A0A2R9CAF4 is the bonobo (Pan paniscus) ortholog of human SLC26A11 (also known as KBAT, kidney and brain anion transporter), a member of the SLC26/SulP transporter family. SLC26A11 is a dual-function protein that operates both as an electroneutral proton-coupled sulfate/chloride exchanger and as a chloride-selective channel. The transporter contains a transmembrane domain with 14 helices arranged in two inverted repeats and a cytosolic STAS (Sulfate Transporter and Anti-Sigma factor antagonist) domain. It functions as a homodimer. The primary physiological role is lysosomal sulfate export: the protein uses the lysosomal proton gradient to selectively transport sulfate from the acidic lysosomal lumen to the cytoplasm, preventing product inhibition of lysosomal sulfatases. A unique glutamate residue (Glu-320 in human) serves as a pH-sensitive switch that increases sulfate binding affinity approximately 50-fold at acidic pH, enabling selective sulfate transport despite much higher luminal chloride concentrations. The protein is broadly expressed, with highest levels in brain and kidney, consistent with a housekeeping role in lysosomal catabolite clearance. Under pathological acidic conditions (e.g., brain ischemia), plasmalemmal SLC26A11 chloride channel activity may contribute to cytotoxic neuronal swelling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005765
lysosomal membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Multiple independent studies from 2024-2025 establish that SLC26A11 localizes predominantly to lysosomes in mammalian cells. Confocal microscopy with fluorescently tagged SLC26A11 in HEK293T, COS1, CHO, and renal intercalated cells shows significant overlap with the lysosomal marker Lamp1 (Manders coefficient 0.45-0.50). Both mouse and human orthologs show similar lysosomal localization. This is the primary functional location where the protein exports sulfate using the lysosomal proton gradient.
Reason: Lysosomal membrane is the primary functional location of SLC26A11, strongly supported by recent localization studies and consistent with its role as a lysosomal sulfate exporter.
|
|
GO:0008271
secondary active sulfate transmembrane transporter activity
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: Reconstitution experiments with purified human SLC26A11 in proteoliposomes demonstrate that it catalyzes symport of one proton with one sulfate ion coupled to antiport of one chloride ion. The transport is strongly pH-dependent, with highest sulfate accumulation at pH gradients of 2.0-2.5 units with acidic pH on the luminal side. The apparent KM for sulfate is 39.7 +/- 5.5 uM under optimal conditions. This is a core molecular function of SLC26A11.
Reason: Sulfate transporter activity is a core function of SLC26A11, directly demonstrated by reconstitution studies with purified protein.
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|
GO:0015698
inorganic anion transport
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: SLC26A11 does transport inorganic anions (sulfate, chloride), so this term is technically correct. However, it is very broad and does not capture the specific transport substrates or mechanism. More informative process terms such as sulfate transmembrane transport (GO:1902358) are also annotated.
Reason: Correct but too general to be informative when more specific transport process annotations are present.
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000120 |
MARK AS OVER ANNOTATED |
Summary: SLC26A11 is indeed an integral membrane protein with 10 predicted transmembrane helices (per Phobius) and 14 TM helices in the cryo-EM structure. However, the term 'membrane' is extremely broad and adds no information beyond what is conveyed by the more specific lysosomal membrane annotation.
Reason: The generic 'membrane' term is redundant with the more specific lysosomal membrane (GO:0005765) and plasma membrane (GO:0005886) annotations.
|
|
GO:0016323
basolateral plasma membrane
|
IEA
GO_REF:0000120 |
MARK AS OVER ANNOTATED |
Summary: This annotation is transferred from the mouse ortholog Q80ZD3 via Ensembl. However, recent 2024 localization studies show that SLC26A11 predominantly localizes to lysosomes in multiple mammalian cell types, with minimal overlap with plasma membrane markers. The basolateral plasma membrane annotation likely derives from older immunohistochemistry studies in kidney intercalated cells that may have detected the protein in transit through the secretory pathway or at low levels on the plasma membrane. The primary functional location is the lysosomal membrane.
Reason: Recent comprehensive localization studies demonstrate predominant lysosomal localization. Basolateral plasma membrane is not the primary functional location and likely represents a minor or transient pool.
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|
GO:0016324
apical plasma membrane
|
IEA
GO_REF:0000120 |
MARK AS OVER ANNOTATED |
Summary: Like the basolateral annotation, this is transferred from the mouse ortholog. The same concerns apply: SLC26A11 predominantly localizes to lysosomes, not to the apical plasma membrane. The 2024 Bungert-Plumke et al. study showed that SLC26A11 localization is independent of cell type and consistently intracellular/lysosomal.
Reason: SLC26A11 predominantly localizes to lysosomes. Apical plasma membrane is not the primary functional location based on recent localization data.
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|
GO:0055085
transmembrane transport
|
IEA
GO_REF:0000002 |
KEEP AS NON CORE |
Summary: SLC26A11 is a transmembrane transporter, so involvement in transmembrane transport is correct. However, this is a very broad parent term that adds little information when more specific process terms (sulfate transmembrane transport, chloride transmembrane transport) are annotated.
Reason: Correct but too general; subsumed by the more specific sulfate and chloride transmembrane transport annotations.
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GO:0098656
monoatomic anion transmembrane transport
|
IEA
GO_REF:0000108 |
KEEP AS NON CORE |
Summary: This was inferred from monoatomic anion transmembrane transporter activity (GO:0008509) via logical inference. SLC26A11 does transport monoatomic anions (chloride, sulfate). The term is correct but represents an intermediate level of specificity between the very broad transmembrane transport and the specific sulfate/chloride transport annotations.
Reason: Logically inferred and correct, but redundant with more specific transport process annotations.
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|
GO:1902358
sulfate transmembrane transport
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Sulfate transmembrane transport is the primary biological process mediated by SLC26A11. The protein functions as the lysosomal sulfate exporter, using the proton gradient to drive sulfate from the acidic lysosomal lumen to the cytoplasm. This prevents product accumulation that would inhibit lysosomal sulfatases. Reconstitution studies confirm direct sulfate transport with KM of approximately 40 uM.
