Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:1902600 proton transmembrane transport	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process. As the non-catalytic B subunit of the V1 head, ATP6V1B1 is part of the V-ATPase that couples ATP hydrolysis to transmembrane proton transport. Directly supported by functional studies of B1 mutants. Reason: Proton transmembrane transport is the defining function of the V-ATPase, and B1 is required for the assembly and activity of the pump. Phylogenetic (IBA) transfer is corroborated by direct experimental evidence in B1-expressing cells. Supporting Evidence: PMID:16769747 Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells. file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IBA GO_REF:0000033	ACCEPT	Summary: Core localization/complex membership. ATP6V1B1 is one of the three B subunits of the (AB)3 hexamer that forms the ATP-hydrolytic V1 domain of the V-ATPase. Reason: Membership of the B subunit in the V1 domain is established by the cryo-EM structure of the complete human V-ATPase and is consistent across orthologs. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Plasma membrane localization. In specialized cells (notably renal intercalated cells), the V-ATPase containing B1 is targeted to the plasma membrane where it acidifies the extracellular space. More specifically captured by the apical plasma membrane annotation below. Reason: Correct but general; the functionally relevant compartment for B1 is the apical plasma membrane (GO:0016324), which is annotated separately with direct evidence. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment
GO:0016324 apical plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Core localization. The plasma-membrane V-ATPase containing B1 is active at the apical membrane of renal intercalated cells and other distal nephron epithelia, where it secretes protons into the urine. Reason: Apical plasma membrane localization is directly demonstrated by immunoelectron microscopy and cell-based studies and is the physiologically relevant site of B1 function. Supporting Evidence: PMID:29993276 by immunoelectron microscopy the subunit is localized to the apical plasma membrane in the DCT PMID:16769747 GFP-B1WT and GFP-B1M are present in the apical membrane and increased with cellular acidification
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: V-ATPase-mediated acidification of intracellular compartments. This is the ancestral/general function of B subunits conserved across eukaryotes. Reason: Acidification of intracellular compartments is the canonical V-ATPase function; the phylogenetic transfer is appropriate for a B subunit, supported by the UniProt FUNCTION statement. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000117	ACCEPT	Summary: V1 domain membership (ARBA machine-learning electronic annotation). Redundant with the IBA and IDA annotations of the same term, which carry stronger evidence. Reason: Correct complex membership; supported by direct structural evidence elsewhere in this review. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: Core molecular function. The B subunit binds ATP at non-catalytic nucleotide sites of the (AB)3 hexamer; UniProt annotates an ATP-binding residue at position 394. Reason: ATP binding at the non-catalytic site is a conserved property of V-ATPase B subunits and is consistent with the InterPro nucleotide-binding domain assignment and the UniProt ATP-binding feature. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt BINDING 394
GO:0016323 basolateral plasma membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Basolateral plasma membrane (electronic orthology transfer from mouse/rat orthologs). B1 localization is predominantly apical; basolateral V-ATPase is seen in some intercalated cell subtypes (type B), but for B1 the dominant and functionally relevant localization is apical. Reason: Transferred by orthology from rodent (Q91YH6); plausible in a subset of cells but not the core localization of B1, which is apical. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Basolateral cell membrane {ECO:0000250\|UniProtKB:Q91YH6}
GO:0016324 apical plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: Apical plasma membrane (electronic orthology transfer). Redundant with the IDA/IBA apical plasma membrane annotations, which carry direct evidence. Reason: Correct core localization, corroborated by direct experimental evidence in this review. Supporting Evidence: PMID:29993276 by immunoelectron microscopy the subunit is localized to the apical plasma membrane in the DCT
GO:0033180 proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000002	ACCEPT	Summary: V1 domain membership (general, non-vacuolar-specific parent of GO:0000221). InterPro-based electronic annotation; correct complex membership. Reason: Correct V1 domain membership; the more specific vacuolar V1 domain term (GO:0000221) is also annotated with direct structural support. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:0046034 ATP metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: ATP metabolic process (InterPro electronic transfer). The V-ATPase hydrolyzes ATP, but B1 is the non-catalytic subunit; this broad term is a generic property of the holoenzyme rather than an informative B1-specific process. Reason: Overly broad and derived from the catalytic A-subunit-like domain signature. ATP hydrolysis is performed by the catalytic A subunits; B1 binds but does not hydrolyze ATP. Proton transmembrane transport better captures the relevant process. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Non-catalytic subunit of the V1 complex of vacuolar(H+)-
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Rotational proton-transporting ATPase activity. This is the molecular function of the assembled V-ATPase holoenzyme. As a non-catalytic structural subunit of the ATP-hydrolytic head, B1 contributes to but does not by itself enable this activity; GO commonly annotates obligate subunits with the holoenzyme activity. Reason: The rotational ATPase activity is a property of the holoenzyme; B1 is an essential non-catalytic subunit. Accepting the term as a subunit contribution is reasonable but it is not an autonomous B1 function, so it is retained as non-core. Supporting Evidence: PMID:33065002 ATP hydrolysis-driven proton pumps that acidify intracellular vesicles file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Essential for the proper assembly and activity of V-
GO:1902600 proton transmembrane transport	IEA GO_REF:0000120	ACCEPT	Summary: Core process (electronic orthology transfer). Redundant with the IBA and IMP proton transmembrane transport annotations, which carry direct evidence. Reason: Correct core function; corroborated by direct experimental evidence elsewhere in this review. Supporting Evidence: PMID:16769747 Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a large-scale neurodegeneration yeast-two-hybrid interactome (partners include ATXN1, TARDBP, WFS1, HSPB1, DNAJB6). Uninformative as a molecular function and not specific to ATP6V1B1 biology. Reason: Bare protein binding conveys no specific molecular function. The hits are high-throughput Y2H interactions; biologically meaningful binding (PDZ→NHERF1/SLC4A7 and the AB hexamer assembly) is captured by complex-membership and domain annotations rather than this generic term. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins
GO:0005737 cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cytoplasm (electronic orthology transfer). The V1 domain is cytoplasmic and peripheral, so a cytoplasmic pool of the soluble V1 subassembly is expected, but this is a low-information localization. Reason: Consistent with the cytoplasmic V1 domain but uninformative; the functionally relevant localization is the apical plasma membrane / V1 domain of the assembled pump. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cytosol (electronic orthology transfer). Same rationale as the cytoplasm annotation; consistent with a soluble cytosolic V1 pool but low information. Reason: Consistent with the cytoplasmic V1 domain; redundant with the Reactome TAS cytosol annotations and not the core functional site. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005902 microvillus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Microvillus (electronic orthology transfer from rodent ortholog). Consistent with apical brush-border localization in renal epithelia but not directly demonstrated for human B1. Reason: Plausible apical/microvillar localization transferred from the mouse ortholog; a refinement of the apical plasma membrane localization rather than an independent core function. Supporting Evidence: PMID:29993276 significant signal was also observed in apical membrane domains of the distal nephron
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Proton transmembrane transporter activity (electronic orthology transfer). This activity is mediated by the membrane-embedded V0 proton-conducting subunits; the cytoplasmic B1 subunit does not itself conduct protons. Reason: B1 is a non-membrane, non-catalytic subunit; the transporter activity is a holoenzyme property residing in V0. Retained as a subunit-level contribution rather than an autonomous B1 function. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a membrane integral complex (V0) that translocates protons
GO:0016020 membrane	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Generic "membrane" localization (electronic orthology transfer). Uninformative parent of the more specific apical/basolateral plasma membrane annotations. Reason: Too general to be useful; the specific membrane localization (apical plasma membrane) is annotated with direct evidence. Supporting Evidence: PMID:29993276 by immunoelectron microscopy the subunit is localized to the apical plasma membrane in the DCT
GO:0016328 lateral plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Lateral plasma membrane (electronic orthology transfer from rodent ortholog). B1's dominant and functionally relevant localization is apical; lateral/basolateral localization is minor. Reason: Transferred by orthology; not the core localization of B1, which is apical. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Basolateral cell membrane {ECO:0000250\|UniProtKB:Q91YH6}
GO:0044877 protein-containing complex binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Protein-containing complex binding (electronic orthology transfer). Generic binding term; B1 is an integral constituent of the V-ATPase rather than a binder of an external complex. Reason: Low-information binding term transferred by orthology; B1's relationship to the V-ATPase is captured by complex-membership (part_of) annotations, which are more informative than a generic complex-binding molecular function. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Non-catalytic subunit of the V1 complex of vacuolar(H+)-
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Synaptic vesicle lumen acidification (electronic orthology transfer). This is a neuronal V-ATPase function attributable to the ubiquitous/brain B2 isoform (ATP6V1B2), not the kidney/inner-ear-restricted B1 isoform. Reason: B1 is tissue-restricted (kidney, inner ear, epididymis, salivary gland) and is not the neuronal/synaptic isoform; this annotation is an inappropriate orthology transfer better assigned to ATP6V1B2. Supporting Evidence: PMID:14585495 Northern blotting detects a 2.2-kb Atp6v1b1 transcript in the kidney and testis, but not other major organs
GO:0098850 extrinsic component of synaptic vesicle membrane	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Extrinsic component of synaptic vesicle membrane (electronic orthology transfer). A neuronal localization attributable to the brain B2 isoform, not the kidney/inner-ear B1 isoform. Reason: Inappropriate orthology transfer; B1 is not the neuronal/synaptic isoform. The relevant V1 localization for B1 is the apical plasma membrane V-ATPase. Supporting Evidence: PMID:14585495 Northern blotting detects a 2.2-kb Atp6v1b1 transcript in the kidney and testis, but not other major organs
GO:0016323 basolateral plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Basolateral plasma membrane (ISS from mouse ortholog Q91YH6). Duplicate of the IEA basolateral annotation; B1's core localization is apical. Reason: Sequence-similarity transfer from rodent; plausible in a subset of cells but not the core apical localization of B1. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Basolateral cell membrane {ECO:0000250\|UniProtKB:Q91YH6}
GO:0097254 renal tubular secretion	IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive...	ACCEPT	Summary: Renal tubular secretion of protons. B1-containing apical V-ATPase secretes H+ into the urine in distal nephron cells; loss-of-function mutations impair this and cause distal renal tubular acidosis. Reason: Strong genetic and physiological evidence that B1 is required for distal nephron acid (proton) secretion into the tubular lumen. Supporting Evidence: PMID:12414817 subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Core complex membership with direct structural evidence. Cryo-EM of the complete human V-ATPase places the B subunit in the (AB)3 hexamer of the V1 ATP-hydrolytic head. Reason: Direct structural (IDA) evidence for B-subunit membership in the V1 domain; this is the strongest evidence for this localization. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:0016324 apical plasma membrane	IDA PMID:16769747 Vacuolar H+ -ATPase B1 subunit mutations that cause inherite...	ACCEPT	Summary: Core localization with direct evidence. GFP-tagged B1 localizes to the apical membrane of inner medullary collecting duct cells, increasing with cellular acidification. Reason: Direct experimental demonstration of apical plasma membrane localization in renal epithelial cells. Supporting Evidence: PMID:16769747 GFP-B1WT and GFP-B1M are present in the apical membrane and increased with cellular acidification
GO:0016324 apical plasma membrane	IDA PMID:29993276 H(+)-ATPase B1 subunit localizes to thick ascending limb and...	ACCEPT	Summary: Core localization with direct evidence. Immunoelectron microscopy in human and rodent kidney localizes the B1 subunit to the apical plasma membrane of intercalated cells and the early distal nephron (TAL, DCT). Reason: Antibody specificity validated in Atp6v1b1-deficient mice; immuno-EM directly demonstrates apical plasma membrane localization. Supporting Evidence: PMID:29993276 by immunoelectron microscopy the subunit is localized to the apical plasma membrane in the DCT
GO:0045851 pH reduction	IMP PMID:16769747 Vacuolar H+ -ATPase B1 subunit mutations that cause inherite...	ACCEPT	Summary: B1 is required for V-ATPase-mediated lowering of pH (proton accumulation). Disease mutants abolish proton-pump-mediated intracellular pH transport. Reason: Direct functional evidence that wild-type but not mutant B1 supports proton-pump-mediated acidification. Supporting Evidence: PMID:16769747 Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells.
GO:0070072 vacuolar proton-transporting V-type ATPase complex assembly	IMP PMID:16769747 Vacuolar H+ -ATPase B1 subunit mutations that cause inherite...	ACCEPT	Summary: Core process. B1 is required for proper assembly of the V-ATPase; disease point mutants fail to form complexes with other subunits. Reason: Direct functional evidence that wild-type B1 assembles with other H+-ATPase subunits whereas mutants do not, demonstrating a role in complex assembly. Supporting Evidence: PMID:16769747 GFP-B1WT formed complexes with other H+ -ATPase subunits (c, H, and E), whereas GFP-B1M did not file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Essential for the proper assembly and activity of V-
GO:1902600 proton transmembrane transport	IMP PMID:16769747 Vacuolar H+ -ATPase B1 subunit mutations that cause inherite...	ACCEPT	Summary: Core process with direct functional evidence. Wild-type B1 supports proton-pump-mediated transmembrane pH transport; disease mutants do not. Reason: Direct mutational evidence that B1 is required for V-ATPase proton transport activity. Supporting Evidence: PMID:16769747 Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells.
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: NAS annotation from a lipofuscin/senescence study that concerns lysosomal and autophagic activity generally, not ATP6V1B1 specifically. V-ATPase-driven lysosomal acidification supports autophagic flux, but this is a generic V-ATPase property and B1 is the tissue-restricted kidney/inner-ear isoform. Reason: Weak NAS link; the cited paper does not provide direct evidence that the B1 subunit regulates macroautophagy. Any contribution is an indirect, generic consequence of lysosomal acidification mediated by V-ATPase as a whole. Supporting Evidence: PMID:22982048 macroautophagy is responsible for the uptake of lipofuscin into the lysosomes
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: Detection in prostatic-secretion/urinary exosomes by high-throughput mass-spectrometry proteomics. Reflects presence in secreted vesicles (consistent with apical plasma-membrane V-ATPase shedding) rather than a site of function. Reason: Proteomic identification in exosomes is a bystander localization, not a functional compartment for the V-ATPase B1 subunit. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	MARK AS OVER ANNOTATED	Summary: Detection in parotid gland exosomes by high-throughput proteomics (MudPIT). Bystander localization in secreted vesicles, not a functional compartment. Reason: Proteomic identification in exosomes does not indicate a site of B1 function. Supporting Evidence: PMID:19199708 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT)
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: Detection in urinary exosomes by large-scale proteomics/phosphoproteomics. Bystander localization in secreted vesicles, not a functional compartment. Reason: Proteomic identification in exosomes does not indicate a site of B1 function; consistent with apical V-ATPase shedding into urinary vesicles. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes
GO:0005737 cytoplasm	ISS PMID:14585495 Molecular cloning and characterization of Atp6v1b1, the muri...	KEEP AS NON CORE	Summary: Cytoplasm (ISS from mouse ortholog Q91YH6). Consistent with the cytoplasmic V1 domain but low-information; duplicate of the IEA cytoplasm annotation. Reason: Consistent with the cytoplasmic peripheral V1 domain but not the core functional site. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005902 microvillus	ISS PMID:14585495 Molecular cloning and characterization of Atp6v1b1, the muri...	KEEP AS NON CORE	Summary: Microvillus (ISS from mouse ortholog). Consistent with apical brush-border localization in renal epithelia; a refinement of the apical plasma membrane localization. Reason: Plausible apical/microvillar localization transferred from the mouse ortholog; not an independent core function. Supporting Evidence: PMID:29993276 significant signal was also observed in apical membrane domains of the distal nephron
GO:0016323 basolateral plasma membrane	ISS PMID:14585495 Molecular cloning and characterization of Atp6v1b1, the muri...	KEEP AS NON CORE	Summary: Basolateral plasma membrane (ISS from mouse ortholog). Duplicate of the other basolateral annotations; B1's core localization is apical. Reason: Sequence-similarity transfer; plausible minor localization but not the core apical localization of B1. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Basolateral cell membrane {ECO:0000250\|UniProtKB:Q91YH6}
GO:0016328 lateral plasma membrane	ISS PMID:14585495 Molecular cloning and characterization of Atp6v1b1, the muri...	KEEP AS NON CORE	Summary: Lateral plasma membrane (ISS from mouse ortholog). Duplicate of the IEA lateral annotation; not the core apical localization of B1. Reason: Sequence-similarity transfer; minor localization relative to the dominant apical pool. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt Basolateral cell membrane {ECO:0000250\|UniProtKB:Q91YH6}
GO:0015078 proton transmembrane transporter activity	ISS PMID:14585495 Molecular cloning and characterization of Atp6v1b1, the muri...	KEEP AS NON CORE	Summary: Proton transmembrane transporter activity (ISS from mouse ortholog). The proton-conducting activity resides in the membrane-embedded V0 subunits; the cytoplasmic B1 subunit contributes to the holoenzyme but does not itself conduct protons. Reason: Holoenzyme-level activity assigned to a non-membrane, non-catalytic subunit; retained as a subunit contribution rather than an autonomous B1 function. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a membrane integral complex (V0) that translocates protons
GO:0042472 inner ear morphogenesis	IMP PMID:19639346 Inner ear abnormalities in four patients with dRTA and SNHL:...	KEEP AS NON CORE	Summary: ATP6V1B1 mutations are associated with inner-ear structural abnormalities, notably enlarged vestibular aqueduct (EVA), in patients with dRTA and sensorineural hearing loss. This is a downstream developmental/physiological consequence of impaired endolymph pH homeostasis rather than a direct morphogenetic function. Reason: Disease-phenotype association (EVA) is a downstream consequence of defective V-ATPase-mediated endolymph acidification, not a primary morphogenetic role of the B1 subunit. Retained as a non-core process. Supporting Evidence: PMID:19639346 confirms the association of EVA and mutations in the ATP6V1B1 gene
GO:0007605 sensory perception of sound	IMP PMID:20622307 Distal renal tubular acidosis and its relationship with hear...	KEEP AS NON CORE	Summary: ATP6V1B1 mutations cause sensorineural hearing loss; the gene is expressed in cochlea and endolymphatic sac, where V-ATPase activity maintains endolymph pH required for normal hearing. Reason: A genuine physiological role (via endolymph pH homeostasis), but it is a tissue-specific downstream consequence of the core proton-transport function rather than a distinct molecular activity. Retained as a non-core process. Supporting Evidence: PMID:20622307 a significant percentage of the children with DRTA had sensorineural hearing loss and mutation in ATP6V1B1 gene PMID:9916796 implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function
GO:0045851 pH reduction	IMP PMID:20622307 Distal renal tubular acidosis and its relationship with hear...	ACCEPT	Summary: pH reduction (proton accumulation) via V-ATPase. This clinical-genetics hearing-loss study supports the disease association; pH reduction is the core consequence of B1-dependent proton pumping (also directly demonstrated in PMID:16769747). Reason: B1-dependent V-ATPase lowers luminal/compartmental pH; the core function is well supported, though this particular reference is a clinical correlation study. Supporting Evidence: PMID:16769747 Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells.
GO:0055074 calcium ion homeostasis	IMP PMID:20622307 Distal renal tubular acidosis and its relationship with hear...	MARK AS OVER ANNOTATED	Summary: Calcium ion homeostasis. The cited paper is a clinical correlation report on hearing loss in dRTA and provides no direct calcium-homeostasis experiment. Disturbed calcium handling (nephrocalcinosis, decreased urinary calcium solubility) is a downstream consequence of distal renal tubular acidosis, not a direct B1 function. Reason: Indirect downstream physiological consequence of impaired urinary acidification; not a direct molecular role of the B1 subunit, and the cited reference does not test calcium homeostasis. Supporting Evidence: PMID:20622307 a significant percentage of the children with DRTA had sensorineural hearing loss and mutation in ATP6V1B1 gene
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic, so cytosol is acceptable but low-information and redundant across many Reactome pathway records. Reason: Consistent with the cytoplasmic V1 domain but not the core functional site; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP
GO:0016324 apical plasma membrane	IDA PMID:16928804 Expression of the ammonia transporter, rh C glycoprotein, in...	ACCEPT	Summary: Apical plasma membrane localization. In this study the apical H+-ATPase is used as a marker for co-localization with the RhCG ammonia transporter in A-type intercalated cells; it documents apical H+-ATPase localization but is not a dedicated functional study of B1. Reason: Consistent with the well-supported apical plasma membrane localization of the renal H+-ATPase; corroborated by the stronger IDA evidence (PMID:16769747, PMID:29993276). Supporting Evidence: PMID:16928804 the non-A, non-B cell expresses apical H + -ATPase in conjunction with apical pendrin and apical RhCG
GO:0001503 ossification	IMP PMID:16433694 Molecular investigation and long-term clinical progress in G...	MARK AS OVER ANNOTATED	Summary: The cited paper is a clinical genetics study of dRTA/deafness families that notes rickets/impaired bone among the clinical spectrum. Bone phenotype is a downstream consequence of chronic metabolic acidosis, not a direct role of B1 in ossification. Reason: Indirect, disease-phenotype-derived annotation; the bone manifestations (rickets) result from systemic acidosis secondary to impaired renal acid secretion, not from a direct molecular function of B1 in bone formation. Supporting Evidence: PMID:16433694 The five patients demonstrated the whole clinical spectrum of the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis, nephrolithiasis
GO:0006885 regulation of pH	IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive...	ACCEPT	Summary: B1 contributes to regulation of pH through V-ATPase-mediated apical proton secretion; loss-of-function mutations impair urinary acidification and cause distal renal tubular acidosis. Reason: Strong genetic evidence linking B1 loss of function to impaired control of pH (urinary acidification / systemic acid-base balance). Supporting Evidence: PMID:12414817 subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive...	ACCEPT	Summary: Core complex membership. ATP6V1B1 is a subunit of the vacuolar H+-ATPase complex; this is the whole-complex term (parent of the V1 domain term). Reason: B1 is an integral subunit of the V-ATPase; well supported genetically and structurally. Supporting Evidence: PMID:12414817 subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:1902600 proton transmembrane transport	IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive...	ACCEPT	Summary: Core process. B1 loss-of-function mutations impair apical proton transport in distal nephron cells, causing dRTA. Reason: Genetic evidence that B1 is required for V-ATPase proton transport in the distal nephron. Supporting Evidence: PMID:12414817 subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA
GO:0006885 regulation of pH	IMP PMID:9916796 Mutations in the gene encoding B1 subunit of H+-ATPase cause...	ACCEPT	Summary: Regulation of pH via apical proton secretion. The founding dRTA paper showed ATP6B1 mutations impair distal nephron acid secretion and implicated the gene in endolymph pH homeostasis. Reason: Genetic evidence that B1 is required for control of pH in the distal nephron and inner ear. Supporting Evidence: PMID:9916796 implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function
GO:0007605 sensory perception of sound	IMP PMID:9916796 Mutations in the gene encoding B1 subunit of H+-ATPase cause...	KEEP AS NON CORE	Summary: ATP6B1 mutations cause sensorineural hearing loss; the gene is expressed in cochlea and endolymphatic sac, where V-ATPase maintains endolymph pH required for hearing. A tissue-specific downstream consequence of the core proton-transport function. Reason: Genuine physiological role in hearing via endolymph pH homeostasis, but downstream of the core proton-transport activity rather than a distinct molecular function. Supporting Evidence: PMID:9916796 we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac

