SLC52A3 (riboflavin transporter 3, RFVT3; formerly C20orf54) is a multi-pass plasma-membrane transporter of the SLC52 solute-carrier family that mediates cellular uptake of the water-soluble vitamin B2 (riboflavin). Riboflavin is the precursor of the flavin cofactors FMN and FAD, which are essential for numerous oxidation-reduction reactions in carbohydrate, lipid and amino-acid metabolism; because humans cannot synthesize riboflavin, it must be acquired from the diet by intestinal absorption. RFVT3 localizes to the apical (brush-border) membrane of polarized epithelia and is the principal transporter for riboflavin absorption at the intestinal apical surface; it is most highly expressed in testis and is also abundant in small intestine, kidney and prostate. Transport is riboflavin-selective, Na(+)-independent at low pH, and is inhibited by riboflavin analogs (lumiflavin, FMN, FAD) and by methylene blue. The protein has 11 transmembrane helices. Two splice isoforms exist: isoform 1 (SLC52A3a) traffics to the cell membrane and is the functional transporter, whereas isoform 2 (SLC52A3b) is cytoplasmic and transport-deficient. Biallelic loss-of-function variants in SLC52A3 cause riboflavin transporter deficiency, presenting as Brown-Vialetto-Van Laere syndrome type 1 and Fazio-Londe disease: progressive bulbar palsy with sensorimotor neuronopathy, sensorineural deafness and respiratory compromise that is responsive to high-dose oral riboflavin.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation placing RFVT3 activity at the plasma membrane. This matches the well-established, experimentally supported localization of RFVT3 as a cell-surface/apical membrane riboflavin transporter and is a correct statement of a core cellular location. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Apical cell membrane |
| GO:0032217 riboflavin transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the core molecular function. RFVT3 is a riboflavin transmembrane transporter, directly demonstrated by multiple uptake assays; this is the central function of the gene. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Plasma membrane transporter mediating the uptake by cells of |
| GO:0032218 riboflavin transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the core biological process, riboflavin transport. Consistent with all experimental evidence and with the transporter molecular function. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Plasma membrane transporter mediating the uptake by cells of |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProtKB-SubCell (IEA) mapping to cytoplasm. Cytoplasmic localization is real but is a property of the transport-deficient isoform 2 (SLC52A3b) and, in a cancer study, of isoform 1; it is not the canonical location where RFVT3 exerts its transporter function. Retained as a genuine but non-core localization. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assignment of plasma membrane, consistent with the abundant experimental evidence for cell-surface localization. This is the gene's own correct core location, so it is accepted (not treated as a redundant over-annotation). Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProtKB-SubCell (IEA) mapping to apical plasma membrane. This is the correct, experimentally supported functional location of RFVT3 in polarized (intestinal) epithelia and represents a core cellular component. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Apical cell membrane |
| GO:0031965 nuclear membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProtKB-SubCell (IEA) mapping to nuclear membrane, derived from a single cancer study (PMID:29428966) reporting isoform 1 at the nucleus membrane. This is an isoform-1 / cancer-context observation, not the canonical apical-membrane transporter location; retained as a non-core localization rather than a core function. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Nucleus membrane {ECO:0000269|PubMed:29428966} |
| GO:0032217 riboflavin transmembrane transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA, ARBA/InterPro) assignment of the core riboflavin transmembrane transporter activity. This is the gene's own correct molecular function and is strongly supported experimentally; accepted rather than flagged as redundant. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Belongs to the riboflavin transporter family |
