Affinage

SLC37A4

Glucose-6-phosphate exchanger SLC37A4 · UniProt O43826

Length
429 aa
Mass
46.4 kDa
Annotated
2026-06-10
29 papers in source corpus 9 papers cited in narrative 8 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

SLC37A4 encodes the endoplasmic reticulum glucose-6-phosphate transporter (G6PT), an ER membrane antiporter that imports cytosolic glucose-6-phosphate (G6P) into the ER lumen in exchange for inorganic phosphate, delivering G6P for hydrolysis by glucose-6-phosphatase (PMID:41225049, PMID:37238286). Cryo-EM structures captured in four functional states define an alternating-access mechanism in which a single conserved substrate-binding pocket switches between cytoplasm-facing and lumen-facing conformations and selects G6P versus Pi by electrostatic complementarity, with the inhibitor S-4048 trapping a cytoplasm-facing state by occluding the cytosolic entry pathway (PMID:41225049). Beyond bulk glucose metabolism, in neutrophils G6PT transports 1,5-anhydroglucitol-6-phosphate into the ER for detoxification by G6PC3, and its loss causes neutrophil dysfunction through accumulation of this hexokinase inhibitor (PMID:37238286). The transporter is ER-retained, and a dominant truncating mutation (p.Arg423*) that abolishes its ER retention signal mislocalizes the protein toward the Golgi, perturbing Golgi morphology, lowering intraluminal pH, and producing a congenital disorder of glycosylation with abnormal serum N-glycans rather than glycogen storage disease (PMID:33964207, PMID:33728255, PMID:32884905). SLC37A4 deficiency also triggers ER stress, the unfolded protein response, and apoptosis in renal and leukocyte models (PMID:30951856).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2019 Medium

    Established that loss of SLC37A4 has cell-autonomous consequences beyond metabolic substrate handling, linking its deficiency to ER stress and cell death.

    Evidence CRISPR/Cas9 SLC37A4 knockout in Flp-In T-REx-293 kidney cells with RT-qPCR of UPR and apoptosis markers

    PMID:30951856

    Open questions at the time
    • Single cell line and single lab
    • Did not connect ER stress to transport activity directly
    • No in vivo renal phenotype
  2. 2020 Medium

    Resolved why some SLC37A4 mutations cause glycosylation disease rather than glycogen storage disease, by showing a dominant mutation redirects the transporter from the ER to the Golgi.

    Evidence Mutation identification and subcellular localization studies

    PMID:32884905

    Open questions at the time
    • Mechanism connecting mislocalization to glycosylation defects not fully resolved
    • Single lab
  3. 2020 Low

    Reinforced the ER-stress/apoptosis axis of SLC37A4 deficiency in patient-derived material, implicating it in the leukocytopenia of GSD-Ib.

    Evidence Whole-exome sequencing and RT-qPCR/caspase assays in leukocytes from a single GSD-Ib patient (p.P119L)

    PMID:33280276

    Open questions at the time
    • Single patient sample with no isogenic control or rescue
    • Correlative marker data only
    • Cannot separate transporter loss from secondary effects
  4. 2021 High

    Defined the molecular basis of the SLC37A4-CDG by showing the p.Arg423* truncation removes the ER retention signal, mislocalizing the transporter and disrupting Golgi function and N-glycosylation.

    Evidence CRISPR base-edited isogenic hepatoma cells, immunofluorescence, serum/cell N-glycan profiling, iPSC-derived models, confirmed in an independent patient

    PMID:33728255 PMID:33964207

    Open questions at the time
    • Exact non-Golgi compartment of mislocalization not definitively identified
    • Causal chain from mislocalization to Golgi pH change incomplete
  5. 2023 Medium

    Extended SLC37A4 substrate scope beyond G6P, showing it imports 1,5-anhydroglucitol-6-phosphate for detoxification in neutrophils, explaining neutrophil dysfunction in GSD1b.

    Evidence Biochemical analysis of GSD1b patient samples, metabolite measurement, and SGLT2-inhibitor rescue

    PMID:37238286

    Open questions at the time
    • Primarily a review/analysis paper
    • Direct transport assay of 1,5-AG6P not shown in this entry
    • Tissue-specific substrate preferences unclear
  6. 2024 Medium

    Identified a non-metabolic, epithelial-barrier role wherein SLC37A4 supports tight-junction integrity through an HMX3-JAM1 axis.

    Evidence SLC37A4 knockout in human gingival epithelial cells, RT-qPCR, siRNA, HMX3 overexpression rescue, 3D epithelial permeability assay

    PMID:39433915

    Open questions at the time
    • Link between transporter activity and HMX3 transcription unexplained
    • Single lab and cell system
    • Physiological relevance in vivo untested
  7. 2025 High

    Determined the atomic transport mechanism, capturing four conformational states that establish G6P/Pi antiport via a single alternating-access binding pocket and revealing the inhibitor S-4048's mode of action.

