SLC14A1 encodes urea transporter 1 (UT-B), a facilitative urea transporter that forms the molecular basis of the Kidd (JK) blood group system. The protein functions as a homotrimer, with each subunit containing a membrane-spanning pore formed by 10 transmembrane helices. UT-B enables rapid, energy-independent equilibration of urea across cell membranes via a channel-like mechanism. It is abundantly expressed on erythrocytes where it protects red blood cells from osmotic stress during circulation through the hyperosmotic renal medulla, and on endothelial cells of the renal vasa recta where it contributes to the urinary concentrating mechanism. Recent structural studies (2023-2024) have resolved the human UT-B structure, revealing conserved urea recognition motifs and providing insight into selective inhibitor binding. Notably, at physiological expression levels, UT-B is a selective urea transporter and does NOT function as a water channel.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0071918 urea transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: This IBA annotation correctly identifies urea transmembrane transport as a core biological process for SLC14A1. The phylogenetic inference is well-supported by extensive experimental evidence across the urea transporter family. Multiple publications demonstrate that SLC14A1/HUT11 mediates facilitated urea transport in erythrocytes and kidney [PMID:7989337, PMID:7797558, PMID:8997401, PMID:10514515]. Reason: Urea transmembrane transport is the primary and defining function of SLC14A1. The protein belongs to the urea transporter family (PANTHER PTHR10464) and all functional studies confirm this activity. The phylogenetic inference from IBA is strongly supported by direct experimental evidence in human cells. Supporting Evidence: PMID:7989337 Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport that was inhibited, as described in mammalian erythrocytes, by very low concentrations of phloretin, p-chloromercuribenzene sulfonate, and urea analogues. PMID:7797558 Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity file:human/SLC14A1/SLC14A1-deep-research-falcon.md UT-B is a facilitative channel specialized for urea. High-resolution structures of human UT-B and UT-A paralogs, together with cryo-EM across multiple states, reveal a conserved urea recognition motif and an H-bond transfer path that guides urea through the pore |
| GO:0006833 water transport | IEA GO_REF:0000108 | REMOVE | Summary: This annotation is problematic and should be removed. While SLC14A1 can facilitate water transport when overexpressed at unphysiological levels in oocytes, this is an artifact of overexpression. PMID:10514515 explicitly demonstrates that at physiological expression levels, the Kidd/urea transporter does NOT function as a water channel. The paper title states this conclusion directly. Reason: The annotation of water transport to SLC14A1 is incorrect under physiological conditions. PMID:10514515 definitively shows that water permeability is only observed at unphysiological overexpression levels. At plasma membrane expression levels close to those in red cells, HUT11A-mediated water transport was absent. Jk(a-b-) red cells that lack UT-B have normal water permeability (PMID:7797558), further confirming water transport is not a function of this protein. Supporting Evidence: PMID:10514515 at plasma membrane expression levels close to the level observed in the red cell membrane, HUT11A-mediated water transport and small solutes uptake were absent PMID:10514515 These findings show that, at physiological expression levels, the HUT11A transporter confers urea permeability but not water permeability, and that the observed water permeability is a feature of the red cell urea transporter when expressed at unphysiological high levels. PMID:7797558 Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity, but a normal water permeability |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localization is well-supported by multiple experimental studies. SLC14A1 is a multi-pass membrane protein expressed on erythrocyte plasma membranes and endothelial cells of the renal vasa recta [PMID:7797558, PMID:10514515]. Reason: The IEA annotation is correct and corroborated by multiple IDA annotations from experimental studies. The protein has been localized to the plasma membrane by immunoprecipitation, immunoblotting, and functional studies in erythrocytes. Supporting Evidence: PMID:7797558 A rabbit antibody raised against the predicted NH2-terminal amino-acids of the HUT11 protein reacted on immunoblots with a 46-60-kDa component present in all human erythrocytes except those from Jk(a-b-) individuals. |
