uniporter: purified MFSD1 selectively binds diverse dipeptides; MFSD1-GLMP transports cationic, neutral, and anionic dipeptides as a uniporter (shown by electrophysiology, isotope tracer, and fluorescence assays in Xenopus oocytes and proteoliposomes). Cryo-EM structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation defined the heterodimer interface and structural basis for dipeptide selectivity. Cryo-EM structure determination, untargeted metabolomics of MFSD1-deficient mouse lysosomes, electrophysiology in Xenopus oocytes, isotope tracer transport assays, fluorescence transport assays in proteoliposomes, molecular dynamics simulations Nature cell biology High 38839979
2025 GLMP overexpression in non-small cell lung cancer cells promotes EGFR-TKI (osimertinib) resistance by regulating RhoA ubiquitination, activating the RhoA pathway to drive EMT, and activating the late stage of autophagy via lysosomal hyperactivity. In vitro and in vivo overexpression/knockdown models, ubiquitination assays, RhoA pathway inhibition, autophagy flux assays NPJ precision oncology Medium 41298761

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation. Hepatology (Baltimore, Md.) 90 30865310
2023 N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway. Cell death & disease 39 37914704
2019 The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP. eLife 26 31661432
2014 Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells. Disease models & mechanisms 21 24487409
2009 NCU-G1 is a highly glycosylated integral membrane protein of the lysosome. The Biochemical journal 20 19489740
2021 BRG1 regulates lipid metabolism in hepatocellular carcinoma through the PIK3AP1/PI3K/AKT pathway by mediating GLMP expression. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 15 34158256
2015 Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver. PloS one 13 26047317
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
2016 Increased glucose utilization and decreased fatty acid metabolism in myotubes from Glmp(gt/gt) mice. Archives of physiology and biochemistry 9 26707125
2016 Age-dependent development of liver fibrosis in Glmp (gt/gt) mice. Fibrogenesis & tissue repair 9 27141234
2024 MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes. Nature cell biology 8 38839979
2007 Human NCU-G1 can function as a transcription factor and as a nuclear receptor co-activator. BMC molecular biology 7 18021396
2025 GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer. NPJ precision oncology 5 41298761

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