Reason: This is the core biological process of SLC26A11, directly supported by functional reconstitution studies.
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|
GO:1902476
chloride transmembrane transport
|
IEA
GO_REF:0000108 |
KEEP AS NON CORE |
Summary: This was inferred from chloride channel activity (GO:0005254). SLC26A11 does conduct chloride, both as the counter-ion in sulfate/chloride exchange and through its chloride channel mode. The chloride channel activity is gated by proton and sulfate transport. Under physiological lysosomal conditions, chloride fluxes may help maintain lysosomal chloride homeostasis.
Reason: Chloride transport occurs as part of the coupled sulfate/chloride exchange mechanism and through the channel mode, but is secondary to the primary sulfate export function. The annotation is valid but represents a supporting rather than core activity.
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|
GO:0005254
chloride channel activity
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SLC26A11 does exhibit chloride-selective channel conductance, as demonstrated by whole-cell patch clamp experiments. The channel activity is gated by conditions favoring sulfate binding and transport, with current reversal potentials near the Nernst equilibrium potential for chloride. This dual transporter-channel behavior is well-established for SLC26A11 and places it among a small group of transporters with both coupled transport and channel-like properties. The annotation is transferred from the mouse ortholog via Ensembl.
Reason: Chloride channel activity is a genuine molecular function of SLC26A11, directly demonstrated by electrophysiology. The dual transporter-channel mechanism is a distinctive feature of this protein.
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|
GO:0005783
endoplasmic reticulum
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: This annotation is transferred from the human ortholog Q86WA9 via Ensembl. The 2024 Bungert-Plumke et al. study specifically showed minimal overlap between SLC26A11 and the ER marker calnexin (Manders coefficient 0.09-0.12). Some ER localization is expected for any integral membrane protein in transit through the secretory pathway, but the ER is not a functional location for SLC26A11.
Reason: ER localization is minimal and likely reflects transient biosynthetic trafficking rather than functional residence. Recent studies explicitly show low overlap with ER markers.
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|
GO:0005794
Golgi apparatus
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Transferred from the human ortholog via Ensembl. Like the ER annotation, Golgi localization likely reflects transit through the secretory pathway en route to lysosomes rather than functional residence. The 2024 localization studies consistently show predominant lysosomal localization across multiple cell types.
Reason: Golgi localization likely represents biosynthetic trafficking to lysosomes rather than the functional site of this protein.
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|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: SLC26A11 can reach the plasma membrane under certain conditions (e.g., in Sf9 insect cells used for electrophysiology), and a small fraction may be present on the plasma membrane in mammalian cells. However, the predominant localization is lysosomal. Plasmalemmal SLC26A11 has been implicated in pathological neuronal swelling during ischemia, but this appears to be a pathological rather than physiological context.
Reason: Plasma membrane localization is real but minor under physiological conditions. The primary functional location is the lysosomal membrane. The plasma membrane pool becomes pathologically relevant during ischemia.
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|
GO:0008509
monoatomic anion transmembrane transporter activity
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: SLC26A11 transports sulfate (SO4 2-), chloride (Cl-), oxalate, thiosulfate, selenate, and other anions, so this broad transporter activity term is correct. However, more specific molecular function terms (secondary active sulfate transmembrane transporter activity, chloride channel activity, chloride:bicarbonate antiporter activity) are also annotated and provide much more information about the actual transport mechanism.
Reason: Correct as a broad classification but redundant with more specific molecular function annotations.
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GO:0140900
chloride:bicarbonate antiporter activity
|
IEA
GO_REF:0000107 |
MODIFY |
Summary: This annotation is transferred from the mouse ortholog via Ensembl. Early literature proposed that SLC26A11 mediates chloride-bicarbonate exchange in kidney. However, recent 2025 reconstitution studies with purified SLC26A11 showed that bicarbonate shows little to no competition for the substrate binding site. The primary exchange mechanism is proton-coupled sulfate/chloride exchange, not chloride/bicarbonate antiport. This may represent an older functional characterization that has been superseded by more recent direct biochemical evidence.
Reason: Recent direct biochemical evidence indicates bicarbonate is not a significant substrate. The actual mechanism is proton-coupled sulfate/chloride exchange. The term should be replaced with a more accurate description of the exchange activity.
Proposed replacements:
secondary active sulfate transmembrane transporter activity
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
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this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
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The protein encoded by A0A2R9CAF4 in Pan paniscus (bonobo) is the ortholog of human SLC26A11 (solute carrier family 26 member 11), also known as KBAT (kidney and brain anion transporter) or SUT1. While no direct literature exists for this specific bonobo protein, the UniProt annotation correctly identifies it as a sodium-independent sulfate anion transporter belonging to the SLC26/SulP transporter family. High sequence conservation among primate orthologs allows us to confidently infer the bonobo protein's function from extensive recent research on human and mammalian SLC26A11 (kuhn2025slc26a11isan pages 1-4, bungertplumke2024oligomerizationandcellular pages 1-3, lee2024chloridemultipleanionexchanger pages 1-2).
Recent breakthrough structural and functional studies from 2024-2025 have resolved the long-standing controversy about SLC26A11 function, demonstrating that it is a dual-function protein capable of operating as both a secondary active transporter and an anion channel (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14).
As a transporter, SLC26A11 functions as an electroneutral proton:sulfate/chloride exchanger (kuhn2025slc26a11isan pages 1-4). Reconstitution experiments with purified human SLC26A11 in proteoliposomes revealed that the protein catalyzes symport of one proton with one sulfate ion (net charge -1) coupled to antiport of one chloride ion (net charge -1), resulting in electroneutral exchange (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 1-4). This transport is strongly pH-dependent, with the highest sulfate accumulation observed at pH gradients of 2.0-2.5 units with the acidic pH on the extracellular (or luminal) side (kuhn2025slc26a11isan pages 1-4).