Core Functions

As the non-catalytic B1 subunit of the V1 domain of the vacuolar H+-ATPase, binds ATP at non-catalytic nucleotide sites and is an essential structural component of the (AB)3 hexameric catalytic head, enabling ATP-hydrolysis-coupled proton transport by the holoenzyme.

Molecular Function:

ATP binding

Supporting Evidence:

PMID:33065002
The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
Essential for the proper assembly and activity of V-

Required for assembly and activity of the vacuolar H+-ATPase, which secretes protons across the apical plasma membrane of renal intercalated cells (and other distal nephron segments) to acidify the urine and maintain systemic acid-base balance.

Molecular Function:

proton-transporting ATPase activity, rotational mechanism

Cellular Locations:

apical plasma membrane

Supporting Evidence:

PMID:16769747
Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells.
PMID:12414817
subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA

Maintains endolymph pH in the cochlea and endolymphatic sac, which is required for normal auditory function; loss of function causes sensorineural hearing loss.

Molecular Function:

proton-transporting ATPase activity, rotational mechanism

Supporting Evidence:

PMID:9916796
implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12414817

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

PMID:14585495

Molecular cloning and characterization of Atp6v1b1, the murine vacuolar H+ -ATPase B1-subunit.

PMID:16433694

Molecular investigation and long-term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene.

PMID:16769747

Vacuolar H+ -ATPase B1 subunit mutations that cause inherited distal renal tubular acidosis affect proton pump assembly and trafficking in inner medullary collecting duct cells.

PMID:16928804

Expression of the ammonia transporter, rh C glycoprotein, in normal and neoplastic human kidney.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

PMID:19639346

Inner ear abnormalities in four patients with dRTA and SNHL: clinical and genetic heterogeneity.

PMID:20622307

Distal renal tubular acidosis and its relationship with hearing loss in children: preliminary report.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:29993276

H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33065002

Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.

PMID:9916796

Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

Reactome:R-HSA-9639286

RRAGC,D exchanges GTP for GDP

Reactome:R-HSA-9640167

RRAGA,B exchanges GDP for GTP

Reactome:R-HSA-9640168

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine

Reactome:R-HSA-9640175

v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine

Reactome:R-HSA-9640195

RRAGA,B hydrolyzes GTP

Reactome:R-HSA-9645598

RRAGC,D hydrolyzes GTP

Reactome:R-HSA-9645608

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1

Reactome:R-HSA-9646468

mTORC1 binds RHEB:GTP

Suggested Experiments

Experiment: Cell-type-specific (intercalated vs TAL/DCT) conditional Atp6v1b1 knockout in mouse to dissect the contribution of each segment to urinary acidification.

Experiment: Cryo-EM or biochemical reconstitution of a B1-containing human V-ATPase to confirm the B1 paralog occupies the canonical B-subunit position and characterize its non-catalytic nucleotide site.

Experiment: Structure-function analysis of the PDZ-binding motif (e.g. L513G knock-in) to test its role in apical targeting and in the renal/auditory phenotypes.