    Evidence Cryo-EM in four states with mutagenesis, MD simulations, and functional transport assays

    PMID:41225049

    Open questions at the time
    • Structural basis for 1,5-AG6P transport not addressed
    • Regulation of conformational cycling in vivo unknown
  8. 2025 Medium

    Showed SLC37A4 is itself a regulated splicing target, with SRSF9-driven exon 7 skipping generating an oncogenic truncated isoform in oral cancer.

    Evidence RT-PCR, minigene reporter, FRAP, siRNA, proliferation/invasion assays, and in vivo tumor models

    PMID:40064440

    Open questions at the time
    • Functional/transport properties of SLC37A4-S not characterized
    • Mechanism linking the isoform to proliferation unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SLC37A4's transport function mechanistically connects to its diverse downstream phenotypes — ER stress, glycosylation, epithelial barrier, and cancer isoform behavior — remains unresolved.
  • No unified link between transport activity and ER-stress signaling
  • Transport properties of disease-associated isoforms uncharacterized
  • Tissue-specific substrate range incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-382551 Transport of small molecules 2 R-HSA-1430728 Metabolism 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
G6PC1G6PC3

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 Cryo-EM structures of human SLC37A4 in four functional states reveal conformational transitions between lumen-facing and cytoplasm-facing states. A conserved substrate-binding pocket alternately accommodates G6P and Pi through electrostatic complementarity and domain-dependent interactions, establishing the antiport mechanism. The inhibitor S-4048 sterically occludes the cytoplasmic entry pathway by trapping the transporter in a cytoplasm-facing conformation. Cryo-EM structure determination, mutational analysis, molecular dynamics simulations, functional transport assays Nature structural & molecular biology High 41225049
2023 SLC37A4 encodes the endoplasmic reticulum glucose-6-phosphate transporter (G6PT) that transports G6P from the cytosol across the ER membrane, where it is hydrolyzed by glucose-6-phosphatase (G6PC1). In neutrophils, G6PT transports 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) into the ER for hydrolysis by G6PC3, preventing accumulation of this hexokinase inhibitor; loss of G6PT function causes neutrophil dysfunction via 1,5-AG6P accumulation. Biochemical analysis of G6PT deficiency in GSD1b patients, mechanistic dissection via metabolite measurement and SGLT2 inhibitor treatment rescue experiments Diagnostics (Basel, Switzerland) Medium 37238286
2021 A dominant heterozygous truncating mutation (p.Arg423*) in SLC37A4 abolishes the ER retention signal of the glucose-6-phosphate transporter, causing mislocalization of the mutant protein to a non-Golgi compartment (possibly ER exit sites) and altering Golgi morphology and reducing intraluminal Golgi pH, resulting in a congenital disorder of glycosylation with abnormal serum N-glycans. CRISPR base-edited hepatoma cell line harboring the mutation, immunofluorescence localization, N-glycan profiling of patient serum and cell lines, iPSC-derived models American journal of human genetics High 33728255 33964207
2020 A single dominant mutation in SLC37A4 abolishes the ER retention signal of the glucose-6-phosphate transporter and generates a weak Golgi retention signal, causing intracellular mislocalization to the Golgi and resulting in a congenital disorder of glycosylation rather than glycogen storage disease. Identification and functional characterization of the mutation, subcellular localization studies Molecular genetics and metabolism reports Medium 32884905
2019 In a human kidney cell model with CRISPR/Cas9-introduced SLC37A4 deficiency, SLC37A4 loss triggers ER stress and the unfolded protein response (UPR), with suppression of ATF4, DDIT3, and HSPA5 under chronic stress, but ultimately induces apoptosis through decreased BCL2/BAX ratio, suggesting renal dysfunction in GSD1b is partly mediated by ER stress and increased apoptosis. CRISPR/Cas9-mediated gene editing of SLC37A4 in Flp-In T-REx-293 cells, RT-qPCR analysis of UPR and apoptosis markers Gene Medium 30951856
2024 SLC37A4 localizes to the endoplasmic reticulum in gingival epithelial cells. SLC37A4 knockout decreases expression of the transcription factor HMX3, which in turn reduces JAM1 (junctional adhesion molecule 1) expression at tight junctions, increasing epithelial permeability to LPS and peptidoglycan. HMX3 overexpression rescues JAM1 expression in SLC37A4-knockout cells. SLC37A4 knockout in immortalized human gingival epithelial cells, immunofluorescence localization, RT-qPCR, siRNA knockdown, HMX3 overexpression rescue, 3D multilayered epithelial tissue permeability assay Scientific reports Medium 39433915
2025 SRSF9, an RNA splicing factor capable of liquid-liquid phase separation via its RS domain, promotes skipping of SLC37A4 exon 7 in oral cancer cells, generating a truncated isoform SLC37A4-S. This truncated isoform enhances proliferation, metastatic potential, and cisplatin resistance. Disruption of SRSF9 phase separation (by inhibitors or RS-domain mutants) prevents the aberrant splicing of SLC37A4. Semi-quantitative RT-PCR, minigene reporter assay, FRAP, live-cell immunofluorescence, siRNA knockdown, CCK8, EdU, transwell invasion assays, in vivo subcutaneous tumor models Journal of advanced research Medium 40064440
2020 In leukocytes from a GSD-Ib patient harboring the novel p.P119L SLC37A4 mutation, loss of SLC37A4 function causes increased ER stress markers (sXBP-1, BIP, CHOP mRNA), elevated BAX mRNA, and increased caspase-3 activity, suggesting that SLC37A4 deficiency-induced ER stress and apoptosis contribute to leukocytopenia. Whole-exome sequencing, RT-qPCR of UPR and apoptosis markers in patient leukocytes, caspase-3 activity assay Molecular genetics & genomic medicine Low 33280276