As a channel, SLC26A11 exhibits chloride-selective conductance that is gated by proton and sulfate transport (kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 18-20). Whole-cell patch clamp experiments demonstrated that SLC26A11 currents are activated by conditions favoring sulfate binding and transport, with current reversal potentials near the Nernst equilibrium potential for chloride (kuhn2025slc26a11isan pages 10-12, kuhn2025slc26a11isan pages 12-14). This dual functionality places SLC26A11 among a small group of transporters, including members of the SLC1 and ClC families, that exhibit both coupled transport and channel-like properties (kuhn2025slc26a11isan pages 14-16).
SLC26A11 transports multiple anions with varying affinities. Direct transport assays and competition studies identify the following substrates in order of effectiveness: sulfate (SOβΒ²β»), oxalate (CβOβΒ²β»), thiosulfate, selenate, and chloride (Clβ»), with weaker interactions with molybdate, iodide, and acetate (kuhn2025slc26a11isan pages 4-7, lee2024chloridemultipleanionexchanger pages 1-2). Bicarbonate and phosphate show minimal or no competition for the substrate binding site (kuhn2025slc26a11isan pages 4-7).
The apparent KM for sulfate transport is 39.7 Β± 5.5 Β΅M under optimal pH gradient conditions (pHout 5.0; pHin 7.5) (kuhn2025slc26a11isan pages 1-4). Substrate binding affinities are strongly pH-dependent: sulfate exhibits an apparent KD of 57 Β± 11 Β΅M at pH 5.0 versus 2.9 Β± 0.4 mM at pH 7.5, representing nearly a 50-fold change, while chloride binding remains relatively constant at approximately 5-6 mM regardless of pH (kuhn2025slc26a11isan pages 10-12).
A unique feature of SLC26A11 is the presence of glutamate-320 (Glu-320), a residue not found at the equivalent position in other mammalian SLC26 family members (kuhn2025slc26a11isan pages 7-10, kuhn2025slc26a11isan pages 12-14). This residue acts as a pH-sensitive "signal integration node" that determines substrate preference (kuhn2025slc26a11isan pages 10-12, kuhn2025slc26a11isan pages 12-14).
Molecular dynamics simulations and differential scanning fluorimetry revealed that protonation of Glu-320 at acidic pH selectively increases sulfate binding affinity by approximately two orders of magnitude while leaving chloride affinity essentially unchanged (kuhn2025slc26a11isan pages 7-10, kuhn2025slc26a11isan pages 10-12). This mechanism is critical for SLC26A11's physiological function: in the acidic lysosomal lumen (pH ~4.6), protonated Glu-320 enables SLC26A11 to selectively bind sulfate despite the presence of 80-120 mM chloride that exceeds lysosomal sulfate concentrations by orders of magnitude (kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16).
Multiple independent lines of evidence from 2024 studies establish that SLC26A11 localizes predominantly to lysosomes in mammalian cells (bungertplumke2024oligomerizationandcellular pages 1-3, bungertplumke2024oligomerizationandcellular pages 3-5, kuhn2025slc26a11isan pages 1-4). Confocal microscopy experiments using fluorescently tagged SLC26A11 expressed in HEK293T cells, COS1 cells, CHO cells, and immortalized renal intercalated cells (Clone C) demonstrated exclusive intracellular localization with significant overlap with Lamp1, a lysosomal marker protein (Manders coefficient 0.45-0.50), and minimal overlap with the endoplasmic reticulum marker calnexin (Manders coefficient 0.09-0.12) (bungertplumke2024oligomerizationandcellular pages 1-3, bungertplumke2024oligomerizationandcellular pages 3-5).
This lysosomal localization is independent of cell type, protein expression level, or the presence of fluorescent protein tags (bungertplumke2024oligomerizationandcellular pages 1-3, bungertplumke2024oligomerizationandcellular pages 3-5). Both mouse and human SLC26A11 show similar intracellular distributions (bungertplumke2024oligomerizationandcellular pages 3-5). Importantly, proteomic and transcriptomic studies have independently identified SLC26A11 as a lysosomal membrane protein, and its expression is upregulated during lysosomal biogenesis (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14).
Although SLC26A11 is co-expressed with SLC26A4/pendrin and SLC26A7 in certain cell types, such as renal collecting duct intercalated cells, co-expression experiments and native gel electrophoresis demonstrated that SLC26A11 does not form heterodimers with SLC26A1, SLC26A2, SLC26A4, SLC26A6, SLC26A7, or SLC26A9 (bungertplumke2024oligomerizationandcellular pages 1-3, bungertplumke2024oligomerizationandcellular pages 3-5, bungertplumke2024oligomerizationandcellular pages 6-8). The protein functions exclusively as a homodimer, and heterodimerization does not alter its subcellular distribution (bungertplumke2024oligomerizationandcellular pages 3-5).
The structure of human SLC26A11 was determined by cryo-electron microscopy at 2.8 Γ resolution in 2025, providing atomic-level insights into its mechanism (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10). SLC26A11 forms a homodimer with each protomer containing 14 transmembrane helices (TM1-14) arranged in two inverted repeats of seven TMs (kuhn2025slc26a11isan pages 7-10). The membrane domain is subdivided into a compact transport domain flanked by an elongated scaffold domain, with the two subdomains connected by Ξ±-helical interdomain linkers on both sides of the membrane (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10).
This architecture is shared with other SLC26 family members and related families (SLC4, SLC23), reflecting the conserved elevator-type transport mechanism characteristic of this superfamily (kuhn2025slc26a11isan pages 4-7, wang2021structureandfunction pages 1-2). However, SLC26A11 exhibits several unique structural features that distinguish it from other mammalian SLC26 proteins (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10).