| GO:0015204 urea transmembrane transporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: Urea transmembrane transporter activity is the core molecular function of SLC14A1. This IEA annotation is strongly supported by direct experimental evidence from multiple publications demonstrating facilitated urea transport in Xenopus oocyte expression systems [PMID:7989337, PMID:8997401, PMID:10514515]. Reason: This is the defining molecular function of UT-B. The IEA is correct and reinforced by multiple IDA annotations in this same annotation set. Supporting Evidence: PMID:7989337 Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport PMID:8997401 Both proteins allow the rapid transfer of urea but not of water. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: The annotation to the generic 'membrane' term is correct but less informative than the plasma membrane annotation. SLC14A1 is a multi-pass membrane protein with 10 predicted transmembrane helices. Reason: While this is a very general term, it is not incorrect. SLC14A1 is indeed an integral membrane protein. The more specific plasma membrane annotations are also present, so this broader annotation provides general context from InterPro domain analysis. Supporting Evidence: file:human/SLC14A1/SLC14A1-uniprot.txt Multi-pass membrane protein |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Basolateral plasma membrane localization is supported by sequence similarity to mouse UT-B, which has been shown to be restricted to the basolateral membrane in urothelium. This is consistent with the protein's role in kidney urea handling. Reason: The basolateral localization is documented in UniProt based on similarity evidence (ISS) from mouse studies. This subcellular localization is important for the protein's physiological role in the kidney concentrating mechanism. Supporting Evidence: file:human/SLC14A1/SLC14A1-uniprot.txt Basolateral cell membrane ... Restricted to the basolateral membrane in various portions of the urothelium. file:human/SLC14A1/SLC14A1-deep-research-falcon.md UT-B is also expressed on endothelial cells of the renal vasa recta (descending limbs), contributing to the medullary urea handling necessary for the urine-concentrating mechanism. |
| GO:0071918 urea transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation from InterPro correctly identifies urea transmembrane transport as a core biological process. It is a duplicate of the IBA annotation above but from a different evidence source. Reason: The InterPro-derived annotation is correct and consistent with the IBA annotation and direct experimental evidence. Duplicates with different evidence codes are acceptable and provide independent support. Supporting Evidence: PMID:7989337 HUT11 mediates a facilitated urea transport |
| GO:0005372 water transmembrane transporter activity | IEA GO_REF:0000107 | REMOVE | Summary: This annotation is incorrect and should be removed. PMID:10514515 directly demonstrates that at physiological expression levels, SLC14A1 does NOT have water transmembrane transporter activity. The paper title explicitly states: "At physiological expression levels the Kidd blood group/urea transporter protein is not a water channel." Reason: Water transport activity is an artifact of overexpression in Xenopus oocytes. At physiological levels, the protein is selective for urea and does not transport water. This IEA annotation is propagated from Ensembl orthologs but contradicts direct experimental evidence on the human protein. Supporting Evidence: PMID:10514515 at physiological expression levels, the HUT11A transporter confers urea permeability but not water permeability PMID:8997401 Both proteins allow the rapid transfer of urea but not of water. PMID:7989337 No unidirectional movements of charged molecules, glycerol, or water were associated with HUT11 expression in oocytes. |