| GO:0032218 riboflavin transport | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IEA) assignment of riboflavin transport based on the riboflavin transporter domain (IPR009357). Correct and consistent with the gene's core biological process. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Belongs to the riboflavin transporter family |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Generic "protein binding" from a large-scale yeast two-hybrid neurodegeneration interactome screen (interactors ATXN3, DNM2 isoform 2, TOR1A). The bare protein-binding term is uninformative about RFVT3 function and these are screen-scale interactions of unclear physiological relevance. Kept (experimental IPI) but flagged as an over-annotation; a specific molecular function is not derivable from it. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening |
| GO:0006771 riboflavin metabolic process | TAS Reactome:R-HSA-196843 | KEEP AS NON CORE | Summary: Reactome (TAS) placement of RFVT3 within vitamin B2 (riboflavin) metabolism. RFVT3 transports riboflavin across the membrane but does not chemically modify or metabolize it; the broad metabolic-process term generalizes beyond the specific transport role. Transport does contribute to whole-body riboflavin handling, so it is retained as a non-core parent process rather than removed. The specific and more appropriate BP terms are riboflavin transport (GO:0032218) and intestinal absorption (GO:0050892). Supporting Evidence: Reactome:R-HSA-196843 Riboflavin is present in many vegetables and meat and during digestion |
| GO:0016324 apical plasma membrane | IDA PMID:21854757 Differential expression of human riboflavin transporters -1,... | ACCEPT | Summary: Direct assay (live-cell confocal imaging in polarized Caco-2 and MDCK cells) of apical membrane localization. Note the nomenclature: this paper (Said lab) calls SLC52A3/RFVT3 "hRFT-2", the 469-aa C20orf54 product shown to be exclusively apical; GOA correctly attributes this to Q9NQ40. Core cellular location. Supporting Evidence: PMID:21854757 hRFT-2 is exclusively expressed at the apical membrane |
| GO:0032217 riboflavin transmembrane transporter activity | IDA PMID:21854757 Differential expression of human riboflavin transporters -1,... | ACCEPT | Summary: Direct assay of RFVT3-mediated [3H]riboflavin transport ("hRFT-2" in this paper = SLC52A3). Over-expression significantly increased carrier-mediated RF uptake, and gene-specific siRNA knockdown reduced apical RF uptake. Core molecular function. Supporting Evidence: PMID:21854757 predominant role for the hRFT-2 in intestinal RF absorption |
| GO:0032218 riboflavin transport | IMP PMID:21854757 Differential expression of human riboflavin transporters -1,... | ACCEPT | Summary: siRNA knockdown of RFVT3 ("hRFT-2") significantly reduced carrier-mediated [3H]riboflavin uptake in intestinal Caco-2 monolayers, demonstrating involvement in riboflavin transport. Core biological process. Supporting Evidence: PMID:21854757 predominant role for the hRFT-2 in intestinal RF absorption |
| GO:0050892 intestinal absorption | IMP PMID:21854757 Differential expression of human riboflavin transporters -1,... | ACCEPT | Summary: Loss-of-function (siRNA) evidence that RFVT3 contributes to riboflavin uptake across the apical membrane of intestinal epithelial cells, establishing a role in intestinal absorption. This is a core physiological process for RFVT3. Supporting Evidence: PMID:21854757 predominant role for the hRFT-2 in intestinal RF absorption |
| GO:0005515 protein binding | IPI PMID:30892938 Identification of transmembrane protein 237 as a novel inter... | MARK AS OVER ANNOTATED | Summary: IPI evidence for interaction with TMEM237 (UniProtKB:Q96Q45), a genuine and functionally validated interactor (colocalization, co-immunoprecipitation, and modulation of RFVT3 protein stability and riboflavin uptake). The interaction is biologically meaningful, but the bare "protein binding" term is uninformative about RFVT3's molecular function. Kept (experimental IPI) but flagged as over-annotated; a more specific MF is not warranted from this evidence. Supporting Evidence: PMID:30892938 Expressing TMEM237 in HuTu-80 cells led to a significant induction in RF uptake |
| GO:0016324 apical plasma membrane | IDA PMID:24264046 Functional involvement of RFVT3/SLC52A3 in intestinal ribofl... | ACCEPT | Summary: Direct evidence that RFVT3/SLC52A3 operates at the apical membrane of intestinal epithelial cells (T84 cells and mouse jejunum/ileum), with apical [3H]riboflavin uptake sensitive to the RFVT3 inhibitor methylene blue and to RFVT3 siRNA. Core cellular location. Supporting Evidence: PMID:24264046 RFVT3 would functionally be involved in riboflavin absorption in the apical |
| GO:0032217 riboflavin transmembrane transporter activity | IDA PMID:24264046 Functional involvement of RFVT3/SLC52A3 in intestinal ribofl... | ACCEPT | Summary: Direct assay of RFVT3-mediated apical riboflavin uptake in T84 cells; uptake was pH-dependent, inhibited by the RFVT3-selective inhibitor methylene blue, and reduced by RFVT3 siRNA. Core molecular function. Supporting Evidence: PMID:24264046 prominently inhibited by the RFVT3 |