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Nitrate-NRT1.1B-SPX4 cascade integrates nitrogen and phosphorus signalling networks in plants. Nature plants 316 30911122
2014 SPX4 Negatively Regulates Phosphate Signaling and Homeostasis through Its Interaction with PHR2 in Rice. The Plant cell 266 24692424
2020 SPX4 interacts with both PHR1 and PAP1 to regulate critical steps in phosphorus-status-dependent anthocyanin biosynthesis. The New phytologist 76 33617039
2023 Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors. Diagnostics (Basel, Switzerland) 32 37238286
2023 The D14-SDEL1-SPX4 cascade integrates the strigolactone and phosphate signalling networks in rice. The New phytologist 23 37194447
2017 Novel SLC37A4 Mutations in Korean Patients With Glycogen Storage Disease Ib. Annals of laboratory medicine 21 28224773
2017 Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and 3 novel SLC37A4 variants. Clinical genetics 21 28685844
2000 Molecular analysis in glycogen storage disease 1 non-A: DHPLC detection of the highly prevalent exon 8 mutations of the G6PT1 gene in German patients. Human mutation 18 10923042
2021 A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction. American journal of human genetics 16 33964207
2004 Genetic testing of glycogen storage disease type Ib in Japan: five novel G6PT1 mutations and a rapid detection method for a prevalent mutation W118R. Molecular genetics and metabolism 12 15059622
2021 SLC37A4-CDG: Second patient. JIMD reports 10 33728255
2020 SLC37A4-CDG: Mislocalization of the glucose-6-phosphate transporter to the Golgi causes a new congenital disorder of glycosylation. Molecular genetics and metabolism reports 9 32884905
2020 Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b). Orphanet journal of rare diseases 8 32005221
2019 CRISPR/Cas9 genome editing of SLC37A4 gene elucidates the role of molecular markers of endoplasmic reticulum stress and apoptosis in renal involvement in glycogen storage disease type Ib. Gene 8 30951856
2002 Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease type 1b. Molecular genetics and metabolism 8 12409273
2025 SRSF9 mediates oncogenic RNA splicing of SLC37A4 via liquid-liquid phase separation to promote oral cancer progression. Journal of advanced research 7 40064440
2013 Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib. Genetics and molecular biology 7 24385852
2011 [Mutation in the SLC37A4 gene of glycogen storage disease type Ib in 15 families of the mainland of China]. Zhonghua er ke za zhi = Chinese journal of pediatrics 7 21575371
2023 A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype. Frontiers in endocrinology 6 38034009
2022 Novel mutation of SLC37A4 in a glycogen storage disease type Ib patient with neutropenia, horseshoe kidney, and arteriovenous malformation: a case report. Immunologic research 6 36129616
2005 A novel mutation (A148V) in the glucose 6-phosphate translocase (SLC37A4) gene in a Korean patient with glycogen storage disease type 1b. Journal of Korean medical science 6 15953877
2019 Mutation analysis of SLC37A4 in a patient with glycogen storage disease-type Ib. The Journal of international medical research 5 31617422
2014 Glycogen storage disease type 1b: an early onset severe phenotype associated with a novel mutation (IVS4) in the glucose 6-phosphate translocase (SLC37A4) gene in a Turkish patient. Genetic counseling (Geneva, Switzerland) 4 25804016
2023 Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review. The Journal of international medical research 3 38087503
2024 SLC37A4, gene responsible for glycogen storage disease type 1b, regulates gingival epithelial barrier function via JAM1 expression. Scientific reports 2 39433915
2020 A novel SLC37A4 missense mutation in GSD-Ib without hepatomegaly causes enhanced leukocytes endoplasmic reticulum stress and apoptosis. Molecular genetics & genomic medicine 2 33280276
2025 Structural basis of G6P/Pi transport and inhibition in SLC37A4. Nature structural & molecular biology 1 41225049
2026 Decoding genetic complexity in glycogen storage diseases: three novel variants in SLC37A4, GAA, and PHKG2 identified in an Iranian cohort. Neuromuscular disorders : NMD 0 41771245
2009 WITHDRAWN: Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease type 1b. Molecular genetics and metabolism 0 19321372

Missed literature

Know a paper Affinage missed for SLC37A4? Flag it for the maintainers and the community.

No submissions yet.