Each protomer contains a C-terminal cytosolic STAS (Sulfate Transporter and Anti-Sigma factor antagonist) domain that is swapped between neighboring subunits in the dimer (kuhn2025slc26a11isan pages 4-7, wang2021structureandfunction pages 1-2). SLC26A11 has the most compact STAS domain of all human SLC26 transporters due to the absence of an internal intrinsically disordered "intervening sequence" and a comparatively short disordered C-terminus (kuhn2025slc26a11isan pages 7-10). The dimer interface is composed primarily of interactions between STAS domains and the scaffold domain elements (TM5, TM12, TM13, and the intracellular interdomain linker) (kuhn2025slc26a11isan pages 7-10).
The STAS domain plays a regulatory role in transport function. Studies of the related plant sulfate transporter AtSULTR4;1 demonstrated that deletion of the STAS domain or mutations at the STAS-transmembrane domain interface compromise dimer formation and reduce sulfate transport (wang2021structureandfunction pages 1-2).
Three structural deviations distinguish SLC26A11 from other mammalian SLC26 proteins (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10):
Alternative glycosylation site: While other human SLC26 isoforms carry glycosylation sites in the elongated extracellular loop TM3-4, SLC26A11 has a compact TM3-4 loop and instead features a Ξ²-hairpin extension in loop TM7-8 that carries an N-glycosylation site at Asn-294 (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10).
Kinked TM7 helix: TM7 in the scaffold domain is unusually long and kinked at Ala-246 within the membrane, creating a 107Β° angle between the extracellular and intracellular halves. This arrangement extends the intracellular loop TM6-7, which presents a potential class VIII SH3 domain binding sequence (PxxPxxP motif) that may mediate protein-protein interactions (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10, kuhn2025slc26a11isan pages 14-16).
Compact STAS domain: The absence of the intervening sequence found in other SLC26 proteins results in a smaller STAS domain with a reduced interface between adjacent STAS domains compared to other family members (kuhn2025slc26a11isan pages 7-10).
The primary physiological role of SLC26A11 is to function as the lysosomal sulfate exporter, a role that resolves a long-standing question in lysosomal biology (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16). Lysosomes are the primary degradative compartments of eukaryotic cells, and lysosomal recycling depends on the concerted action of hydrolases and transporters for catabolite export (kuhn2025slc26a11isan pages 1-4).
During lysosomal degradation, sulfur-containing macromolecules (amino acids, lipids, and glycosaminoglycans) are broken down, and sulfate groups are released by sulfatase enzymes (kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16). Accumulation of sulfate in the lysosomal lumen would cause competitive inhibition of sulfatases, impairing lysosomal function (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14). SLC26A11 mediates the export of sulfate from the lysosome using the proton gradient as a driving force, preventing product accumulation and maintaining optimal sulfatase activity (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 14-16).
The transport mechanism is well-suited to this function: at the acidic lysosomal pH (~4.6), Glu-320 is predominantly protonated, selectively increasing sulfate binding affinity and enabling sulfate-bound SLC26A11 to form despite high luminal chloride concentrations (80-120 mM) (kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16). After reorientation of the substrate binding site to the cytoplasm, the neutral pH leads to deprotonation of Glu-320, reducing sulfate affinity and promoting sulfate release (kuhn2025slc26a11isan pages 12-14).
The chloride channel activity of SLC26A11 may contribute to lysosomal chloride homeostasis (kuhn2025slc26a11isan pages 14-16). Since the Nernst potential for chloride in lysosomes is likely close to the membrane potential, chloride fluxes through the SLC26A11 channel are expected to be limited under physiological conditions (kuhn2025slc26a11isan pages 14-16). However, if luminal chloride concentrations exceed the range maintainable by the membrane potential, the chloride conductance may serve to decrease chloride levels, providing negative feedback that ensures high transport rates by accelerating the chloride-dependent transport mode (kuhn2025slc26a11isan pages 14-16).
While SLC26A11 in lysosomes serves a housekeeping function, plasmalemmal SLC26A11 has been implicated in pathological neuronal swelling and brain edema during ischemia (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16). Under physiological conditions at neutral pH and sub-millimolar extracellular sulfate concentrations, plasmalemmal SLC26A11 is unlikely to reach the chloride-conductive state (kuhn2025slc26a11isan pages 14-16). However, during brain trauma and ischemia, tissue acidification causes both external and internal pH to fall below 6.5, activating high SLC26A11 chloride currents that contribute to cytotoxic edema (kuhn2025slc26a11isan pages 14-16). This has led to proposals for SLC26A11 inhibition as a therapeutic strategy for ischemic stroke (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 14-16).
SLC26A11 exhibits broad tissue distribution, with highest expression in brain and additional expression in kidney (intercalated cells), pancreatic ducts, endothelial cells, and other tissues (kuhn2025slc26a11isan pages 1-4, lee2024chloridemultipleanionexchanger pages 1-2). This widespread expression pattern is consistent with a housekeeping role in lysosomal function across cell types (kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16). The protein's upregulation during lysosomal biogenesis further supports its essential role in lysosomal metabolism (kuhn2025slc26a11isan pages 1-4).
The SLC26 family comprises 11 members in mammals (SLC26A1-11, with A10 being a pseudogene) that function as anion exchangers or channels with diverse physiological roles (lee2024chloridemultipleanionexchanger pages 1-2). Family members share a common structural architecture but exhibit distinct substrate specificities, subcellular localizations, and tissue distributions (wang2021structureandfunction pages 1-2).
Other SLC26 members involved in sulfate homeostasis include:
SLC26A1 (Sat1): A plasma membrane sulfate/bicarbonate exchanger expressed in kidney, liver, and intestine that plays a major role in renal sulfate reabsorption and systemic sulfate homeostasis (pfau2023slc26a1isa pages 1-2). Loss-of-function mutations in human SLC26A1 cause hyposulfatemia and hypersulfaturia (pfau2023slc26a1isa pages 1-2).
SLC26A2 (DTDST): A sulfate transporter in chondrocytes essential for cartilage proteoglycan sulfation; mutations cause diastrophic dysplasia and other skeletal dysplasias (lee2024chloridemultipleanionexchanger pages 1-2).