| GO:0032217 riboflavin transmembrane transporter activity | IMP PMID:30892938 Identification of transmembrane protein 237 as a novel inter... | ACCEPT | Summary: RFVT3-dependent riboflavin uptake modulated by the interactor TMEM237 (overexpression increases, knockdown decreases RF uptake), corroborating RFVT3's riboflavin transporter activity. Core molecular function. Supporting Evidence: PMID:30892938 its knockdown (with the use of gene-specific siRNA) led to a significant |
| GO:0032218 riboflavin transport | IMP PMID:30892938 Identification of transmembrane protein 237 as a novel inter... | ACCEPT | Summary: Perturbation of RFVT3-mediated riboflavin uptake via its interactor TMEM237 supports RFVT3's role in riboflavin transport. Core biological process. Supporting Evidence: PMID:30892938 apically localized riboflavin (RF) transporter-3 (RFVT-3) is involved in |
| GO:0050892 intestinal absorption | IDA PMID:24264046 Functional involvement of RFVT3/SLC52A3 in intestinal ribofl... | ACCEPT | Summary: Direct evidence for RFVT3 involvement in intestinal riboflavin absorption: apical RF uptake in intestinal T84 cells and reduced jejunal/ileal riboflavin permeability upon methylene-blue inhibition of RFVT3. Core physiological process. Supporting Evidence: PMID:24264046 RFVT3 would functionally be involved in riboflavin absorption in the apical |
| GO:0050892 intestinal absorption | IMP PMID:30892938 Identification of transmembrane protein 237 as a novel inter... | ACCEPT | Summary: RFVT3 is the apically localized intestinal riboflavin transporter; modulating its function via TMEM237 changes RF uptake in intestinal epithelial cells, supporting a role in intestinal absorption. Core physiological process. Supporting Evidence: PMID:30892938 apically localized riboflavin (RF) transporter-3 (RFVT-3) is involved in |
| GO:0005737 cytoplasm | EXP PMID:29428966 SLC52A3 expression is activated by NF-ΞΊB p65/Rel-B and serve... | KEEP AS NON CORE | Summary: Experimental (confocal) localization from the esophageal-cancer study. Cytoplasmic localization is characteristic of the transport-deficient isoform 2 (SLC52A3b) and is also reported for isoform 1 in this cancer context; it is a genuine but non-core localization, distinct from the functional apical/plasma-membrane pool. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm |
| GO:0005886 plasma membrane | EXP PMID:27702554 SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialett... | ACCEPT | Summary: Experimental (live-cell confocal) evidence that wild-type RFVT3 (hRFVT-3) is expressed at the cell membrane, whereas the BVVLS variant p.N21S is retained intracellularly. Confirms the core plasma-membrane localization. Supporting Evidence: PMID:27702554 drastic inhibition in RF uptake and impairment in membrane expression |
| GO:0005886 plasma membrane | EXP PMID:29428966 SLC52A3 expression is activated by NF-ΞΊB p65/Rel-B and serve... | ACCEPT | Summary: Experimental evidence that isoform 1 (SLC52A3a) localizes to the cell membrane. Consistent with the core plasma-membrane location of the functional transporter. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane |
| GO:0016324 apical plasma membrane | EXP PMID:20463145 Identification and comparative functional characterization o... | ACCEPT | Summary: Experimental characterization of the cloned human riboflavin transporter (RFVT3/SLC52A3; called "hRFT3" in this paper) including its membrane localization and riboflavin transport function. Supports the apical/plasma-membrane location of the transporter. Core cellular component. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Apical cell membrane |
| GO:0031965 nuclear membrane | EXP PMID:29428966 SLC52A3 expression is activated by NF-ΞΊB p65/Rel-B and serve... | KEEP AS NON CORE | Summary: Experimental (confocal) report of isoform 1 at the nuclear membrane in the esophageal-cancer study. This is an isoform-1 / cancer-context observation and does not represent the canonical apical-membrane transporter function; retained as a non-core localization. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Nucleus membrane {ECO:0000269|PubMed:29428966} |
| GO:0032217 riboflavin transmembrane transporter activity | TAS Reactome:R-HSA-3165230 | ACCEPT | Summary: Reactome (TAS) statement of RFVT3 riboflavin transporter activity (reaction "SLC52A1,2,3 transport RIB from extracellular region to cytosol"). Correct core molecular function. Supporting Evidence: Reactome:R-HSA-3165230 transports riboflavin (RIB) from the lumen into small intestine epithelial cells |