| GO:0015837 amine transport | TAS Reactome:R-HSA-549127 | REMOVE | Summary: This annotation appears to be a misannotation. The Reactome pathway R-HSA-549127 is "SLC-mediated transport of organic cations" which involves OCT1-3 (SLC22 family), not SLC14A1. SLC14A1 is a urea transporter, not an organic cation or amine transporter. There is no experimental evidence that SLC14A1 transports amines. Reason: This annotation is incorrect. The Reactome pathway referenced concerns organic cation transporters of the SLC22 family. SLC14A1 belongs to the SLC14 urea transporter family and has not been shown to transport amines. The Reactome pathway summary explicitly describes OCT1-3 members, not urea transporters. Supporting Evidence: Reactome:R-HSA-549127 The organic cation transporters comprise three SLC22 members, OCT1-3. They can transport a wide range of organic cations including weak bases. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane localization based on immunofluorescence data. This is consistent with UT-B being an erythrocyte membrane protein and kidney endothelial membrane protein. Reason: IDA from immunofluorescence is appropriate evidence for plasma membrane localization. Multiple experimental studies confirm this localization. Supporting Evidence: PMID:7797558 The anti-Jk3 antibody also immunoprecipitated a protein material of 46-60 kDa from all red cell membranes |
| GO:0005886 plasma membrane | IDA PMID:10514515 At physiological expression levels the Kidd blood group/urea... | ACCEPT | Summary: This publication demonstrates plasma membrane localization through functional expression studies in Xenopus oocytes and by comparison to red cell membrane expression levels. The study shows that at physiological plasma membrane expression levels, the protein functions as a selective urea transporter. Reason: PMID:10514515 provides direct evidence for plasma membrane localization through expression studies and comparison to native red cell membrane levels. Supporting Evidence: PMID:10514515 at plasma membrane expression levels close to the level observed in the red cell membrane |
| GO:0005886 plasma membrane | IDA PMID:7797558 Kidd blood group and urea transport function of human erythr... | ACCEPT | Summary: This landmark paper identifies SLC14A1 (HUT11) as the Kidd blood group antigen carrier and demonstrates its presence on red cell membranes through immunoprecipitation and immunoblotting experiments. Reason: The paper provides direct evidence through antibody-based detection of the protein on erythrocyte membranes. Anti-Jk3 antibody immunoprecipitates a 46-60 kDa protein from red cell membranes, and anti-HUT11 antibody detects the same component. Supporting Evidence: PMID:7797558 The anti-Jk3 antibody also immunoprecipitated a protein material of 46-60 kDa from all red cell membranes, except those from Jk(a-b-) cells. PMID:7797558 A rabbit antibody raised against the predicted NH2-terminal amino-acids of the HUT11 protein reacted on immunoblots with a 46-60-kDa component present in all human erythrocytes except those from Jk(a-b-) individuals. |
| GO:0015204 urea transmembrane transporter activity | IDA PMID:10514515 At physiological expression levels the Kidd blood group/urea... | ACCEPT | Summary: This paper demonstrates urea transport activity of the physiological HUT11A variant in Xenopus oocytes. Importantly, it shows that at physiological expression levels, the protein selectively transports urea (inhibited by phloretin) but not water. Reason: Direct assay evidence demonstrating urea transport activity with pharmacological characterization including phloretin sensitivity at physiological expression levels. Supporting Evidence: PMID:10514515 at plasma membrane expression levels close to the level observed in the red cell membrane, HUT11A-mediated water transport and small solutes uptake were absent and the urea transport was poorly inhibited by p-chloromercuribenzene sulfonate, but strongly inhibited by phloretin. |
| GO:0015204 urea transmembrane transporter activity | IDA PMID:7797558 Kidd blood group and urea transport function of human erythr... | ACCEPT | Summary: This paper demonstrates that Jk(a-b-) red cells, which lack SLC14A1 protein, have a selective defect in urea transport capacity, providing genetic evidence that SLC14A1 is responsible for urea transport activity in erythrocytes. Reason: Genetic loss-of-function evidence: Jk(null) individuals who lack SLC14A1 protein have defective urea transport, directly linking the protein to urea transport activity. Supporting Evidence: PMID:7797558 Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity, but a normal water permeability |