Deep Research

Falcon

(ATP6V1B1-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1B1 Gene Function and Annotation Falcon

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.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
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.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: ATP6V1B1 Gene Function and Annotation

1. Gene Identity Verification

The ATP6V1B1 gene (UniProt accession: P15313) encodes the B1 subunit of the vacuolar-type H+-ATPase (V-ATPase) in Homo sapiens (jamalpoor2020thelysosomalvatpase pages 1-5, a2023thepathophysiologyof pages 1-5). This protein is specifically described as the V-type proton ATPase subunit B, kidney isoform, confirming alignment with the UniProt annotation provided. The gene belongs to the ATPase alpha/beta chains family and contains the ATP-synt_ab, ATP-synt_ab_N, and ATP-synt_VA_C domains as specified (jamalpoor2020thelysosomalvatpase pages 1-5, eaton2021theh+atpase(vatpase) pages 1-5).

2. Primary Molecular Function and Enzymatic Mechanism

Structural Context

ATP6V1B1 encodes a critical component of the V-ATPase, a large multiprotein complex of approximately 830,000 Da that functions as an ATP-driven proton pump (eaton2021theh+atpase(vatpase) pages 1-5). The V-ATPase consists of two major domains: the cytosolic V1 sector responsible for ATP hydrolysis and the membrane-integrated V0 sector that translocates protons across membranes (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2).

Catalytic Mechanism

Within the V1 domain, the A and B subunits form a hexameric structure (A3B3) that provides the catalytic sites for ATP hydrolysis (chen2022thevatpasesin pages 1-2). The B subunit plays both structural and regulatory roles in this complex. The V1 domain harnesses the energy from ATP hydrolysis to power a rotary mechanism that drives proton translocation through the V0 domain (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). This rotary motor mechanism is evolutionarily conserved and structurally related to the mitochondrial F0F1-ATPase, though V-ATPases function exclusively to hydrolyze ATP and pump protons rather than synthesizing ATP (chen2022thevatpasesin pages 1-2).

Substrate Specificity

The chemical substrate for the V-ATPase complex is ATP, which is hydrolyzed to ADP and inorganic phosphate. The transported species is the proton (H+). The B1 isoform is specifically the kidney-enriched variant, distinguishing it from the B2 isoform expressed in other tissues (pepe2023arolein pages 1-4, a2023thepathophysiologyof pages 1-5). This isoform specificity enables tissue-specific regulation and function of V-ATPases in different physiological contexts.

3. Subcellular Localization

Kidney-Specific Expression

Immunohistochemical studies of human kidney tissue demonstrate that ATP6V1B1 is expressed in both proximal and distal tubules, with high-intensity staining predominantly in distal tubules and lower-intensity staining in proximal tubules (jamalpoor2020thelysosomalvatpase pages 5-9). No expression was detected in glomeruli (jamalpoor2020thelysosomalvatpase pages 5-9).

Intercalated Cell Localization

In the kidney collecting duct system, ATP6V1B1-containing V-ATPases are highly expressed in intercalated cells, which are specialized cells responsible for acid-base homeostasis (a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8). In type A (acid-secreting) intercalated cells, the V-ATPase localizes to the apical plasma membrane where it secretes protons into the urine (a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8). The protein is also present in intracellular tubulovesicular compartments that undergo regulated trafficking to and from the plasma membrane in response to acid-base status (eaton2021theh+atpase(vatpase) pages 9-12).

In non-type A intercalated cells (type B), V-ATPases containing the B1 subunit are expressed basolaterally and apically, where they play essential roles in bicarbonate secretion and defense against alkalosis (a2023thepathophysiologyof pages 5-8).

Organellar Localization

Beyond the plasma membrane, ATP6V1B1-containing V-ATPases are present in lysosomes, endosomes, and other acidic intracellular organelles where they maintain the low pH required for proper organellar function (eaton2021theh+atpase(vatpase) pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9, chen2022thevatpasesin pages 1-2). This lysosomal localization has been demonstrated in renal proximal tubule cells and is critical for normal degradative pathways (jamalpoor2020thelysosomalvatpase pages 5-9).

Regulated Trafficking

The V-ATPase undergoes dynamic regulation through exocytic and endocytic recycling between intracellular vesicular compartments and the plasma membrane (eaton2021theh+atpase(vatpase) pages 9-12). This trafficking mechanism allows for acute regulation of proton secretion in response to physiological demands. The B subunits associate with the actin cytoskeleton and contain profilin-like binding sites, consistent with their involvement in trafficking regulation (eaton2021theh+atpase(vatpase) pages 9-12).

4. Biological Pathways and Processes

Renal Acid-Base Homeostasis

The primary physiological role of ATP6V1B1 is in renal acid-base homeostasis (giglio2021distalrenaltubular pages 1-2, a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8). In type A intercalated cells of the collecting duct, V-ATPases drive apical H+ secretion into the urine, enabling the kidney to excrete the daily acid load (~30 mEq per day in adults) and maintain systemic pH balance (a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8). This process works in concert with basolateral anion exchanger AE1 (SLC4A1), which returns bicarbonate to the bloodstream (a2023thepathophysiologyof pages 1-5).

Carbonic anhydrase II (CAII) in the cytoplasm facilitates the conversion of CO2 and H2O into H+ and HCO3-, providing the protons that V-ATPase secretes (a2023thepathophysiologyof pages 5-8). The ability to acidify urine below pH 5.5 is a hallmark of normal V-ATPase function in the distal nephron (a2023thepathophysiologyof pages 1-5).

Defense Against Alkalosis

Recent research has revealed an expanded role for ATP6V1B1 in non-type A intercalated cells. A 2023 study demonstrated that the B1 subunit is required for driving pendrin activity during metabolic alkalosis (a2023thepathophysiologyof pages 5-8). Loss of Atp6v1b1 in mice resulted in impaired renal defense against alkali loading, with more pronounced hypokalemic alkalosis compared to wild-type animals (a2023thepathophysiologyof pages 5-8). Both apical and basolateral H+-ATPase activity were strongly reduced in these cells, and pendrin-mediated bicarbonate secretion was blunted (a2023thepathophysiologyof pages 5-8).

Lysosomal Acidification and Cystinosin Coupling

ATP6V1B1 plays a critical role in lysosomal acidification, which is essential for numerous cellular processes (jamalpoor2020thelysosomalvatpase pages 5-9, chen2022thevatpasesin pages 1-2). The V-ATPase establishes the proton gradient that powers secondary active transporters in the lysosomal membrane, including cystinosin (encoded by CTNS), an H+/cystine symporter (jamalpoor2020thelysosomalvatpase pages 5-9).

Studies using CRISPR-generated ATP6V1B1-deficient human renal proximal tubule cells demonstrated that loss of the B1 subunit disrupts the chemiosmotic coupling between V-ATPase and cystinosin, resulting in intralysosomal accumulation of cystine (~3-fold increase) (jamalpoor2020thelysosomalvatpase pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9). This accumulation, while less severe than in CTNS-deficient cells, was completely normalized by cysteamine treatment (jamalpoor2020thelysosomalvatpase pages 5-9). This finding establishes a mechanistic link between ATP6V1B1 function and proximal tubule physiology beyond its canonical role in distal tubules.

Autophagy and mTORC1-TFEB Signaling

V-ATPases participate in nutrient-sensing and signaling pathways at the lysosomal membrane, particularly through interactions with the mechanistic target of rapamycin complex 1 (mTORC1) (jamalpoor2020thelysosomalvatpase pages 5-9). In ATP6V1B1-deficient proximal tubule cells, loss of the B1 subunit led to increased nuclear translocation of transcription factor EB (TFEB) (~3-fold), a master regulator of autophagy and lysosomal biogenesis (jamalpoor2020thelysosomalvatpase pages 5-9). This effect was comparable to that observed in CTNS-deficient cells, indicating that ATP6V1B1 disruption activates autophagy through impaired mTORC1 signaling (jamalpoor2020thelysosomalvatpase pages 5-9).

Vesicle Trafficking and Endosomal pH Regulation

V-ATPases establish organellar pH gradients that are essential for intracellular membrane trafficking, protein processing, and vesicle maturation along the endosomal pathway (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). The acidification of endosomes, the trans-Golgi network, and other compartments is critical for receptor-ligand dissociation, protein sorting, and the function of pH-dependent enzymes (eaton2021theh+atpase(vatpase) pages 1-5).

5. Clinical Disease Associations

Distal Renal Tubular Acidosis (dRTA)

Biallelic pathogenic variants in ATP6V1B1 cause autosomal recessive distal renal tubular acidosis (AR-dRTA), a rare inherited disorder characterized by the inability to acidify urine below pH 5.5 in the presence of metabolic acidosis (jamalpoor2020thelysosomalvatpase pages 1-5, giglio2021distalrenaltubular pages 1-2, guo2023geneticdiagnosisand pages 1-3, a2023thepathophysiologyof pages 1-5). The disease typically presents in infancy or early childhood with hyperchloremic metabolic acidosis, hypokalemia, and failure to thrive (jamalpoor2020thelysosomalvatpase pages 1-5, giglio2021distalrenaltubular pages 1-2).

Long-term consequences of untreated or insufficiently treated dRTA include nephrocalcinosis, nephrolithiasis, rickets or osteomalacia, growth retardation, and progressive chronic kidney disease (giglio2021distalrenaltubular pages 1-2, a2023thepathophysiologyof pages 1-5). The metabolic acidosis results from impaired H+ secretion by type A intercalated cells in the collecting duct (a2023thepathophysiologyof pages 1-5).

Sensorineural Hearing Loss

ATP6V1B1-associated dRTA is strongly associated with sensorineural hearing loss (jamalpoor2020thelysosomalvatpase pages 1-5, giglio2021distalrenaltubular pages 1-2, ay2023hearinglossrelated pages 1-1). In a 2023 clinical study, all patients with ATP6V1B1 mutations (9 out of 9) exhibited hearing loss of variable degrees, making it the gene with the strongest hearing loss association among dRTA genes examined (ay2023hearinglossrelated pages 1-1). The hearing loss can be congenital or late-onset and progressive, underscoring the need for regular audiological surveillance in affected patients (ay2023hearinglossrelated pages 1-1).

Large vestibular aqueduct syndrome (LVAS) was detected in 67% (6 out of 9) of patients who underwent radiological evaluation, suggesting that inner ear structural abnormalities contribute to the hearing phenotype (ay2023hearinglossrelated pages 1-1). The V-ATPase is expressed in the inner ear where it maintains the ionic composition of endolymph, and its dysfunction leads to disruption of this specialized fluid environment (ay2023hearinglossrelated pages 1-1).

Proximal Tubulopathy

Although classically considered a distal tubule disease, recent evidence has expanded the phenotypic spectrum of ATP6V1B1 deficiency to include proximal tubule dysfunction (jamalpoor2020thelysosomalvatpase pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9). A case report of a patient with biallelic ATP6V1B1 variants described increased granulocyte cystine levels and symptoms of renal Fanconi syndrome (generalized aminoaciduria, hypophosphatemia, rickets), in addition to metabolic acidosis and hearing loss (jamalpoor2020thelysosomalvatpase pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9).

This expanded phenotype reflects the expression of ATP6V1B1 in proximal tubules, where it contributes to lysosomal acidification and cystine transport (jamalpoor2020thelysosomalvatpase pages 5-9). The patient's cystine levels normalized completely with cysteamine treatment, an unusual response that helped distinguish this presentation from classic cystinosis (jamalpoor2020thelysosomalvatpase pages 5-9).

6. Recent Developments (2023-2024)

Pathophysiology Review (2023)

A comprehensive 2023 review in Nature Reviews Nephrology synthesized current understanding of dRTA pathophysiology, emphasizing ATP6V1B1 as one of the core genes underlying inherited forms of the disease (a2023thepathophysiologyof pages 1-5). The review highlighted the central role of intercalated cells in acid secretion, discussed extrarenal manifestations including hearing loss, and provided prevalence estimates suggesting 0.46 recorded cases per 10,000 people in the UK (a2023thepathophysiologyof pages 1-5).

Expanded Physiological Role in Alkalosis Defense (2023)

A 2023 study published in the Journal of the American Society of Nephrology demonstrated that the B1 subunit is essential not only in type A intercalated cells for acid secretion but also in non-type A intercalated cells for pendrin-mediated bicarbonate secretion and defense against alkalosis (a2023thepathophysiologyof pages 5-8). Atp6v1b1 knockout mice exhibited impaired ability to compensate for alkali loading or chronic furosemide treatment, developing more severe hypokalemic alkalosis than controls (a2023thepathophysiologyof pages 5-8). This work revealed that both apical and basolateral H+-ATPase activity depend on the B1 subunit in these cells, and that pendrin activity requires functional B1-containing V-ATPases (a2023thepathophysiologyof pages 5-8).

Genetic Diagnosis and Treatment Guidelines (2023)

A 2023 review in Kidney Diseases systematically summarized the pathogenic genes, protein functions, and treatment strategies for inherited renal tubular acidosis, highlighting ATP6V1B1 as encoding an apical H+-ATPase subunit essential for distal nephron function (guo2023geneticdiagnosisand pages 1-3). The review emphasized the value of next-generation sequencing in molecular diagnosis and the importance of early alkali therapy to prevent long-term complications (guo2023geneticdiagnosisand pages 1-3).

Audiology and Genotype-Phenotype Correlations (2023)

A 2023 clinical study in Audiology and Neurotology characterized hearing loss across different dRTA gene mutations and confirmed that ATP6V1B1 mutations are associated with the highest penetrance of hearing impairment (ay2023hearinglossrelated pages 1-1). The study documented the prevalence of LVAS in these patients and recommended regular audiological follow-up for early detection of progressive hearing loss (ay2023hearinglossrelated pages 1-1).