The physiological importance of sulfate homeostasis has been increasingly recognized, with links to bone and cartilage health, intervertebral disc disorders, and musculoskeletal conditions (pfau2023slc26a1isa pages 1-2). SLC26A11's role as the lysosomal sulfate exporter complements the systemic sulfate homeostasis functions of SLC26A1 and the biosynthetic sulfate import functions of SLC26A2.
| Functional Category | Key Information | Evidence Source |
|---|---|---|
| Primary Function | A0A2R9CAF4 from Pan paniscus is best interpreted as the bonobo ortholog of SLC26A11, a sodium-independent sulfate anion transporter in the SLC26/SulP family. Recent mechanistic work identifies SLC26A11 as the lysosomal sulfate exporter and a dual-function protein capable of both coupled sulfate transport and chloride conductance. | (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14) |
| Substrate Specificity | Direct functional studies show transport or strong competition by sulfate, chloride, oxalate, thiosulfate, selenate, and molybdate; iodide, acetate, and chloride inhibit sulfate uptake to lesser extents, while phosphate and bicarbonate show little to no effect in the reconstituted assay. Earlier family summaries also list Clβ, HCO3β, SO4^2β, and oxalate for SLC26A11/KBAT. | (kuhn2025slc26a11isan pages 4-7, lee2024chloridemultipleanionexchanger pages 1-2) |
| Transport Mechanism | SLC26A11 operates primarily as an electroneutral proton:sulfate/chloride exchanger. The most parsimonious model is symport of 1 H+ with 1 SO4^2β coupled to antiport of 1 Clβ. Independent electrophysiology further shows a chloride-selective channel-like conductance gated by proton/sulfate transport, establishing dual transporter-channel behavior. | (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 12-14) |
| Kinetic Parameters | Apparent sulfate transport KM in proteoliposomes: 39.7 Β± 5.5 Β΅M under a strong pH gradient (pHout 5.0; pHin 7.5). Apparent KD values from DSF: chloride 6.0 Β± 1.4 mM at pH 5.0 and 5.3 Β± 0.7 mM at pH 7.5; sulfate 57 Β± 11 Β΅M at pH 5.0 versus 2.9 Β± 0.4 mM at pH 7.5, showing strong pH-dependent sulfate selectivity. | (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 10-12) |
| Subcellular Localization | In mammalian cells, SLC26A11 localizes predominantly to lysosomes, with significant overlap with Lamp1 and minimal overlap with the ER marker calnexin. Co-expression with SLC26A4 or SLC26A7 does not relocalize it, and no evidence for heterodimerization with those paralogs was found. A fraction reaches the plasma membrane in Sf9 insect cells, enabling electrophysiology, but lysosomal localization is the dominant mammalian pattern. | (bungertplumke2024oligomerizationandcellular pages 1-3, bungertplumke2024oligomerizationandcellular pages 3-5, bungertplumke2024oligomerizationandcellular pages 6-8, kuhn2025slc26a11isan pages 10-12) |
| Structural Features | SLC26A11 forms a homodimer. Each protomer contains 14 transmembrane helices organized into transport and scaffold domains plus a cytosolic STAS domain. The STAS domains are domain-swapped between protomers. SLC26A11 has a notably compact STAS domain, an alternative N-glycosylation site at Asn-294 in the TM7-8 loop, and a kinked TM7 that exposes a potential SH3-binding motif. | (kuhn2025slc26a11isan pages 4-7, kuhn2025slc26a11isan pages 7-10) |
| Biological Processes | The transporter participates in lysosomal sulfate homeostasis and catabolite clearance. Sulfate produced by lysosomal degradation and sulfatase reactions must be exported to prevent product accumulation and competitive inhibition of sulfatases; SLC26A11 is proposed to mediate this efflux using the lysosomal proton gradient. It is also discussed as contributing to lysosomal chloride homeostasis and transport-rate optimization. | (kuhn2025slc26a11isan pages 1-4, kuhn2025slc26a11isan pages 12-14, kuhn2025slc26a11isan pages 14-16) |
| Tissue Expression | SLC26A11 is broadly expressed, with highest reported expression in brain and additional expression in kidney/intercalated cells, pancreatic ducts, endothelial cells, and other tissues. Broad distribution is consistent with a housekeeping role in lysosomal function. | (kuhn2025slc26a11isan pages 1-4, lee2024chloridemultipleanionexchanger pages 1-2, kuhn2025slc26a11isan pages 12-14) |
| Unique Features | A distinctive Glu-320 residue, unique among mammalian SLC26 family members at the aligned position, acts as a pH-sensitive determinant of substrate preference. Protonation of Glu-320 selectively increases sulfate affinity by nearly two orders of magnitude while leaving chloride affinity largely unchanged, explaining how SLC26A11 favors sulfate export from the acidic lysosomal lumen despite high luminal chloride. | (kuhn2025slc26a11isan pages 7-10, kuhn2025slc26a11isan pages 10-12, kuhn2025slc26a11isan pages 12-14) |
| Clinical Relevance | SLC26A11 chloride currents have been implicated in pathological neuronal swelling and ischemia-associated brain edema under acidic conditions, making SLC26A11 a potential therapeutic target. More broadly, recent sulfate-transporter work in related SLC26 members underscores the physiological importance of sulfate homeostasis in humans, including musculoskeletal and cartilage biology, which strengthens interest in SLC26A11 as a lysosomal sulfate-handling protein. | (kuhn2025slc26a11isan pages 14-16, pfau2023slc26a1isa pages 1-2) |
Table: This table summarizes the current functional annotation for bonobo A0A2R9CAF4 as the SLC26A11 ortholog, integrating recent structural, mechanistic, localization, and clinical evidence. It is useful for quickly mapping primary function, substrate handling, localization, and biological significance to specific cited sources.