| GO:0015204 urea transmembrane transporter activity | IDA PMID:7989337 Cloning and functional expression of a urea transporter from... | ACCEPT | Summary: This is the original cloning paper demonstrating facilitated urea transport activity of HUT11 (SLC14A1) when expressed in Xenopus oocytes. The activity was inhibited by classical urea transport inhibitors. Reason: First direct demonstration of urea transport activity by heterologous expression. The transport showed characteristic pharmacological inhibition by phloretin and p-chloromercuribenzene sulfonate. Supporting Evidence: PMID:7989337 Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport that was inhibited, as described in mammalian erythrocytes, by very low concentrations of phloretin, p-chloromercuribenzene sulfonate, and urea analogues. |
| GO:0015204 urea transmembrane transporter activity | IDA PMID:8997401 Functional differentiation of the human red blood cell and k... | ACCEPT | Summary: This paper provides detailed pharmacological characterization of human UT-B (HUT11) comparing it to the kidney urea transporter HUT2. Both transporters mediate rapid urea transfer but not water transport, with distinct inhibitor sensitivity profiles. Reason: Detailed functional characterization demonstrating urea transport activity with pharmacological profiling. The study explicitly notes that HUT11 allows rapid transfer of urea but not water. Supporting Evidence: PMID:8997401 Both proteins allow the rapid transfer of urea but not of water. Both are inhibited by phloretin, although with different half-maximal inhibitory concentrations (IC50; 75 microM, for HUT11 and 230 microM for HUT2). PMID:8997401 We demonstrate that thiourea diffuses through HUT11 with a Michaelis constant (Km) of 40 mM, but not through HUT2. |
| GO:0016323 basolateral plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Basolateral plasma membrane localization inferred from mouse ortholog data. This is consistent with the protein's role in kidney epithelial cells where basolateral localization is important for urea countercurrent exchange. Reason: ISS from mouse ortholog is appropriate for subcellular localization. The basolateral localization is relevant to the protein's physiological function in kidney. Supporting Evidence: file:human/SLC14A1/SLC14A1-uniprot.txt Basolateral cell membrane ... Restricted to the basolateral membrane in various portions of the urothelium. |
| GO:0015204 urea transmembrane transporter activity | TAS Reactome:R-HSA-444126 | ACCEPT | Summary: The Reactome pathway correctly describes HUT11 (SLC14A1) as an erythrocyte-specific urea transporter mediating rapid urea movement across cell membranes. Reason: The Reactome pathway accurately captures the core molecular function of SLC14A1 in urea transport, consistent with experimental evidence. Supporting Evidence: Reactome:R-HSA-444126 Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Two carriers exist in humans, HUT2 which is renal-specific (Olives B et al, 1996) and HUT11, which is erythrocyte-specific (Olives B et al, 1994). |
| GO:0005886 plasma membrane | IDA PMID:19865084 Crystal structure of a bacterial homologue of the kidney ure... | UNDECIDED | Summary: PMID:19865084 describes the crystal structure of a bacterial urea transporter homolog (Desulfovibrio vulgaris), not human SLC14A1 directly. While the structure provides insight into the UT family architecture, this IDA for plasma membrane should not cite this paper for human SLC14A1 localization. Reason: The citation appears misattributed. PMID:19865084 is about a bacterial homolog structure, not human SLC14A1 localization. However, the plasma membrane localization is well-supported by other references, so this may be an error in the original GO annotation citation. Supporting Evidence: PMID:19865084 Here we present the 2.3 A structure of a functional urea transporter from the bacterium Desulfovibrio vulgaris. |
| GO:0015265 urea channel activity | IDA PMID:19865084 Crystal structure of a bacterial homologue of the kidney ure... | ACCEPT | Summary: PMID:19865084 provides structural evidence that urea transporters operate via a channel-like mechanism with a continuous membrane-spanning pore. While this study is on a bacterial homolog, the findings established that UTs function as channels rather than carriers. Recent human UT-B structures (2023-2024) confirm the conserved channel architecture. GO:0015265 (urea channel activity) may be more mechanistically precise than GO:0015204 (urea transmembrane transporter activity). Reason: The structural evidence demonstrates a channel-like mechanism for urea permeation. While the primary citation is for a bacterial homolog, the human UT-B structure confirms the same architecture. The annotation captures the mechanistic insight that UT-B functions as a channel rather than a carrier-type transporter. Supporting Evidence: PMID:19865084 These results establish that the urea transporter operates by a channel-like mechanism and reveal the physical and chemical basis of urea selectivity. file:human/SLC14A1/SLC14A1-deep-research-falcon.md Human UTs are homotrimers; each subunit forms an independent pore with 10 transmembrane helices arranged with pseudo-C2 symmetry. |