| GO:0005886 plasma membrane | IDA PMID:22273710 Effect of clinical mutations on functionality of the human r... | ACCEPT | Summary: Direct assay (live-cell confocal imaging and cell-surface biotinylation) showing wild-type RFVT3 ("hRFT-2" in this paper = SLC52A3) at the cell membrane; several BVVLS mutants are instead ER-retained. Confirms core plasma-membrane localization. Supporting Evidence: PMID:22273710 expressed at the cell membrane |
| GO:0032218 riboflavin transport | IDA PMID:22273710 Effect of clinical mutations on functionality of the human r... | ACCEPT | Summary: Direct [3H]riboflavin uptake assay in Caco-2 cells expressing wild-type versus BVVLS-mutant RFVT3; disease mutants (W17R, P28T, E36K, E71K, R132W) significantly impair RF uptake, demonstrating RFVT3's role in riboflavin transport. Core biological process. Supporting Evidence: PMID:22273710 significant (P < 0.01) inhibition in riboflavin uptake in Caco-2 cells expressing W17R |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3165230 | ACCEPT | Summary: Reactome (TAS) placement of RFVT3 transport at the plasma membrane (extracellular region to cytosol). Consistent with experimental data; core cellular location. Supporting Evidence: Reactome:R-HSA-3165230 transport RIB from extracellular region to cytosol |
| GO:0005886 plasma membrane | IDA PMID:20463145 Identification and comparative functional characterization o... | ACCEPT | Summary: Direct experimental evidence that the cloned human riboflavin transporter (RFVT3/SLC52A3; "hRFT3" in this paper) localizes to the plasma membrane and mediates riboflavin uptake. Core cellular location. Supporting Evidence: file:human/SLC52A3/SLC52A3-uniprot.txt Apical cell membrane |
| GO:0007605 sensory perception of sound | IMP PMID:20206331 Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with... | MARK AS OVER ANNOTATED | Summary: This annotation is inferred from the sensorineural deafness observed in Brown-Vialetto-Van Laere syndrome patients carrying SLC52A3 mutations. Hearing loss is a downstream clinical consequence of systemic riboflavin transporter deficiency, not a molecular role of RFVT3 in the auditory process; RFVT3 is a riboflavin transporter, not a component of sound-sensory machinery. This is a phenotype-to- process over-annotation. As an experimental (IMP) annotation it is retained but flagged as over-annotated rather than removed. Supporting Evidence: PMID:20206331 ponto-bulbar palsy and bilateral sensorineural deafness |
| GO:0032217 riboflavin transmembrane transporter activity | IDA PMID:20463145 Identification and comparative functional characterization o... | ACCEPT | Summary: Direct riboflavin-uptake assay of the cloned human transporter (RFVT3/SLC52A3, "hRFT3"): [3H]riboflavin uptake in transfected HEK293 cells, Na(+)/Cl(-)- independent, saturable (low-micromolar KM), and inhibited by riboflavin analogs. Core molecular function. Supporting Evidence: PMID:20463145 uptake of [3H]riboflavin was evaluated using human embryonic kidney 293 cells |
| GO:0032218 riboflavin transport | IDA PMID:20463145 Identification and comparative functional characterization o... | ACCEPT | Summary: Direct demonstration that the cloned human riboflavin transporter (RFVT3/SLC52A3) mediates riboflavin transport into cells. Core biological process. Supporting Evidence: PMID:20463145 uptake of [3H]riboflavin was evaluated using human embryonic kidney 293 cells |
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Download this section (compressed HTML)Q: Do isoform 1 (SLC52A3a) and isoform 2 (SLC52A3b) differ functionally beyond localization, i.e. does the cytoplasmic isoform 2 have any transport or regulatory role, or is it purely a non-functional/regulatory variant?
Q: What is the physiological significance of the nuclear-membrane and cytoplasmic localizations reported in cancer cells, and are they related to the pro-proliferative activity of SLC52A3a in esophageal squamous cell carcinoma?
Q: Is the TMEM237-RFVT3 interaction a general regulator of RFVT3 trafficking/stability in the intestine, and does it modulate riboflavin absorption in vivo?
Experiment: Structure-guided mutagenesis of the cryo-EM-resolved riboflavin-binding site (PDB 8XSN) combined with [3H]riboflavin uptake assays to map residues required for substrate recognition versus membrane trafficking, and to explain transport-null variants (e.g. W17R) that retain normal cell-surface expression.
Experiment: Tissue-specific conditional knockout / knock-in of disease alleles in mouse intestine with measurement of intestinal riboflavin absorption, plasma riboflavin, and neurological phenotype, with and without high-dose riboflavin rescue.
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