While no direct studies exist for the bonobo protein A0A2R9CAF4, the high conservation of SLC26A11 orthologs and the comprehensive mechanistic understanding derived from recent human studies (2024-2025) allow confident functional annotation. The protein functions primarily as the lysosomal sulfate exporter, utilizing an elegant pH-sensing mechanism via Glu-320 to selectively transport sulfate from the acidic lysosomal lumen despite high competing chloride concentrations. Its dual transporter-channel function represents a sophisticated regulatory mechanism linking sulfate export to chloride homeostasis.
The identification of SLC26A11's lysosomal function has implications for understanding lysosomal storage diseases and may provide new therapeutic approaches. Additionally, its role in pathological brain edema suggests potential for therapeutic intervention in ischemic stroke through specific SLC26A11 inhibition (kuhn2025slc26a11isan pages 14-16).
References
(kuhn2025slc26a11isan pages 1-4): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(bungertplumke2024oligomerizationandcellular pages 1-3): Stefanie Bungert-PlΓΌmke, Raul E. Guzman, and Christoph Fahlke. Oligomerization and cellular localization of slc26a11. bioRxiv, May 2024. URL: https://doi.org/10.1101/2024.04.29.591613, doi:10.1101/2024.04.29.591613. This article has 2 citations.
(lee2024chloridemultipleanionexchanger pages 1-2): Dongun Lee and Jeong Hee Hong. Chloride/multiple anion exchanger slc26a family: systemic roles of slc26a4 in various organs. International Journal of Molecular Sciences, 25:4190, Apr 2024. URL: https://doi.org/10.3390/ijms25084190, doi:10.3390/ijms25084190. This article has 10 citations.
(kuhn2025slc26a11isan pages 12-14): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(kuhn2025slc26a11isan pages 4-7): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(kuhn2025slc26a11isan pages 18-20): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(kuhn2025slc26a11isan pages 10-12): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(kuhn2025slc26a11isan pages 14-16): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(kuhn2025slc26a11isan pages 7-10): Benedikt T Kuhn, Peter Kovermann, Bassam G Haddad, Tim Rasmussen, Tamsanga Hove, Stefanie Bungert-Pluemke, Bettina Boettcher, Jan-Philipp Machtens, Christoph Fahlke, and Eric R. Geertsma. Slc26a11 is an atypical solute carrier with dual transport-channel function mediating lysosomal sulfate transport. BioRxiv, Aug 2025. URL: https://doi.org/10.1101/2025.08.17.670773, doi:10.1101/2025.08.17.670773. This article has 1 citations.
(bungertplumke2024oligomerizationandcellular pages 3-5): Stefanie Bungert-PlΓΌmke, Raul E. Guzman, and Christoph Fahlke. Oligomerization and cellular localization of slc26a11. bioRxiv, May 2024. URL: https://doi.org/10.1101/2024.04.29.591613, doi:10.1101/2024.04.29.591613. This article has 2 citations.
(bungertplumke2024oligomerizationandcellular pages 6-8): Stefanie Bungert-PlΓΌmke, Raul E. Guzman, and Christoph Fahlke. Oligomerization and cellular localization of slc26a11. bioRxiv, May 2024. URL: https://doi.org/10.1101/2024.04.29.591613, doi:10.1101/2024.04.29.591613. This article has 2 citations.
(wang2021structureandfunction pages 1-2): Lie Wang, Kehan Chen, and Ming Zhou. Structure and function of an arabidopsis thaliana sulfate transporter. Nature Communications, Jul 2021. URL: https://doi.org/10.1038/s41467-021-24778-2, doi:10.1038/s41467-021-24778-2. This article has 77 citations and is from a highest quality peer-reviewed journal.
(pfau2023slc26a1isa pages 1-2): Anja Pfau, Karen I. LΓ³pez-Cayuqueo, Nora Scherer, Matthias Wuttke, Annekatrin Wernstedt, Daniela GonzΓ‘lez Fassrainer, Desiree E.C. Smith, Jiddeke M. van de Kamp, Katharina Ziegeler, Kai-Uwe Eckardt, Friedrich C. Luft, Peter S. Aronson, Anna KΓΆttgen, Thomas J. Jentsch, and Felix Knauf. Slc26a1 is a major determinant of sulfate homeostasis in humans. The Journal of Clinical Investigation, Feb 2023. URL: https://doi.org/10.1172/jci161849, doi:10.1172/jci161849. This article has 21 citations.
id: A0A2R9CAF4
gene_symbol: A0A2R9CAF4
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9597
label: Pan paniscus
description: >-
A0A2R9CAF4 is the bonobo (Pan paniscus) ortholog of human SLC26A11 (also known
as KBAT, kidney and brain anion transporter), a member of the SLC26/SulP
transporter family. SLC26A11 is a dual-function protein that operates both as an
electroneutral proton-coupled sulfate/chloride exchanger and as a chloride-selective
channel. The transporter contains a transmembrane domain with 14 helices arranged
in two inverted repeats and a cytosolic STAS (Sulfate Transporter and Anti-Sigma
factor antagonist) domain. It functions as a homodimer. The primary physiological
role is lysosomal sulfate export: the protein uses the lysosomal proton gradient
to selectively transport sulfate from the acidic lysosomal lumen to the cytoplasm,
preventing product inhibition of lysosomal sulfatases. A unique glutamate residue
(Glu-320 in human) serves as a pH-sensitive switch that increases sulfate binding
affinity approximately 50-fold at acidic pH, enabling selective sulfate transport
despite much higher luminal chloride concentrations. The protein is broadly expressed,
with highest levels in brain and kidney, consistent with a housekeeping role in
lysosomal catabolite clearance. Under pathological acidic conditions (e.g., brain
ischemia), plasmalemmal SLC26A11 chloride channel activity may contribute to
cytotoxic neuronal swelling.
existing_annotations:
- term:
id: GO:0005765
label: lysosomal membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
Multiple independent studies from 2024-2025 establish that SLC26A11 localizes
predominantly to lysosomes in mammalian cells. Confocal microscopy with
fluorescently tagged SLC26A11 in HEK293T, COS1, CHO, and renal intercalated
cells shows significant overlap with the lysosomal marker Lamp1 (Manders
coefficient 0.45-0.50). Both mouse and human orthologs show similar lysosomal
localization. This is the primary functional location where the protein exports
sulfate using the lysosomal proton gradient.
action: ACCEPT
reason: >-
Lysosomal membrane is the primary functional location of SLC26A11, strongly
supported by recent localization studies and consistent with its role as a
lysosomal sulfate exporter.