7. Current Applications and Real-World Implementations

Clinical Diagnostics

ATP6V1B1 is included in diagnostic gene panels for inherited renal tubular acidosis and is routinely sequenced in patients presenting with unexplained metabolic acidosis, nephrocalcinosis, or failure to thrive (jamalpoor2020thelysosomalvatpase pages 1-5, giglio2021distalrenaltubular pages 1-2, guo2023geneticdiagnosisand pages 1-3). Molecular diagnosis enables precise genetic counseling, prenatal diagnosis, and informs prognosis regarding extrarenal manifestations such as hearing loss.

Therapeutic Management

Management of ATP6V1B1-associated dRTA centers on alkali therapy (typically potassium citrate or sodium bicarbonate) to correct metabolic acidosis and prevent long-term complications (jamalpoor2020thelysosomalvatpase pages 1-5, giglio2021distalrenaltubular pages 1-2, guo2023geneticdiagnosisand pages 1-3). Electrolyte supplementation (particularly potassium) is often necessary. Regular monitoring includes assessment of growth, bone health, kidney function, and hearing (giglio2021distalrenaltubular pages 1-2, ay2023hearinglossrelated pages 1-1). The discovery of proximal tubule involvement suggests that some patients may benefit from additional interventions targeting lysosomal dysfunction (jamalpoor2020thelysosomalvatpase pages 5-9).

Research Models

CRISPR/Cas9-generated ATP6V1B1 knockout cell lines and Atp6v1b1 knockout mice serve as valuable research tools for studying V-ATPase biology, lysosomal function, and acid-base homeostasis (jamalpoor2020thelysosomalvatpase pages 5-9, a2023thepathophysiologyof pages 5-8). These models have elucidated mechanisms of autophagy regulation, cystine transport, and intercalated cell plasticity.

8. Summary Table

Aspect	Details	Evidence/Citations
Verified identity	ATP6V1B1 is the human gene encoding the B1 subunit of the vacuolar H+-ATPase (V-ATPase), described as the kidney isoform; pathogenic variants cause distal renal tubular acidosis (dRTA) with hearing loss.	(jamalpoor2020thelysosomalvatpase pages 1-5, a2023thepathophysiologyof pages 1-5)
Protein family and complex membership	ATP6V1B1 encodes a B subunit of the cytosolic V1 sector of the multisubunit V-ATPase. The holoenzyme contains a peripheral V1 domain that hydrolyzes ATP and a membrane V0 domain that translocates protons.	(eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Structural role within V1	In the V1 domain, A and B subunits assemble into an A3B3 hexamer. This catalytic head provides ATP hydrolysis interfaces that drive the rotary motor coupled to proton translocation through V0.	(chen2022thevatpasesin pages 1-2)
Primary molecular function	ATP6V1B1 does not itself form the proton pore; rather, as part of V1, it contributes to ATP-driven energization of the complex that creates proton gradients across organelle and plasma membranes.	(eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Enzymatic mechanism	V-ATPase uses ATP hydrolysis in V1 to power rotation of central stalk/c-ring elements and move protons through the V0 sector. This is the fundamental mechanism by which ATP6V1B1-containing complexes acidify compartments or extracellular space.	(eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Substrate specificity / transported species	The chemical energy substrate used by the complex is ATP, and the transported ion is H+. In kidney physiology, this supports urinary acidification and acid-base homeostasis.	(giglio2021distalrenaltubular pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Kidney cell-type localization	In the collecting system, V-ATPases are expressed in intercalated cells. Type A intercalated cells secrete H+ apically into urine, whereas type B intercalated cells use basolateral V-ATPases during bicarbonate secretion.	(a2023thepathophysiologyof pages 5-8)
Membrane and organelle localization	In proton-secreting epithelia, V-ATPase localizes to the apical plasma membrane and intracellular tubulovesicular compartments; more broadly, V-ATPases acidify lysosomes, endosomes, and other intracellular vesicles.	(eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 9-12)
Human kidney distribution	ATP6V1B1 protein is expressed strongly in distal tubules and at lower levels in proximal tubules of human kidney; no staining was observed in glomeruli in the cited study.	(jamalpoor2020thelysosomalvatpase pages 5-9)
Regulated trafficking	In kidney intercalated cells, proton secretion is acutely regulated by exocytic/endocytic recycling of V-ATPase-rich tubulovesicles, altering the amount of pump at the plasma membrane. B subunits also associate with actin, consistent with a trafficking/regulatory role.	(eaton2021theh+atpase(vatpase) pages 9-12)
Core physiological pathway: renal acid-base homeostasis	ATP6V1B1-containing V-ATPase complexes are essential for distal nephron H+ secretion. Impaired acid excretion by collecting-duct intercalated cells is a central mechanism of inherited dRTA.	(giglio2021distalrenaltubular pages 1-2, a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8)
Lysosomal acidification pathway	V-ATPase-driven acidification of lysosomes and endolysosomal compartments is required for normal degradative and transport functions. ATP6V1B1 loss disrupts this acidification-dependent physiology in renal proximal tubule cells.	(jamalpoor2020thelysosomalvatpase pages 1-5, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Cystinosin coupling / cystine transport support	ATP6V1B1 supports the proton gradient that powers cystinosin-mediated H+/cystine symport from lysosomes. Loss of ATP6V1B1 caused increased cystine accumulation in proximal tubule cells, linking B1 to cystinosin function.	(jamalpoor2020thelysosomalvatpase pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9)
Autophagy and mTORC1/TFEB signaling	V-ATPase participates in nutrient-sensing/signaling at lysosomes. In ATP6V1B1-deficient proximal tubule cells, TFEB nuclear translocation increased and autophagy-related changes resembled CTNS deficiency, indicating involvement in mTORC1-autophagy regulation.	(jamalpoor2020thelysosomalvatpase pages 1-5, eaton2021theh+atpase(vatpase) pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9)
Vesicle trafficking and pH homeostasis	V-ATPases establish organellar pH gradients needed for membrane traffic, protein processing, and intracellular transport, consistent with a broader role for ATP6V1B1 in endomembrane physiology beyond the distal nephron.	(eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Canonical disease association	Biallelic ATP6V1B1 variants cause autosomal recessive dRTA, typically presenting with inability to acidify urine, hyperchloremic metabolic acidosis, hypokalemia, nephrocalcinosis/nephrolithiasis risk, and growth/bone complications if untreated.	(giglio2021distalrenaltubular pages 1-2, a2023thepathophysiologyof pages 1-5, guo2023geneticdiagnosisand pages 1-3)
Hearing phenotype	ATP6V1B1-associated dRTA is strongly associated with sensorineural hearing loss. In one 2023 cohort, all patients with ATP6V1B1 mutations (9/9) had hearing loss.	(ay2023hearinglossrelated pages 1-1)
Inner-ear/vestibular finding	Large vestibular aqueduct syndrome was common among evaluated dRTA patients and may influence the severity/type of hearing loss; a patient with ATP6V1B1 variants in the proximal-tubule study had enlarged vestibular aqueduct and early hearing impairment.	(ay2023hearinglossrelated pages 1-1, jamalpoor2020thelysosomalvatpase pages 5-9)
Expanded proximal-tubule phenotype	Although classically a distal-tubule disease gene, ATP6V1B1 is also expressed in proximal tubules, and deficiency can produce a cystinosis-like proximal tubulopathy/Fanconi-like phenotype with cystine accumulation and autophagy activation.	(jamalpoor2020thelysosomalvatpase pages 1-5, jamalpoor2020thelysosomalvatpase pages 5-9)
2023 review advance	A 2023 Nature Reviews Nephrology synthesis updated dRTA pathophysiology, listing ATP6V1B1 among the core inherited dRTA genes and emphasizing intercalated-cell acid secretion, extrarenal manifestations, and prevalence estimates.	(a2023thepathophysiologyof pages 1-5)
2023 inherited RTA review advance	A 2023 review summarized ATP6V1B1 as an apical H+-ATPase gene in inherited dRTA and integrated molecular diagnosis with treatment strategies, underscoring its value in genetic workup.	(guo2023geneticdiagnosisand pages 1-3)
2023 audiology advance	A 2023 clinical study refined genotype-phenotype interpretation by showing differential hearing burden across dRTA genes, with ATP6V1B1 carrying the strongest hearing-loss association in that cohort.	(ay2023hearinglossrelated pages 1-1)
2023/2024 physiological advance	Recent work showed B1 is not only required in type A intercalated cells for acid secretion but also in non-type A intercalated cells for pendrin activity and defense against alkalosis, broadening its renal physiological role.	(a2023thepathophysiologyof pages 5-8)
Practical/real-world application	ATP6V1B1 is used clinically in diagnostic gene panels for inherited renal tubular acidosis and informs management such as alkali therapy, electrolyte correction, and audiologic surveillance because of the strong kidney-ear phenotype.	(jamalpoor2020thelysosomalvatpase pages 1-5, giglio2021distalrenaltubular pages 1-2, guo2023geneticdiagnosisand pages 1-3, ay2023hearinglossrelated pages 1-1)

Table: This table summarizes verified identity, molecular function, localization, pathways, disease relevance, and recent research developments for human ATP6V1B1. It is useful as a compact evidence map linking the kidney-specific V-ATPase B1 subunit to mechanism and phenotype.

Conclusion

ATP6V1B1 encodes the kidney-specific B1 subunit of the V-type H+-ATPase, a multiprotein complex that functions as an ATP-driven proton pump. The B1 subunit is a component of the cytosolic V1 domain, which forms a catalytic hexamer with the A subunit to hydrolyze ATP and power proton translocation through the membrane-embedded V0 domain. ATP6V1B1 is predominantly expressed in intercalated cells of the kidney collecting duct, where it localizes to both the apical plasma membrane and intracellular vesicles, as well as in lysosomes and endosomes of proximal tubule cells.

The primary function of ATP6V1B1 is to drive urinary acidification and maintain systemic acid-base homeostasis through proton secretion in the distal nephron. Recent research has expanded this functional repertoire to include roles in alkalosis defense via coupling with pendrin in non-type A intercalated cells, lysosomal acidification supporting cystinosin-mediated cystine transport, and regulation of autophagy through mTORC1-TFEB signaling pathways.

Pathogenic variants in ATP6V1B1 cause autosomal recessive distal renal tubular acidosis with sensorineural hearing loss, and emerging evidence indicates that some patients may also develop proximal tubule dysfunction with cystinosis-like features. The 2023-2024 literature has refined our understanding of the gene's physiological importance beyond acid secretion, its role in hearing through inner ear fluid homeostasis, and the molecular mechanisms linking V-ATPase dysfunction to cellular pathology. These advances inform clinical management strategies and highlight ATP6V1B1 as a critical player in renal and systemic pH regulation.

References

(jamalpoor2020thelysosomalvatpase pages 1-5): Amer Jamalpoor, Albertien M van Eerde, Marc R Lilien, Charlotte AGH van Gelder, Esther A Zaal, Floris A Valentijn, Roel Broekhuizen, Eva Zielhuis, Julia E Egido, Maarten Altelaar, Celia R Berkers, Rosalinde Masereeuw, and Manoe J Janssen. The lysosomal v-atpase b1 subunit in renal proximal tubule is linked to nephropathic cystinosis. bioRxiv, Jul 2020. URL: https://doi.org/10.1101/2020.07.24.219808, doi:10.1101/2020.07.24.219808. This article has 0 citations.
(a2023thepathophysiologyof pages 1-5): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(chen2022thevatpasesin pages 1-2): Fangquan Chen, Rui Kang, Jiao Liu, and Daolin Tang. The v-atpases in cancer and cell death. Cancer Gene Therapy, 29:1529-1541, May 2022. URL: https://doi.org/10.1038/s41417-022-00477-y, doi:10.1038/s41417-022-00477-y. This article has 129 citations and is from a peer-reviewed journal.
(pepe2023arolein pages 1-4): SARA PEPE. A role in ph homeostasis regulation by genes related to neurodevelopmental disorders: tbc1d24 and atp6v1a. May 2023. URL: https://doi.org/10.15167/pepe-sara_phd2023-05-15, doi:10.15167/pepe-sara_phd2023-05-15. This article has 0 citations.
(jamalpoor2020thelysosomalvatpase pages 5-9): Amer Jamalpoor, Albertien M van Eerde, Marc R Lilien, Charlotte AGH van Gelder, Esther A Zaal, Floris A Valentijn, Roel Broekhuizen, Eva Zielhuis, Julia E Egido, Maarten Altelaar, Celia R Berkers, Rosalinde Masereeuw, and Manoe J Janssen. The lysosomal v-atpase b1 subunit in renal proximal tubule is linked to nephropathic cystinosis. bioRxiv, Jul 2020. URL: https://doi.org/10.1101/2020.07.24.219808, doi:10.1101/2020.07.24.219808. This article has 0 citations.
(a2023thepathophysiologyof pages 5-8): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 9-12): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(giglio2021distalrenaltubular pages 1-2): Sabrina Giglio, Giovanni Montini, Francesco Trepiccione, Giovanni Gambaro, and Francesco Emma. Distal renal tubular acidosis: a systematic approach from diagnosis to treatment. Journal of Nephrology, 34:2073-2083, Mar 2021. URL: https://doi.org/10.1007/s40620-021-01032-y, doi:10.1007/s40620-021-01032-y. This article has 98 citations and is from a peer-reviewed journal.
(guo2023geneticdiagnosisand pages 1-3): Wenkai Guo, Pengcheng Ji, and Yuansheng Xie. Genetic diagnosis and treatment of inherited renal tubular acidosis. Kidney Diseases, 9:371-383, Jun 2023. URL: https://doi.org/10.1159/000531556, doi:10.1159/000531556. This article has 8 citations and is from a peer-reviewed journal.
(ay2023hearinglossrelated pages 1-1): Ezgi Ay, Emre Gurses, Filiz Aslan, Bora Gulhan, Asuman Alniacik, Ali Duzova, Munir Demir Bajin, Levent Sennaroglu, Gulsum Aydan Genc, Fatih Ozaltin, and Rezan Topaloglu. Hearing loss related to gene mutations in distal renal tubular acidosis. Audiology and Neurotology, 28:350-359, Apr 2023. URL: https://doi.org/10.1159/000529486, doi:10.1159/000529486. This article has 5 citations.