| GO:0071918 urea transmembrane transport | IDA PMID:19865084 Crystal structure of a bacterial homologue of the kidney ure... | UNDECIDED | Summary: Similar to the channel activity annotation above, this IDA cites the bacterial homolog structure paper. The paper provides mechanistic insight into urea permeation but is not direct evidence for human SLC14A1 function. Reason: While the structural insights are relevant to understanding the UT family mechanism, this citation is for a bacterial homolog rather than direct evidence on human SLC14A1. However, urea transmembrane transport is well-supported by other IDA citations. Supporting Evidence: PMID:19865084 The pore contains a constricted selectivity filter that can accommodate several dehydrated urea molecules in single file. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-444126 | ACCEPT | Summary: The Reactome pathway describes urea transport across cell membranes, implicitly indicating plasma membrane localization for the transporter. Reason: Consistent with extensive experimental evidence for plasma membrane localization. The Reactome description of rapid urea movement across cell membranes requires plasma membrane localization of the transporter. Supporting Evidence: Reactome:R-HSA-444126 Carrier-mediated urea transport allows rapid urea movement across the cell membrane |
| GO:0005886 plasma membrane | TAS PMID:7797558 Kidd blood group and urea transport function of human erythr... | ACCEPT | Summary: The original paper identifying SLC14A1 as the Kidd blood group protein provides evidence for plasma membrane localization through immunoprecipitation from red cell membranes. Reason: Consistent with the IDA annotations from the same paper. The protein was immunoprecipitated from red cell membranes by anti-Jk3 antibody. Supporting Evidence: PMID:7797558 The anti-Jk3 antibody also immunoprecipitated a protein material of 46-60 kDa from all red cell membranes |
| GO:0005886 plasma membrane | TAS PMID:7989337 Cloning and functional expression of a urea transporter from... | ACCEPT | Summary: The original cloning paper demonstrates expression studies showing functional urea transport, implying plasma membrane localization of the heterologously expressed protein. Reason: The functional expression of urea transport activity requires plasma membrane localization of the expressed protein. Supporting Evidence: PMID:7989337 Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport |
| GO:0015840 urea transport | TAS PMID:7989337 Cloning and functional expression of a urea transporter from... | ACCEPT | Summary: GO:0015840 (urea transport) is a broader term than GO:0071918 (urea transmembrane transport). Both are appropriate annotations for SLC14A1, with GO:0071918 being more specific to the transmembrane mechanism. Reason: Urea transport is the core biological process for SLC14A1. This broader term encompasses the more specific urea transmembrane transport annotations. Supporting Evidence: PMID:7989337 These findings suggest that HUT11 is most likely responsible for the facilitated urea transport in human red blood cells. |
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Download this section (compressed HTML)Q: What is the physiological significance of the Jk(a)/Jk(b) polymorphism (D280N) for urea transport kinetics? The D280N variant defines the major Kidd blood group antigens but the functional impact on transport activity is not well characterized.
Q: Is there tissue-specific regulation of SLC14A1 expression and does this affect local urea handling? Expression in brain, prostate, and bladder (per HPA) suggests potential non-classical functions beyond erythrocytes and kidney.
Experiment: Compare urea transport kinetics between Jk(a) and Jk(b) variants in controlled expression systems. This would clarify whether the common D280N polymorphism affects function or is immunologically neutral.
Experiment: Investigate the reported tumor suppressor function of SLC14A1 in bladder and prostate cancer models. Recent studies suggest epigenetic silencing correlates with cancer progression; mechanistic basis is unclear.
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