- term:
id: GO:0008271
label: secondary active sulfate transmembrane transporter activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
Reconstitution experiments with purified human SLC26A11 in proteoliposomes
demonstrate that it catalyzes symport of one proton with one sulfate ion
coupled to antiport of one chloride ion. The transport is strongly pH-dependent,
with highest sulfate accumulation at pH gradients of 2.0-2.5 units with acidic
pH on the luminal side. The apparent KM for sulfate is 39.7 +/- 5.5 uM under
optimal conditions. This is a core molecular function of SLC26A11.
action: ACCEPT
reason: >-
Sulfate transporter activity is a core function of SLC26A11, directly
demonstrated by reconstitution studies with purified protein.
- term:
id: GO:0015698
label: inorganic anion transport
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: >-
SLC26A11 does transport inorganic anions (sulfate, chloride), so this term
is technically correct. However, it is very broad and does not capture the
specific transport substrates or mechanism. More informative process terms
such as sulfate transmembrane transport (GO:1902358) are also annotated.
action: KEEP_AS_NON_CORE
reason: >-
Correct but too general to be informative when more specific transport
process annotations are present.
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
SLC26A11 is indeed an integral membrane protein with 10 predicted
transmembrane helices (per Phobius) and 14 TM helices in the cryo-EM
structure. However, the term 'membrane' is extremely broad and adds no
information beyond what is conveyed by the more specific lysosomal membrane
annotation.
action: MARK_AS_OVER_ANNOTATED
reason: >-
The generic 'membrane' term is redundant with the more specific lysosomal
membrane (GO:0005765) and plasma membrane (GO:0005886) annotations.
- term:
id: GO:0016323
label: basolateral plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
This annotation is transferred from the mouse ortholog Q80ZD3 via Ensembl.
However, recent 2024 localization studies show that SLC26A11 predominantly
localizes to lysosomes in multiple mammalian cell types, with minimal
overlap with plasma membrane markers. The basolateral plasma membrane
annotation likely derives from older immunohistochemistry studies in kidney
intercalated cells that may have detected the protein in transit through
the secretory pathway or at low levels on the plasma membrane. The primary
functional location is the lysosomal membrane.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Recent comprehensive localization studies demonstrate predominant lysosomal
localization. Basolateral plasma membrane is not the primary functional
location and likely represents a minor or transient pool.
- term:
id: GO:0016324
label: apical plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
Like the basolateral annotation, this is transferred from the mouse ortholog.
The same concerns apply: SLC26A11 predominantly localizes to lysosomes,
not to the apical plasma membrane. The 2024 Bungert-Plumke et al. study
showed that SLC26A11 localization is independent of cell type and consistently
intracellular/lysosomal.
action: MARK_AS_OVER_ANNOTATED
reason: >-
SLC26A11 predominantly localizes to lysosomes. Apical plasma membrane is
not the primary functional location based on recent localization data.
- term:
id: GO:0055085
label: transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: >-
SLC26A11 is a transmembrane transporter, so involvement in transmembrane
transport is correct. However, this is a very broad parent term that
adds little information when more specific process terms (sulfate
transmembrane transport, chloride transmembrane transport) are annotated.
action: KEEP_AS_NON_CORE
reason: >-
Correct but too general; subsumed by the more specific sulfate and chloride
transmembrane transport annotations.
- term:
id: GO:0098656
label: monoatomic anion transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: involved_in
review:
summary: >-
This was inferred from monoatomic anion transmembrane transporter activity
(GO:0008509) via logical inference. SLC26A11 does transport monoatomic
anions (chloride, sulfate). The term is correct but represents an
intermediate level of specificity between the very broad transmembrane
transport and the specific sulfate/chloride transport annotations.
action: KEEP_AS_NON_CORE
reason: >-
Logically inferred and correct, but redundant with more specific transport
process annotations.
- term:
id: GO:1902358
label: sulfate transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: involved_in
review:
summary: >-
Sulfate transmembrane transport is the primary biological process mediated
by SLC26A11. The protein functions as the lysosomal sulfate exporter,
using the proton gradient to drive sulfate from the acidic lysosomal lumen
to the cytoplasm. This prevents product accumulation that would inhibit
lysosomal sulfatases. Reconstitution studies confirm direct sulfate
transport with KM of approximately 40 uM.
action: ACCEPT
reason: >-
This is the core biological process of SLC26A11, directly supported by
functional reconstitution studies.
- term:
id: GO:1902476
label: chloride transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: involved_in
review:
summary: >-
This was inferred from chloride channel activity (GO:0005254). SLC26A11
does conduct chloride, both as the counter-ion in sulfate/chloride exchange
and through its chloride channel mode. The chloride channel activity is gated
by proton and sulfate transport. Under physiological lysosomal conditions,
chloride fluxes may help maintain lysosomal chloride homeostasis.
action: KEEP_AS_NON_CORE
reason: >-
Chloride transport occurs as part of the coupled sulfate/chloride exchange
mechanism and through the channel mode, but is secondary to the primary
sulfate export function. The annotation is valid but represents a supporting
rather than core activity.