📚 Additional Documentation

Notes

(ATP6V1B1-notes.md)

ATP6V1B1 (V-type proton ATPase subunit B, kidney isoform; VATB1_HUMAN, P15313)

Summary

ATP6V1B1 encodes the B1 (kidney/tissue-restricted) isoform of the non-catalytic B
subunit of the V1 peripheral domain of the vacuolar H+-ATPase (V-ATPase). The V1
domain hydrolyzes ATP, and this chemical energy drives proton translocation through
the membrane-embedded V0 domain, acidifying intracellular compartments and, in
specialized cells, the extracellular space.

Core identity and function

Non-catalytic V1 subunit: "Non-catalytic subunit of the V1 complex of vacuolar(H+)-
ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that
hydrolyzes ATP and a membrane integral complex (V0) that translocates protons"
[UniProt P15313 FUNCTION, "Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase"].
The B subunits form three AB catalytic heterodimers that constitute the V1
heterohexamer: "The V1 complex consists of three catalytic AB heterodimers that form
a heterohexamer" [UniProt P15313 SUBUNIT]. B subunits hold non-catalytic nucleotide
(ATP) sites; UniProt annotates an ATP-binding residue at position 394 (by similarity
to P21281) [UniProt P15313 FT BINDING 394 "ligand=ATP"].
Essential for assembly/activity: "Essential for the proper assembly and activity of
V-ATPase" [UniProt P15313 FUNCTION].
Renal proton secretion: "In renal intercalated cells, mediates secretion of protons
(H+) into the urine thereby ensuring correct urinary acidification" [UniProt P15313
FUNCTION].

Structural / complex membership (V1 domain)

Cryo-EM of complete human V-ATPase places B subunits in the V1 ATP-hydrolytic head:
"V-ATPases ... comprised of a cytoplasmic V1 complex for ATP hydrolysis and a
membrane-embedded Vo complex for proton transfer... The V1 ATPase is composed of
three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H"
PMID:33065002.
This is the IDA support for GO:0000221 (V-ATPase V1 domain).

Disease and physiology

Loss-of-function mutations cause autosomal recessive distal renal tubular acidosis
with sensorineural deafness (DRTA2): "mutations in ATP6B1, encoding the B-subunit of
the apical proton pump mediating distal nephron acid secretion, cause distal renal
tubular acidosis... Patients with ATP6B1 mutations also have sensorineural hearing
loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea
and endolymphatic sac" PMID:9916796.
Mechanism of disease variants — assembly and apical trafficking defects:
"GFP-B1WT formed complexes with other H+ -ATPase subunits (c, H, and E), whereas
GFP-B1M did not. Proteins that were immunoprecipitated... from GFP-B1WT cells had
ATPase activity, whereas proteins from GFP-B1M cells did not. Proton pump-mediated
intracellular pH transport was inhibited in GFP-B1M-transfected cells... B1 point
mutations prevent normal assembly of the H+ -ATPase and also may act as an inhibitor
of H+ -ATPase function by competing with endogenous intact H+ -ATPase for trafficking"
PMID:16769747. This grounds: V-ATPase complex assembly (GO:0070072), proton
transmembrane transport (GO:1902600), pH reduction (GO:0045851), apical plasma
membrane localization (GO:0016324).
Renal acid secretion / urinary acidification (regulation of pH, renal tubular
secretion): "Defects in the B1 subunit gene ATP6V1B1... cause rdRTA with deafness...
apical H(+)-ATPase that cause rdRTA" PMID:12414817.
Hearing: clinical genetic studies link ATP6V1B1 mutations to early-onset
sensorineural hearing loss and enlarged vestibular aqueduct (EVA):
"Mutations in ATP6V1B1 are associated with early onset SNHL... confirms the
association of EVA and mutations in the ATP6V1B1 gene" PMID:19639346; "a significant
percentage of the children with DRTA had sensorineural hearing loss and mutation in
ATP6V1B1 gene" PMID:20622307.

Localization / tissue specificity

Apical membrane in kidney intercalated cells and early distal nephron (TAL, DCT):
"the B1 subunit is expressed in the apical membrane domains of TAL, macula densa, and
DCT in human and rodent kidney. Furthermore, by immunoelectron microscopy the subunit
is localized to the apical plasma membrane in the DCT" PMID:29993276. Apical
localization also documented in PMID:16769747 ("GFP-B1WT and GFP-B1M are present in
the apical membrane").
Tissue-restricted: kidney/testis (mouse) and cochlea/endolymphatic sac; murine
ortholog 93% identical: "Northern blotting detects a 2.2-kb Atp6v1b1 transcript in the
kidney and testis, but not other major organs. In mouse kidney, the B1-subunit
localizes to intercalated cells" PMID:14585495. The human ISS localization
annotations (cytoplasm, microvillus, basolateral/lateral membrane) are transferred
from this mouse ortholog (Q91YH6).
HPA: "Group enriched (kidney, salivary gland)" [UniProt P15313 DR HPA].

PDZ interactions / apical targeting

C-terminal PDZ-binding motif (residues 510–513) mediates interaction with NHERF1 and
the bicarbonate transporter SLC4A7/NBC3: "The PDZ-binding motif mediates interactions
with NHERF1 and SCL4A7" [UniProt P15313 DOMAIN]; "Forms a complex with NHERF1 and
SCL4A7" [UniProt P15313 SUBUNIT]. Mutagenesis L513G abolishes these interactions
[UniProt P15313 FT MUTAGEN 513]. (Primary ref PubMed:12444018 not cached locally; the
interaction is documented in the UniProt record.)

Notes on weaker / peripheral annotations

GO:0005515 protein binding (IPI, PMID:32814053): bare "protein binding" from a
large-scale neurodegeneration interactome screen (IntAct pairwise hits with ATXN1,
TARDBP, WFS1, HSPB1, etc.). Uninformative for molecular function; the biologically
meaningful binding (PDZ→NHERF1/SLC4A7, AB hexamer assembly) is captured by complex
membership and domain annotations.
GO:0070062 extracellular exosome (HDA; PMID:23533145, PMID:19199708, PMID:19056867):
proteomic detection in urinary/parotid/prostatic-secretion exosomes; consistent with
V-ATPase delivery to/recycling from the apical plasma membrane but a bystander
localization, not a core function.
GO:0016241 regulation of macroautophagy (NAS, PMID:22982048): the cited paper is
about lipofuscin formation in senescent fibroblasts being independent of
macroautophagy/lysosomal activity; weak NAS link, V-ATPase-driven lysosomal
acidification supports autophagy generally but this is a generic V-ATPase property,
not specific to the B1 subunit. Non-core at best.
GO:0001503 ossification (IMP, PMID:16433694): the cited paper is a clinical genetics
study of dRTA/deafness families (rickets noted as a downstream consequence of
acidosis); not direct evidence that B1 functions in ossification. Over-annotation /
indirect.
GO:0055074 calcium ion homeostasis (IMP, PMID:20622307): the cited paper is a
hearing-loss clinical correlation report; no direct calcium-homeostasis experiment.
Likely downstream/indirect (urinary calcium handling in dRTA).
GO:0016928804 (PMID:16928804): apical plasma membrane IDA — this paper is about RhCG
ammonia transporter; H+-ATPase used only as a co-localization marker. Localization
consistent but weak primary evidence for B1 specifically.
Various IEA Ensembl orthology transfers (synaptic vesicle lumen acidification,
extrinsic component of synaptic vesicle membrane, adult behavior, olfactory behavior,
chloride/potassium/sodium homeostasis, prostaglandin metabolism, etc.) derive from
rodent orthologs and broad V-ATPase biology; the B1 isoform is kidney/inner-ear/
epididymis restricted, so neuronal synaptic-vesicle roles are properties of other B
isoforms (B2) rather than B1. Treat as non-core / over-annotation.
Reactome cytosol (TAS) annotations: generic "cytosol" placement for V1 subunits in
many Reactome pathways; the V1 domain is cytoplasmic, so cytosol is acceptable but
low-information and largely redundant.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1B1/ATP6V1B1-deep-research-falcon.md,
17 citations). It corroborates the B1 (kidney-isoform, non-catalytic V1 subunit)
biology above and adds one mechanistically specific finding.

Core confirmed. B1 is a non-catalytic V1 subunit forming the AB heterodimers
of the V1 hexamer; the proton gradient it helps generate (via catalytic A
subunit) acidifies organelles and, in renal type-A intercalated cells, secretes
H+ into urine. No change to the non-catalytic-subunit / acidification calls.
New: chemiosmotic coupling to cystinosin (Jamalpoor 2020). In CRISPR
ATP6V1B1-deficient human proximal tubule cells, loss of B1 disrupts coupling
between the V-ATPase proton gradient and cystinosin (CTNS, H+/cystine
symporter), causing ~3-fold lysosomal cystine accumulation (normalized by
cysteamine) and ~3-fold increased nuclear TFEB (autophagy/lysosomal
biogenesis). This extends B1's relevance to proximal-tubule lysosomal physiology
and mechanistically links V-ATPase activity to lysosomal amino-acid efflux —
good support for the lysosomal-acidification role and the autophagy/mTORC1-TFEB
connection (downstream, non-core).
Disease. Biallelic variants → autosomal-recessive distal renal tubular
acidosis with the strongest sensorineural-hearing-loss association among
dRTA genes (9/9 patients; 67% with large vestibular aqueduct syndrome; Ay 2023),
reflecting V-ATPase maintenance of endolymph composition. Consistent with the
established kidney/inner-ear core.

Net: no change to calls — B1 is the kidney/inner-ear-restricted non-catalytic V1
subunit supporting organellar and renal-luminal acidification.

Pn Notes

(ATP6V1B1-pn-notes.md)

ATP6V1B1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P15313
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1B1/ATP6V1B1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1B1/ATP6V1B1-ai-review.html
Gene notes: present - genes/human/ATP6V1B1/ATP6V1B1-notes.md
GOA TSV: present - genes/human/ATP6V1B1/ATP6V1B1-goa.tsv
UniProt record: present - genes/human/ATP6V1B1/ATP6V1B1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1B1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1B1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: ATP6V1B1 encodes the B1 isoform of the non-catalytic B subunit of the V1 peripheral domain of the vacuolar H+-ATPase (V-ATPase). Three copies of the B subunit alternate with three catalytic A subunits to form the (AB)3 heterohexameric head of the cytoplasmic V1 complex, which hydrolyzes ATP to drive proton translocation through the membrane-embedded V0 domain. The B subunit binds ATP at non-catalytic nucleotide sites and is essential for proper assembly and activity of the holoenzyme. ATP6V1B1 is the tissue-restricted (kidney, inner ear, epididymis, salivary gland) paralog of the ubiquitously expressed B2 subunit. In the kidney it localizes to the apical plasma membrane of intercalated cells (and other early distal nephron segments), where the plasma-membrane V-ATPase secretes protons into the urine to mediate distal urinary acidification; it is also expressed in the cochlea and endolymphatic sac, where V-ATPase activity maintains endolymph pH. A C-terminal PDZ-binding motif mediates interactions (e.g. with NHERF1 and the bicarbonate transporter SLC4A7) implicated in apical membrane targeting and scaffolding. Loss-of-function mutations cause autosomal recessive distal renal tubular acidosis with progressive sensorineural hearing loss (DRTA2).
Existing/core annotation action counts: ACCEPT: 22; KEEP_AS_NON_CORE: 29; MARK_AS_OVER_ANNOTATED: 12

PN Consistency Summary

Consistency: PARTIAL CONFLICT. Deep research/notes and the review establish B1 as the kidney/inner-ear-restricted, non-catalytic B subunit whose functionally relevant site is the apical plasma membrane (intercalated cells; IDA PMID:16769747, PMID:29993276), driving urinary acid secretion (renal tubular secretion, dRTA; PMID:12414817). The review explicitly MARKs_AS_OVER_ANNOTATED a synaptic-vesicle annotation as an inappropriate cross-isoform transfer, and never asserts a lysosomal role. The PN places B1 under "lysosomal v-ATPase" and projects lysosomal lumen acidification + lysosomal V1 domain — which the gene biology does not support. PN Notes ("V1 cytosolic component … pumps protons into the lysosome") mis-frame this plasma-membrane isoform.
PN story / NEW pressure: PN's lysosomal acidification claim OVER-REACHES for B1. GO:0046612/GO:0007042 are verified real but are the wrong specialization: B1's evidenced compartment is apical plasma membrane, not lysosome. Already captured (correctly) by review: GO:0016324 apical plasma membrane, GO:0097254 renal tubular secretion, GO:0006885 regulation of pH. Lysosomal projection should NOT be propagated to B1.
Evidence alignment: No overlap. PN cites generic V-ATPase/mTORC1 reviews; review is richly sourced with B1-specific genetics/structure (PMID:12414817, 16769747, 29993276, 33065002, 9916796). Review strongly better-evidenced.
Verdict: OVER-REACH — PN lysosomal projection (GO:0046612/GO:0007042) is wrong-compartment for this apical-plasma-membrane kidney isoform. Recommended edits: [MAP] exempt ATP6V1B1 from lysosomal-acidification/lysosomal-V1 projection; restrict to vacuolar V1 domain + plasma-membrane/renal acid-secretion terms already in the review.