- term:
id: GO:0005254
label: chloride channel activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: >-
SLC26A11 does exhibit chloride-selective channel conductance, as demonstrated
by whole-cell patch clamp experiments. The channel activity is gated by
conditions favoring sulfate binding and transport, with current reversal
potentials near the Nernst equilibrium potential for chloride. This dual
transporter-channel behavior is well-established for SLC26A11 and places it
among a small group of transporters with both coupled transport and
channel-like properties. The annotation is transferred from the mouse
ortholog via Ensembl.
action: ACCEPT
reason: >-
Chloride channel activity is a genuine molecular function of SLC26A11,
directly demonstrated by electrophysiology. The dual transporter-channel
mechanism is a distinctive feature of this protein.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: located_in
review:
summary: >-
This annotation is transferred from the human ortholog Q86WA9 via Ensembl.
The 2024 Bungert-Plumke et al. study specifically showed minimal overlap
between SLC26A11 and the ER marker calnexin (Manders coefficient 0.09-0.12).
Some ER localization is expected for any integral membrane protein in transit
through the secretory pathway, but the ER is not a functional location for
SLC26A11.
action: MARK_AS_OVER_ANNOTATED
reason: >-
ER localization is minimal and likely reflects transient biosynthetic
trafficking rather than functional residence. Recent studies explicitly
show low overlap with ER markers.
- term:
id: GO:0005794
label: Golgi apparatus
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: located_in
review:
summary: >-
Transferred from the human ortholog via Ensembl. Like the ER annotation,
Golgi localization likely reflects transit through the secretory pathway
en route to lysosomes rather than functional residence. The 2024 localization
studies consistently show predominant lysosomal localization across multiple
cell types.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Golgi localization likely represents biosynthetic trafficking to lysosomes
rather than the functional site of this protein.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
SLC26A11 can reach the plasma membrane under certain conditions (e.g., in
Sf9 insect cells used for electrophysiology), and a small fraction may be
present on the plasma membrane in mammalian cells. However, the predominant
localization is lysosomal. Plasmalemmal SLC26A11 has been implicated in
pathological neuronal swelling during ischemia, but this appears to be a
pathological rather than physiological context.
action: KEEP_AS_NON_CORE
reason: >-
Plasma membrane localization is real but minor under physiological
conditions. The primary functional location is the lysosomal membrane. The
plasma membrane pool becomes pathologically relevant during ischemia.
- term:
id: GO:0008509
label: monoatomic anion transmembrane transporter activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: >-
SLC26A11 transports sulfate (SO4 2-), chloride (Cl-), oxalate, thiosulfate,
selenate, and other anions, so this broad transporter activity term is
correct. However, more specific molecular function terms (secondary active
sulfate transmembrane transporter activity, chloride channel activity,
chloride:bicarbonate antiporter activity) are also annotated and provide
much more information about the actual transport mechanism.
action: KEEP_AS_NON_CORE
reason: >-
Correct as a broad classification but redundant with more specific
molecular function annotations.
- term:
id: GO:0140900
label: chloride:bicarbonate antiporter activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: enables
review:
summary: >-
This annotation is transferred from the mouse ortholog via Ensembl. Early
literature proposed that SLC26A11 mediates chloride-bicarbonate exchange in
kidney. However, recent 2025 reconstitution studies with purified SLC26A11
showed that bicarbonate shows little to no competition for the substrate
binding site. The primary exchange mechanism is proton-coupled
sulfate/chloride exchange, not chloride/bicarbonate antiport. This may
represent an older functional characterization that has been superseded by
more recent direct biochemical evidence.
action: MODIFY
reason: >-
Recent direct biochemical evidence indicates bicarbonate is not a significant
substrate. The actual mechanism is proton-coupled sulfate/chloride exchange.
The term should be replaced with a more accurate description of the exchange
activity.
proposed_replacement_terms:
- id: GO:0008271
label: secondary active sulfate transmembrane transporter activity
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: file:PANPA/A0A2R9CAF4/A0A2R9CAF4-deep-research-falcon.md
title: Deep research report for SLC26A11 ortholog in Pan paniscus
findings:
- statement: >-
SLC26A11 functions primarily as the lysosomal sulfate exporter, using the
proton gradient as driving force
- statement: >-
SLC26A11 localizes predominantly to lysosomes with significant Lamp1 overlap
(Manders coefficient 0.45-0.50) and minimal ER overlap (0.09-0.12)
- statement: >-
SLC26A11 exhibits dual transporter-channel function: electroneutral
proton:sulfate/chloride exchange and chloride-selective channel conductance
- statement: >-
Bicarbonate and phosphate show minimal or no competition for the SLC26A11
substrate binding site
- statement: >-
Glu-320 acts as a pH-sensitive switch, increasing sulfate binding affinity
approximately 50-fold at acidic pH
core_functions:
- description: >-
Lysosomal sulfate export: SLC26A11 mediates electroneutral proton-coupled
sulfate/chloride exchange across the lysosomal membrane, exporting sulfate
released by lysosomal sulfatase activity to prevent product inhibition.
This is the primary housekeeping function of the protein.
molecular_function:
id: GO:0008271
label: secondary active sulfate transmembrane transporter activity
locations:
- id: GO:0005765
label: lysosomal membrane
directly_involved_in:
- id: GO:1902358
label: sulfate transmembrane transport
- description: >-
Chloride channel activity: SLC26A11 has a chloride-selective channel mode
gated by proton and sulfate transport. Under physiological conditions in
lysosomes, this may contribute to chloride homeostasis. Under pathological
acidification (e.g., brain ischemia), plasmalemmal SLC26A11 chloride
currents can contribute to cytotoxic neuronal swelling.
molecular_function:
id: GO:0005254
label: chloride channel activity
locations:
- id: GO:0005765
label: lysosomal membrane
directly_involved_in:
- id: GO:1902476
label: chloride transmembrane transport
supported_by:
- reference_id: file:PANPA/A0A2R9CAF4/A0A2R9CAF4-deep-research-falcon.md
supporting_text: >-
SLC26A11 exhibits dual transporter-channel function: electroneutral
proton:sulfate/chloride exchange and chloride-selective channel conductance