Full Consistency Review

UniProt: P15313 · batch: proteostasis-batch-2026-06-07 · review status: COMPLETE
PN placement: two ALP leaves "V1 lysosomal v-ATPase proton pump component" (Nutrient sensing; Lysosomal acidification). PN-node mapping: leaf→GO:0046612 lysosomal V1 domain (more_specific_than_existing_goa); leaf→GO:0033176 V-type ATPase complex (entailed_by_goa_closure); type→GO:0007042 lysosomal lumen acidification (more_specific_than_existing_goa).
Consistency: PARTIAL CONFLICT. Deep research/notes and the review establish B1 as the kidney/inner-ear-restricted, non-catalytic B subunit whose functionally relevant site is the apical plasma membrane (intercalated cells; IDA PMID:16769747, PMID:29993276), driving urinary acid secretion (renal tubular secretion, dRTA; PMID:12414817). The review explicitly MARKs_AS_OVER_ANNOTATED a synaptic-vesicle annotation as an inappropriate cross-isoform transfer, and never asserts a lysosomal role. The PN places B1 under "lysosomal v-ATPase" and projects lysosomal lumen acidification + lysosomal V1 domain — which the gene biology does not support. PN Notes ("V1 cytosolic component … pumps protons into the lysosome") mis-frame this plasma-membrane isoform.
PN story / NEW pressure: PN's lysosomal acidification claim OVER-REACHES for B1. GO:0046612/GO:0007042 are verified real but are the wrong specialization: B1's evidenced compartment is apical plasma membrane, not lysosome. Already captured (correctly) by review: GO:0016324 apical plasma membrane, GO:0097254 renal tubular secretion, GO:0006885 regulation of pH. Lysosomal projection should NOT be propagated to B1.
Mapping strategy: The shared V-ATPase node maps to lysosomal terms generically, but B1 is a tissue-restricted plasma-membrane isoform — analogous to the TOMM20/HSPA8/RAB7A "too broad" precedent. [MAP] flag B1 as an exception to lysosomal projection (scope=too_broad/wrong_compartment for this isoform); the generic vacuolar V1 term (GO:0000221, already in review) is the safe target.
Evidence alignment: No overlap. PN cites generic V-ATPase/mTORC1 reviews; review is richly sourced with B1-specific genetics/structure (PMID:12414817, 16769747, 29993276, 33065002, 9916796). Review strongly better-evidenced.
Verdict: OVER-REACH — PN lysosomal projection (GO:0046612/GO:0007042) is wrong-compartment for this apical-plasma-membrane kidney isoform. Recommended edits: [MAP] exempt ATP6V1B1 from lysosomal-acidification/lysosomal-V1 projection; restrict to vacuolar V1 domain + plasma-membrane/renal acid-secretion terms already in the review.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07
review_yaml: genes/human/ATP6V1B1/ATP6V1B1-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

UniProt: P15313
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain]
  rationale: This PN leaf is restricted to V1-sector lysosomal V-ATPase components. The GO lysosomal V1-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

UniProt: P15313
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033176 proton-transporting V-type ATPase complex]
  rationale: This PN subtype denotes the V1-sector component of the lysosomal V-ATPase. In the current GO cache, the broader V-type ATPase complex is the safest validated target for this component role.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033176 proton-transporting V-type ATPase complex | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: P15313
gene_symbol: ATP6V1B1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6V1B1 encodes the B1 isoform of the non-catalytic B subunit of the
  V1 peripheral domain of the vacuolar H+-ATPase (V-ATPase). Three copies of the B
  subunit alternate with three catalytic A subunits to form the (AB)3 heterohexameric
  head of the cytoplasmic V1 complex, which hydrolyzes ATP to drive proton translocation
  through the membrane-embedded V0 domain. The B subunit binds ATP at non-catalytic
  nucleotide sites and is essential for proper assembly and activity of the holoenzyme.
  ATP6V1B1 is the tissue-restricted (kidney, inner ear, epididymis, salivary gland)
  paralog of the ubiquitously expressed B2 subunit. In the kidney it localizes to the
  apical plasma membrane of intercalated cells (and other early distal nephron segments),
  where the plasma-membrane V-ATPase secretes protons into the urine to mediate distal
  urinary acidification; it is also expressed in the cochlea and endolymphatic sac,
  where V-ATPase activity maintains endolymph pH. A C-terminal PDZ-binding motif mediates
  interactions (e.g. with NHERF1 and the bicarbonate transporter SLC4A7) implicated in
  apical membrane targeting and scaffolding. Loss-of-function mutations cause autosomal
  recessive distal renal tubular acidosis with progressive sensorineural hearing loss
  (DRTA2).
existing_annotations:
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Core biological process. As the non-catalytic B subunit of the V1 head,
      ATP6V1B1 is part of the V-ATPase that couples ATP hydrolysis to transmembrane
      proton transport. Directly supported by functional studies of B1 mutants.
    action: ACCEPT
    reason: Proton transmembrane transport is the defining function of the V-ATPase,
      and B1 is required for the assembly and activity of the pump. Phylogenetic (IBA)
      transfer is corroborated by direct experimental evidence in B1-expressing cells.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: Proton pump-mediated intracellular pH transport was inhibited
        in GFP-B1M-transfected cells but not in GFP-B1WT cells.
      reference_section_type: ABSTRACT
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a multisubunit enzyme composed of a peripheral complex (V1)
        that hydrolyzes ATP and a membrane integral complex (V0) that translocates
        protons
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Core localization/complex membership. ATP6V1B1 is one of the three B
      subunits of the (AB)3 hexamer that forms the ATP-hydrolytic V1 domain of the
      V-ATPase.
    action: ACCEPT
    reason: Membership of the B subunit in the V1 domain is established by the cryo-EM
      structure of the complete human V-ATPase and is consistent across orthologs.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H
      reference_section_type: RESULTS
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Plasma membrane localization. In specialized cells (notably renal intercalated
      cells), the V-ATPase containing B1 is targeted to the plasma membrane where it
      acidifies the extracellular space. More specifically captured by the apical
      plasma membrane annotation below.
    action: KEEP_AS_NON_CORE
    reason: Correct but general; the functionally relevant compartment for B1 is the
      apical plasma membrane (GO:0016324), which is annotated separately with direct
      evidence.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: in some cell types, is targeted to the plasma membrane, where
        it is responsible for acidifying the extracellular environment
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Core localization. The plasma-membrane V-ATPase containing B1 is active
      at the apical membrane of renal intercalated cells and other distal nephron
      epithelia, where it secretes protons into the urine.
    action: ACCEPT
    reason: Apical plasma membrane localization is directly demonstrated by immunoelectron
      microscopy and cell-based studies and is the physiologically relevant site of
      B1 function.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: by immunoelectron microscopy the subunit is localized to the
        apical plasma membrane in the DCT
      reference_section_type: DISCUSSION
    - reference_id: PMID:16769747
      supporting_text: GFP-B1WT and GFP-B1M are present in the apical membrane and
        increased with cellular acidification
      reference_section_type: ABSTRACT
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: V-ATPase-mediated acidification of intracellular compartments. This is
      the ancestral/general function of B subunits conserved across eukaryotes.
    action: ACCEPT
    reason: Acidification of intracellular compartments is the canonical V-ATPase
      function; the phylogenetic transfer is appropriate for a B subunit, supported
      by the UniProt FUNCTION statement.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the pH
        of intracellular compartments
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: V1 domain membership (ARBA machine-learning electronic annotation). Redundant
      with the IBA and IDA annotations of the same term, which carry stronger evidence.
    action: ACCEPT
    reason: Correct complex membership; supported by direct structural evidence elsewhere
      in this review.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H
      reference_section_type: RESULTS
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Core molecular function. The B subunit binds ATP at non-catalytic nucleotide
      sites of the (AB)3 hexamer; UniProt annotates an ATP-binding residue at position
      394.
    action: ACCEPT
    reason: ATP binding at the non-catalytic site is a conserved property of V-ATPase
      B subunits and is consistent with the InterPro nucleotide-binding domain
      assignment and the UniProt ATP-binding feature.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: BINDING         394
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Basolateral plasma membrane (electronic orthology transfer from mouse/rat
      orthologs). B1 localization is predominantly apical; basolateral V-ATPase is
      seen in some intercalated cell subtypes (type B), but for B1 the dominant and
      functionally relevant localization is apical.
    action: KEEP_AS_NON_CORE
    reason: Transferred by orthology from rodent (Q91YH6); plausible in a subset of
      cells but not the core localization of B1, which is apical.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Basolateral cell membrane {ECO:0000250|UniProtKB:Q91YH6}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Apical plasma membrane (electronic orthology transfer). Redundant with
      the IDA/IBA apical plasma membrane annotations, which carry direct evidence.
    action: ACCEPT
    reason: Correct core localization, corroborated by direct experimental evidence
      in this review.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: by immunoelectron microscopy the subunit is localized to the
        apical plasma membrane in the DCT
      reference_section_type: DISCUSSION
- term:
    id: GO:0033180
    label: proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: V1 domain membership (general, non-vacuolar-specific parent of GO:0000221).
      InterPro-based electronic annotation; correct complex membership.
    action: ACCEPT
    reason: Correct V1 domain membership; the more specific vacuolar V1 domain term
      (GO:0000221) is also annotated with direct structural support.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H
      reference_section_type: RESULTS
- term:
    id: GO:0046034
    label: ATP metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ATP metabolic process (InterPro electronic transfer). The V-ATPase hydrolyzes
      ATP, but B1 is the non-catalytic subunit; this broad term is a generic property
      of the holoenzyme rather than an informative B1-specific process.
    action: MARK_AS_OVER_ANNOTATED
    reason: Overly broad and derived from the catalytic A-subunit-like domain signature.
      ATP hydrolysis is performed by the catalytic A subunits; B1 binds but does not
      hydrolyze ATP. Proton transmembrane transport better captures the relevant process.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Non-catalytic subunit of the V1 complex of vacuolar(H+)-
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Rotational proton-transporting ATPase activity. This is the molecular
      function of the assembled V-ATPase holoenzyme. As a non-catalytic structural
      subunit of the ATP-hydrolytic head, B1 contributes to but does not by itself
      enable this activity; GO commonly annotates obligate subunits with the holoenzyme
      activity.
    action: KEEP_AS_NON_CORE
    reason: The rotational ATPase activity is a property of the holoenzyme; B1 is an
      essential non-catalytic subunit. Accepting the term as a subunit contribution
      is reasonable but it is not an autonomous B1 function, so it is retained as
      non-core.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular
        vesicles
      reference_section_type: INTRODUCTION
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Essential for the proper assembly and activity of V-
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Core process (electronic orthology transfer). Redundant with the IBA and
      IMP proton transmembrane transport annotations, which carry direct evidence.
    action: ACCEPT
    reason: Correct core function; corroborated by direct experimental evidence elsewhere
      in this review.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: Proton pump-mediated intracellular pH transport was inhibited
        in GFP-B1M-transfected cells but not in GFP-B1WT cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare "protein binding" from a large-scale neurodegeneration yeast-two-hybrid
      interactome (partners include ATXN1, TARDBP, WFS1, HSPB1, DNAJB6). Uninformative
      as a molecular function and not specific to ATP6V1B1 biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: "Bare protein binding conveys no specific molecular function. The hits are\
      \ high-throughput Y2H interactions; biologically meaningful binding (PDZ→\
      NHERF1/SLC4A7 and the AB hexamer assembly) is captured by complex-membership and\
      \ domain annotations rather than this generic term."
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: generated by systematic yeast two-hybrid interaction screening
        of ∼500 ND-related proteins
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Cytoplasm (electronic orthology transfer). The V1 domain is cytoplasmic
      and peripheral, so a cytoplasmic pool of the soluble V1 subassembly is expected,
      but this is a low-information localization.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but uninformative; the functionally
      relevant localization is the apical plasma membrane / V1 domain of the assembled
      pump.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Cytosol (electronic orthology transfer). Same rationale as the cytoplasm
      annotation; consistent with a soluble cytosolic V1 pool but low information.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain; redundant with the Reactome
      TAS cytosol annotations and not the core functional site.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005902
    label: microvillus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Microvillus (electronic orthology transfer from rodent ortholog). Consistent
      with apical brush-border localization in renal epithelia but not directly
      demonstrated for human B1.
    action: KEEP_AS_NON_CORE
    reason: Plausible apical/microvillar localization transferred from the mouse ortholog;
      a refinement of the apical plasma membrane localization rather than an independent
      core function.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: significant signal was also observed in apical membrane domains
        of the distal nephron
      reference_section_type: ABSTRACT
- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Proton transmembrane transporter activity (electronic orthology transfer).
      This activity is mediated by the membrane-embedded V0 proton-conducting subunits;
      the cytoplasmic B1 subunit does not itself conduct protons.
    action: KEEP_AS_NON_CORE
    reason: B1 is a non-membrane, non-catalytic subunit; the transporter activity is
      a holoenzyme property residing in V0. Retained as a subunit-level contribution
      rather than an autonomous B1 function.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Generic "membrane" localization (electronic orthology transfer). Uninformative
      parent of the more specific apical/basolateral plasma membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too general to be useful; the specific membrane localization (apical plasma
      membrane) is annotated with direct evidence.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: by immunoelectron microscopy the subunit is localized to the
        apical plasma membrane in the DCT
      reference_section_type: DISCUSSION
- term:
    id: GO:0016328
    label: lateral plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Lateral plasma membrane (electronic orthology transfer from rodent ortholog).
      B1's dominant and functionally relevant localization is apical; lateral/basolateral
      localization is minor.
    action: KEEP_AS_NON_CORE
    reason: Transferred by orthology; not the core localization of B1, which is apical.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Basolateral cell membrane {ECO:0000250|UniProtKB:Q91YH6}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Protein-containing complex binding (electronic orthology transfer). Generic
      binding term; B1 is an integral constituent of the V-ATPase rather than a binder
      of an external complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: Low-information binding term transferred by orthology; B1's relationship
      to the V-ATPase is captured by complex-membership (part_of) annotations, which
      are more informative than a generic complex-binding molecular function.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Non-catalytic subunit of the V1 complex of vacuolar(H+)-
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Synaptic vesicle lumen acidification (electronic orthology transfer).
      This is a neuronal V-ATPase function attributable to the ubiquitous/brain B2
      isoform (ATP6V1B2), not the kidney/inner-ear-restricted B1 isoform.
    action: MARK_AS_OVER_ANNOTATED
    reason: B1 is tissue-restricted (kidney, inner ear, epididymis, salivary gland)
      and is not the neuronal/synaptic isoform; this annotation is an inappropriate
      orthology transfer better assigned to ATP6V1B2.
    supported_by:
    - reference_id: PMID:14585495
      supporting_text: Northern blotting detects a 2.2-kb Atp6v1b1 transcript in the
        kidney and testis, but not other major organs
      reference_section_type: ABSTRACT
- term:
    id: GO:0098850
    label: extrinsic component of synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Extrinsic component of synaptic vesicle membrane (electronic orthology
      transfer). A neuronal localization attributable to the brain B2 isoform, not
      the kidney/inner-ear B1 isoform.
    action: MARK_AS_OVER_ANNOTATED
    reason: Inappropriate orthology transfer; B1 is not the neuronal/synaptic isoform.
      The relevant V1 localization for B1 is the apical plasma membrane V-ATPase.
    supported_by:
    - reference_id: PMID:14585495
      supporting_text: Northern blotting detects a 2.2-kb Atp6v1b1 transcript in the
        kidney and testis, but not other major organs
      reference_section_type: ABSTRACT
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Basolateral plasma membrane (ISS from mouse ortholog Q91YH6). Duplicate
      of the IEA basolateral annotation; B1's core localization is apical.
    action: KEEP_AS_NON_CORE
    reason: Sequence-similarity transfer from rodent; plausible in a subset of cells
      but not the core apical localization of B1.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Basolateral cell membrane {ECO:0000250|UniProtKB:Q91YH6}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0097254
    label: renal tubular secretion
  evidence_type: IMP
  original_reference_id: PMID:12414817
  qualifier: involved_in
  review:
    summary: Renal tubular secretion of protons. B1-containing apical V-ATPase secretes
      H+ into the urine in distal nephron cells; loss-of-function mutations impair
      this and cause distal renal tubular acidosis.
    action: ACCEPT
    reason: Strong genetic and physiological evidence that B1 is required for distal
      nephron acid (proton) secretion into the tubular lumen.
    supported_by:
    - reference_id: PMID:12414817
      supporting_text: subunits of the renal alpha-intercalated cell's apical H(+)-ATPase
        that cause rdRTA
      reference_section_type: ABSTRACT
- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Core complex membership with direct structural evidence. Cryo-EM of the
      complete human V-ATPase places the B subunit in the (AB)3 hexamer of the V1
      ATP-hydrolytic head.
    action: ACCEPT
    reason: Direct structural (IDA) evidence for B-subunit membership in the V1 domain;
      this is the strongest evidence for this localization.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H
      reference_section_type: RESULTS
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:16769747
  qualifier: located_in
  review:
    summary: Core localization with direct evidence. GFP-tagged B1 localizes to the
      apical membrane of inner medullary collecting duct cells, increasing with
      cellular acidification.
    action: ACCEPT
    reason: Direct experimental demonstration of apical plasma membrane localization
      in renal epithelial cells.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: GFP-B1WT and GFP-B1M are present in the apical membrane and
        increased with cellular acidification
      reference_section_type: ABSTRACT
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:29993276
  qualifier: located_in
  review:
    summary: Core localization with direct evidence. Immunoelectron microscopy in human
      and rodent kidney localizes the B1 subunit to the apical plasma membrane of
      intercalated cells and the early distal nephron (TAL, DCT).
    action: ACCEPT
    reason: Antibody specificity validated in Atp6v1b1-deficient mice; immuno-EM directly
      demonstrates apical plasma membrane localization.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: by immunoelectron microscopy the subunit is localized to the
        apical plasma membrane in the DCT
      reference_section_type: DISCUSSION
- term:
    id: GO:0045851
    label: pH reduction
  evidence_type: IMP
  original_reference_id: PMID:16769747
  qualifier: involved_in
  review:
    summary: B1 is required for V-ATPase-mediated lowering of pH (proton accumulation).
      Disease mutants abolish proton-pump-mediated intracellular pH transport.
    action: ACCEPT
    reason: Direct functional evidence that wild-type but not mutant B1 supports
      proton-pump-mediated acidification.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: Proton pump-mediated intracellular pH transport was inhibited
        in GFP-B1M-transfected cells but not in GFP-B1WT cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:0070072
    label: vacuolar proton-transporting V-type ATPase complex assembly
  evidence_type: IMP
  original_reference_id: PMID:16769747
  qualifier: involved_in
  review:
    summary: Core process. B1 is required for proper assembly of the V-ATPase; disease
      point mutants fail to form complexes with other subunits.
    action: ACCEPT
    reason: Direct functional evidence that wild-type B1 assembles with other H+-ATPase
      subunits whereas mutants do not, demonstrating a role in complex assembly.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: GFP-B1WT formed complexes with other H+ -ATPase subunits (c,
        H, and E), whereas GFP-B1M did not
      reference_section_type: ABSTRACT
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Essential for the proper assembly and activity of V-
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IMP
  original_reference_id: PMID:16769747
  qualifier: involved_in
  review:
    summary: Core process with direct functional evidence. Wild-type B1 supports
      proton-pump-mediated transmembrane pH transport; disease mutants do not.
    action: ACCEPT
    reason: Direct mutational evidence that B1 is required for V-ATPase proton transport
      activity.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: Proton pump-mediated intracellular pH transport was inhibited
        in GFP-B1M-transfected cells but not in GFP-B1WT cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: NAS annotation from a lipofuscin/senescence study that concerns lysosomal
      and autophagic activity generally, not ATP6V1B1 specifically. V-ATPase-driven
      lysosomal acidification supports autophagic flux, but this is a generic V-ATPase
      property and B1 is the tissue-restricted kidney/inner-ear isoform.
    action: MARK_AS_OVER_ANNOTATED
    reason: Weak NAS link; the cited paper does not provide direct evidence that the
      B1 subunit regulates macroautophagy. Any contribution is an indirect, generic
      consequence of lysosomal acidification mediated by V-ATPase as a whole.
    supported_by:
    - reference_id: PMID:22982048
      supporting_text: macroautophagy is responsible for the uptake of lipofuscin into
        the lysosomes
      reference_section_type: ABSTRACT
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: Detection in prostatic-secretion/urinary exosomes by high-throughput
      mass-spectrometry proteomics. Reflects presence in secreted vesicles (consistent
      with apical plasma-membrane V-ATPase shedding) rather than a site of function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomic identification in exosomes is a bystander localization, not a
      functional compartment for the V-ATPase B1 subunit.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: In-depth proteomic analyses of exosomes isolated from expressed
        prostatic secretions in urine
      reference_section_type: TITLE
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: Detection in parotid gland exosomes by high-throughput proteomics (MudPIT).
      Bystander localization in secreted vesicles, not a functional compartment.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomic identification in exosomes does not indicate a site of B1 function.
    supported_by:
    - reference_id: PMID:19199708
      supporting_text: Proteomic analysis of human parotid gland exosomes by multidimensional
        protein identification technology (MudPIT)
      reference_section_type: TITLE
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Detection in urinary exosomes by large-scale proteomics/phosphoproteomics.
      Bystander localization in secreted vesicles, not a functional compartment.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomic identification in exosomes does not indicate a site of B1 function;
      consistent with apical V-ATPase shedding into urinary vesicles.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes
      reference_section_type: TITLE
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: PMID:14585495
  qualifier: located_in
  review:
    summary: Cytoplasm (ISS from mouse ortholog Q91YH6). Consistent with the cytoplasmic
      V1 domain but low-information; duplicate of the IEA cytoplasm annotation.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic peripheral V1 domain but not the core
      functional site.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005902
    label: microvillus
  evidence_type: ISS
  original_reference_id: PMID:14585495
  qualifier: located_in
  review:
    summary: Microvillus (ISS from mouse ortholog). Consistent with apical brush-border
      localization in renal epithelia; a refinement of the apical plasma membrane
      localization.
    action: KEEP_AS_NON_CORE
    reason: Plausible apical/microvillar localization transferred from the mouse ortholog;
      not an independent core function.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: significant signal was also observed in apical membrane domains
        of the distal nephron
      reference_section_type: ABSTRACT
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: ISS
  original_reference_id: PMID:14585495
  qualifier: located_in
  review:
    summary: Basolateral plasma membrane (ISS from mouse ortholog). Duplicate of the
      other basolateral annotations; B1's core localization is apical.
    action: KEEP_AS_NON_CORE
    reason: Sequence-similarity transfer; plausible minor localization but not the
      core apical localization of B1.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Basolateral cell membrane {ECO:0000250|UniProtKB:Q91YH6}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016328
    label: lateral plasma membrane
  evidence_type: ISS
  original_reference_id: PMID:14585495
  qualifier: located_in
  review:
    summary: Lateral plasma membrane (ISS from mouse ortholog). Duplicate of the IEA
      lateral annotation; not the core apical localization of B1.
    action: KEEP_AS_NON_CORE
    reason: Sequence-similarity transfer; minor localization relative to the dominant
      apical pool.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: Basolateral cell membrane {ECO:0000250|UniProtKB:Q91YH6}
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: PMID:14585495
  qualifier: enables
  review:
    summary: Proton transmembrane transporter activity (ISS from mouse ortholog). The
      proton-conducting activity resides in the membrane-embedded V0 subunits; the
      cytoplasmic B1 subunit contributes to the holoenzyme but does not itself conduct
      protons.
    action: KEEP_AS_NON_CORE
    reason: Holoenzyme-level activity assigned to a non-membrane, non-catalytic subunit;
      retained as a subunit contribution rather than an autonomous B1 function.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0042472
    label: inner ear morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:19639346
  qualifier: involved_in
  review:
    summary: ATP6V1B1 mutations are associated with inner-ear structural abnormalities,
      notably enlarged vestibular aqueduct (EVA), in patients with dRTA and sensorineural
      hearing loss. This is a downstream developmental/physiological consequence of
      impaired endolymph pH homeostasis rather than a direct morphogenetic function.
    action: KEEP_AS_NON_CORE
    reason: Disease-phenotype association (EVA) is a downstream consequence of defective
      V-ATPase-mediated endolymph acidification, not a primary morphogenetic role of
      the B1 subunit. Retained as a non-core process.
    supported_by:
    - reference_id: PMID:19639346
      supporting_text: confirms the association of EVA and mutations in the ATP6V1B1
        gene
      reference_section_type: ABSTRACT
- term:
    id: GO:0007605
    label: sensory perception of sound
  evidence_type: IMP
  original_reference_id: PMID:20622307
  qualifier: involved_in
  review:
    summary: ATP6V1B1 mutations cause sensorineural hearing loss; the gene is expressed
      in cochlea and endolymphatic sac, where V-ATPase activity maintains endolymph
      pH required for normal hearing.
    action: KEEP_AS_NON_CORE
    reason: A genuine physiological role (via endolymph pH homeostasis), but it is a
      tissue-specific downstream consequence of the core proton-transport function
      rather than a distinct molecular activity. Retained as a non-core process.
    supported_by:
    - reference_id: PMID:20622307
      supporting_text: a significant percentage of the children with DRTA had
        sensorineural hearing loss and mutation in ATP6V1B1 gene
      reference_section_type: ABSTRACT
    - reference_id: PMID:9916796
      supporting_text: implicate ATP6B1 in endolymph pH homeostasis and in normal
        auditory function
      reference_section_type: ABSTRACT
- term:
    id: GO:0045851
    label: pH reduction
  evidence_type: IMP
  original_reference_id: PMID:20622307
  qualifier: involved_in
  review:
    summary: pH reduction (proton accumulation) via V-ATPase. This clinical-genetics
      hearing-loss study supports the disease association; pH reduction is the core
      consequence of B1-dependent proton pumping (also directly demonstrated in
      PMID:16769747).
    action: ACCEPT
    reason: B1-dependent V-ATPase lowers luminal/compartmental pH; the core function
      is well supported, though this particular reference is a clinical correlation
      study.
    supported_by:
    - reference_id: PMID:16769747
      supporting_text: Proton pump-mediated intracellular pH transport was inhibited
        in GFP-B1M-transfected cells but not in GFP-B1WT cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:0055074
    label: calcium ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:20622307
  qualifier: involved_in
  review:
    summary: Calcium ion homeostasis. The cited paper is a clinical correlation report
      on hearing loss in dRTA and provides no direct calcium-homeostasis experiment.
      Disturbed calcium handling (nephrocalcinosis, decreased urinary calcium solubility)
      is a downstream consequence of distal renal tubular acidosis, not a direct B1
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect downstream physiological consequence of impaired urinary acidification;
      not a direct molecular role of the B1 subunit, and the cited reference does not
      test calcium homeostasis.
    supported_by:
    - reference_id: PMID:20622307
      supporting_text: a significant percentage of the children with DRTA had
        sensorineural hearing loss and mutation in ATP6V1B1 gene
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: Cytosol localization (Reactome TAS). The peripheral V1 domain is cytoplasmic,
      so cytosol is acceptable but low-information and redundant across many Reactome
      pathway records.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the cytoplasmic V1 domain but not the core functional
      site; redundant with other cytosol/cytoplasm annotations.
    supported_by:
    - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
      supporting_text: a peripheral complex (V1) that hydrolyzes ATP
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:16928804
  qualifier: located_in
  review:
    summary: Apical plasma membrane localization. In this study the apical H+-ATPase
      is used as a marker for co-localization with the RhCG ammonia transporter in
      A-type intercalated cells; it documents apical H+-ATPase localization but is
      not a dedicated functional study of B1.
    action: ACCEPT
    reason: Consistent with the well-supported apical plasma membrane localization
      of the renal H+-ATPase; corroborated by the stronger IDA evidence (PMID:16769747,
      PMID:29993276).
    supported_by:
    - reference_id: PMID:16928804
      supporting_text: the non-A, non-B cell expresses apical H + -ATPase in conjunction
        with apical pendrin and apical RhCG
      reference_section_type: DISCUSSION
- term:
    id: GO:0001503
    label: ossification
  evidence_type: IMP
  original_reference_id: PMID:16433694
  qualifier: involved_in
  review:
    summary: The cited paper is a clinical genetics study of dRTA/deafness families
      that notes rickets/impaired bone among the clinical spectrum. Bone phenotype
      is a downstream consequence of chronic metabolic acidosis, not a direct role
      of B1 in ossification.
    action: MARK_AS_OVER_ANNOTATED
    reason: Indirect, disease-phenotype-derived annotation; the bone manifestations
      (rickets) result from systemic acidosis secondary to impaired renal acid secretion,
      not from a direct molecular function of B1 in bone formation.
    supported_by:
    - reference_id: PMID:16433694
      supporting_text: The five patients demonstrated the whole clinical spectrum of
        the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis,
        nephrolithiasis
      reference_section_type: ABSTRACT
- term:
    id: GO:0006885
    label: regulation of pH
  evidence_type: IMP
  original_reference_id: PMID:12414817
  qualifier: involved_in
  review:
    summary: B1 contributes to regulation of pH through V-ATPase-mediated apical proton
      secretion; loss-of-function mutations impair urinary acidification and cause
      distal renal tubular acidosis.
    action: ACCEPT
    reason: Strong genetic evidence linking B1 loss of function to impaired control
      of pH (urinary acidification / systemic acid-base balance).
    supported_by:
    - reference_id: PMID:12414817
      supporting_text: subunits of the renal alpha-intercalated cell's apical H(+)-ATPase
        that cause rdRTA
      reference_section_type: ABSTRACT
- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IMP
  original_reference_id: PMID:12414817
  qualifier: part_of
  review:
    summary: Core complex membership. ATP6V1B1 is a subunit of the vacuolar H+-ATPase
      complex; this is the whole-complex term (parent of the V1 domain term).
    action: ACCEPT
    reason: B1 is an integral subunit of the V-ATPase; well supported genetically and
      structurally.
    supported_by:
    - reference_id: PMID:12414817
      supporting_text: subunits of the renal alpha-intercalated cell's apical H(+)-ATPase
        that cause rdRTA
      reference_section_type: ABSTRACT
    - reference_id: PMID:33065002
      supporting_text: The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H
      reference_section_type: RESULTS
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IMP
  original_reference_id: PMID:12414817
  qualifier: involved_in
  review:
    summary: Core process. B1 loss-of-function mutations impair apical proton transport
      in distal nephron cells, causing dRTA.
    action: ACCEPT
    reason: Genetic evidence that B1 is required for V-ATPase proton transport in the
      distal nephron.
    supported_by:
    - reference_id: PMID:12414817
      supporting_text: subunits of the renal alpha-intercalated cell's apical H(+)-ATPase
        that cause rdRTA
      reference_section_type: ABSTRACT
- term:
    id: GO:0006885
    label: regulation of pH
  evidence_type: IMP
  original_reference_id: PMID:9916796
  qualifier: acts_upstream_of_or_within
  review:
    summary: Regulation of pH via apical proton secretion. The founding dRTA paper
      showed ATP6B1 mutations impair distal nephron acid secretion and implicated the
      gene in endolymph pH homeostasis.
    action: ACCEPT
    reason: Genetic evidence that B1 is required for control of pH in the distal nephron
      and inner ear.
    supported_by:
    - reference_id: PMID:9916796
      supporting_text: implicate ATP6B1 in endolymph pH homeostasis and in normal
        auditory function
      reference_section_type: ABSTRACT
- term:
    id: GO:0007605
    label: sensory perception of sound
  evidence_type: IMP
  original_reference_id: PMID:9916796
  qualifier: acts_upstream_of_or_within
  review:
    summary: ATP6B1 mutations cause sensorineural hearing loss; the gene is expressed
      in cochlea and endolymphatic sac, where V-ATPase maintains endolymph pH required
      for hearing. A tissue-specific downstream consequence of the core proton-transport
      function.
    action: KEEP_AS_NON_CORE
    reason: Genuine physiological role in hearing via endolymph pH homeostasis, but
      downstream of the core proton-transport activity rather than a distinct molecular
      function.
    supported_by:
    - reference_id: PMID:9916796
      supporting_text: we demonstrate expression of ATP6B1 in cochlea and endolymphatic
        sac
      reference_section_type: ABSTRACT
core_functions:
- description: As the non-catalytic B1 subunit of the V1 domain of the vacuolar H+-ATPase,
    binds ATP at non-catalytic nucleotide sites and is an essential structural component
    of the (AB)3 hexameric catalytic head, enabling ATP-hydrolysis-coupled proton
    transport by the holoenzyme.
  molecular_function:
    id: GO:0005524
    label: ATP binding
  supported_by:
  - reference_id: PMID:33065002
    supporting_text: The V 1 ATPase is composed of three copies of subunits A, B, E,
      and G, and one copy of subunit C, D, F, and H
    reference_section_type: RESULTS
  - reference_id: file:human/ATP6V1B1/ATP6V1B1-uniprot.txt
    supporting_text: Essential for the proper assembly and activity of V-
    reference_section_type: DATABASE_ENTRY
- description: Required for assembly and activity of the vacuolar H+-ATPase, which
    secretes protons across the apical plasma membrane of renal intercalated cells
    (and other distal nephron segments) to acidify the urine and maintain systemic
    acid-base balance.
  molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  supported_by:
  - reference_id: PMID:16769747
    supporting_text: Proton pump-mediated intracellular pH transport was inhibited
      in GFP-B1M-transfected cells but not in GFP-B1WT cells.
    reference_section_type: ABSTRACT
  - reference_id: PMID:12414817
    supporting_text: subunits of the renal alpha-intercalated cell's apical H(+)-ATPase
      that cause rdRTA
    reference_section_type: ABSTRACT
- description: Maintains endolymph pH in the cochlea and endolymphatic sac, which is
    required for normal auditory function; loss of function causes sensorineural hearing
    loss.
  molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  supported_by:
  - reference_id: PMID:9916796
    supporting_text: implicate ATP6B1 in endolymph pH homeostasis and in normal auditory
      function
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: Beyond intercalated cells, what is the functional contribution of the apical B1-containing V-ATPase in the thick ascending limb and distal convoluted tubule to acid-base handling?
- question: Does the C-terminal PDZ-binding motif (NHERF1/SLC4A7 interaction) regulate apical membrane targeting or stability of the B1-containing V-ATPase in vivo?
- question: Are the salt-losing and hypokalemic features of B1-related dRTA explained by B1 expression outside type A intercalated cells?
suggested_experiments:
- description: Cell-type-specific (intercalated vs TAL/DCT) conditional Atp6v1b1 knockout in mouse to dissect the contribution of each segment to urinary acidification.
- description: Cryo-EM or biochemical reconstitution of a B1-containing human V-ATPase to confirm the B1 paralog occupies the canonical B-subunit position and characterize its non-catalytic nucleotide site.
- description: Structure-function analysis of the PDZ-binding motif (e.g. L513G knock-in) to test its role in apical targeting and in the renal/auditory phenotypes.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  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: PMID:12414817
  title: Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal
    tubular acidosis with new evidence for hearing loss.
  findings: []
- id: PMID:14585495
  title: Molecular cloning and characterization of Atp6v1b1, the murine vacuolar H+
    -ATPase B1-subunit.
  findings: []
- id: PMID:16433694
  title: Molecular investigation and long-term clinical progress in Greek Cypriot
    families with recessive distal renal tubular acidosis and sensorineural deafness
    due to mutations in the ATP6V1B1 gene.
  findings: []
- id: PMID:16769747
  title: Vacuolar H+ -ATPase B1 subunit mutations that cause inherited distal renal
    tubular acidosis affect proton pump assembly and trafficking in inner medullary
    collecting duct cells.
  findings: []
- id: PMID:16928804
  title: Expression of the ammonia transporter, rh C glycoprotein, in normal and neoplastic
    human kidney.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings: []
- id: PMID:19639346
  title: 'Inner ear abnormalities in four patients with dRTA and SNHL: clinical and
    genetic heterogeneity.'
  findings: []
- id: PMID:20622307
  title: 'Distal renal tubular acidosis and its relationship with hearing loss in
    children: preliminary report.'
  findings: []
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
- id: PMID:29993276
  title: H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted
    tubule of rodent and human kidney.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings: []
- id: PMID:9916796
  title: Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular
    acidosis with sensorineural deafness.
  findings: []
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings: []
- id: Reactome:R-HSA-74723
  title: Endosome acidification
  findings: []
- id: Reactome:R-HSA-917841
  title: Acidification of Tf:TfR1 containing endosome
  findings: []
- id: Reactome:R-HSA-9639286
  title: RRAGC,D exchanges GTP for GDP
  findings: []
- id: Reactome:R-HSA-9640167
  title: RRAGA,B exchanges GDP for GTP
  findings: []
- id: Reactome:R-HSA-9640168
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding
    v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640175
  title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640195
  title: RRAGA,B hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645598
  title: RRAGC,D hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645608
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
  findings: []
- id: Reactome:R-HSA-9646468
  title: mTORC1 binds RHEB:GTP
  findings: []

ATP6V1B1

Gene Description

Existing Annotations Review

Core Functions

As the non-catalytic B1 subunit of the V1 domain of the vacuolar H+-ATPase, binds ATP at non-catalytic nucleotide sites and is an essential structural component of the (AB)3 hexameric catalytic head, enabling ATP-hydrolysis-coupled proton transport by the holoenzyme.

Required for assembly and activity of the vacuolar H+-ATPase, which secretes protons across the apical plasma membrane of renal intercalated cells (and other distal nephron segments) to acidify the urine and maintain systemic acid-base balance.

Maintains endolymph pH in the cochlea and endolymphatic sac, which is required for normal auditory function; loss of function causes sensorineural hearing loss.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1B1 Gene Function and Annotation

1. Gene Identity Verification

2. Primary Molecular Function and Enzymatic Mechanism

Structural Context

Catalytic Mechanism

Substrate Specificity

3. Subcellular Localization

Kidney-Specific Expression

Intercalated Cell Localization

Organellar Localization

Regulated Trafficking

4. Biological Pathways and Processes

Renal Acid-Base Homeostasis

Defense Against Alkalosis

Lysosomal Acidification and Cystinosin Coupling

Autophagy and mTORC1-TFEB Signaling

Vesicle Trafficking and Endosomal pH Regulation

5. Clinical Disease Associations

Distal Renal Tubular Acidosis (dRTA)

Sensorineural Hearing Loss

Proximal Tubulopathy

6. Recent Developments (2023-2024)

Pathophysiology Review (2023)

Expanded Physiological Role in Alkalosis Defense (2023)

Genetic Diagnosis and Treatment Guidelines (2023)

Audiology and Genotype-Phenotype Correlations (2023)

7. Current Applications and Real-World Implementations

Clinical Diagnostics

Therapeutic Management

Research Models

8. Summary Table

Conclusion

📚 Additional Documentation

Notes

ATP6V1B1 (V-type proton ATPase subunit B, kidney isoform; VATB1_HUMAN, P15313)

Summary

Core identity and function

Structural / complex membership (V1 domain)

Disease and physiology

Localization / tissue specificity

PDZ interactions / apical targeting

Notes on weaker / peripheral annotations

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1B1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

Projected GO annotations (3)

Note

📄 View Raw YAML