Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IBA GO_REF:0000033	ACCEPT	Summary: Subunit H is a genuine V1 domain component confirmed by cryo-EM and biochemical characterization. Reason: V1 domain membership is well established. Subunit H is a regulatory component of the V1 complex, one copy per holoenzyme (PMID:33065002, PMID:9442887).
GO:0007042 lysosomal lumen acidification	IBA GO_REF:0000033	ACCEPT	Summary: IBA phylogenetic transfer; lysosomal acidification is the core biological output of the assembled V-ATPase containing subunit H. Reason: Lysosomal lumen acidification is the primary downstream consequence of V-ATPase proton pumping. As a regulatory subunit essential for V-ATPase activity, H is rightly annotated as involved in this process.
GO:0097401 synaptic vesicle lumen acidification	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA transfer for synaptic vesicle lumen acidification; non-core neuronal context for this ubiquitously expressed subunit. Reason: Neuronal synaptic vesicle acidification is a non-core context for this ubiquitous regulatory subunit.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro; V1 domain membership is experimentally established. Reason: V1 domain membership is supported by structural and functional data.
GO:0016020 membrane	IEA GO_REF:0000117	MODIFY	Summary: IEA ARBA for membrane localization; overly general term but consistent with lysosomal/endosomal/plasma membrane localization. Reason: Generic membrane is too imprecise. The more specific terms lysosomal membrane (HDA), endosome membrane (NAS), and plasma membrane (NAS) already exist in the annotation set. The IDA annotation to GO:0016020 from PMID:33065002 directly contextualizes which membrane is meant. Proposed replacements: lysosomal membrane
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA from UniProt subcellular location mapping; consistent with the documented AP-2 (clathrin adaptor) interaction of subunit H. Reason: Subunit H directly binds AP2M1 (PMID:12032142), which is a component of clathrin-coated vesicle machinery. Localization at clathrin-coated vesicle membrane is consistent with this interaction. Supporting Evidence: PMID:12032142 V1H binds to the C-terminal flexible loop in Nef from HIV-1 and to the medium chain (mu2) of the adaptor protein complex 2 (AP-2) in vitro and in vivo
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro; proton-transporting ATPase rotational mechanism is the molecular activity of the V-ATPase complex. Reason: The V-ATPase uses a rotational mechanism for proton translocation. Subunit H contributes to this complex activity as a regulatory component.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro; proton transmembrane transport is the core biological process of the V-ATPase. Reason: Proton transmembrane transport is the fundamental function of the V-ATPase complex. Subunit H is essential for this activity as a regulatory component.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from binary interactome reference map; uninformative over-annotation. Reason: High-throughput interactome dataset. The specific informative interaction is with AP2M1 (PMID:12032142), not the generic protein binding term.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from neurodegenerative disease interactome; uninformative over-annotation. Reason: High-throughput interactome dataset; protein binding does not describe specific molecular function of subunit H.
GO:0098850 extrinsic component of synaptic vesicle membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA Ensembl Compara transfer; non-core neuronal context for this ubiquitous subunit. Reason: Synaptic vesicle context is non-core for this ubiquitously expressed regulatory subunit.
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: IDA from immunofluorescence curation; cytosolic localization reflects the free V1 complex state. Reason: Cytosolic localization is a genuine functional state for subunit H. The free V1 complex is present in the cytosol when dissociated from V0, and subunit H specifically inhibits futile ATP hydrolysis in this context.
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: NAS from V-ATPase review; Golgi membrane localization is mentioned for V-ATPase generally. Not specific to subunit H but consistent with the review's description of V-ATPase distribution. Reason: Golgi membrane localization is supported only by NAS from a general V-ATPase review. While V-ATPase does localize to Golgi, this is not a core context for the H subunit.
GO:0005765 lysosomal membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review; lysosomal membrane localization is the core localization for the assembled V-ATPase holoenzyme. Reason: Lysosomal membrane localization is well supported and is the primary localization of the assembled V-ATPase. Also supported by HDA mass spectrometry (PMID:17897319).
GO:0005886 plasma membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: NAS from V-ATPase review; plasma membrane V-ATPase in specialized cell types (e.g., kidney intercalated cells). Reason: Plasma membrane localization is a non-core context for this ubiquitous subunit; it occurs in specialized cells. The more relevant localization is lysosomal/endosomal.
GO:0007035 vacuolar acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review; vacuolar acidification is the core biological process downstream of V-ATPase proton pumping. Reason: Vacuolar acidification is the primary biological function of V-ATPase activity. Subunit H as a regulatory component of the V-ATPase is appropriately annotated to this process.
GO:0007042 lysosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review; lysosomal lumen acidification is the core functional output of lysosome-localized V-ATPase. Reason: Lysosomal lumen acidification is the primary biological process driven by the V-ATPase at the lysosomal membrane. Subunit H is a required regulatory component of this activity.
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from cryo-EM structure paper; lysosomal lumen acidification is the core function of the V-ATPase complex. Reason: The structure paper describes V-ATPase function in intracellular acidification. Lysosomal lumen acidification is a core function.
GO:0010008 endosome membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review; endosome membrane localization of assembled V-ATPase is well established. Reason: Endosomal membrane localization of V-ATPase is well established and important for receptor-mediated endocytosis and iron release from transferrin.
GO:0016020 membrane	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	MODIFY	Summary: IDA from cryo-EM structure study; this directly shows subunit H as part of the membrane-associated V-ATPase holoenzyme. Reason: The cryo-EM structure places subunit H in the V-ATPase complex at membranes. The generic membrane term is less informative than lysosomal membrane. Suggest retaining but noting more specific terms are preferred. Proposed replacements: lysosomal membrane
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from cryo-EM structure paper; V-ATPase complex membership is well established. Reason: Subunit H is a confirmed component of the V-ATPase holoenzyme complex.
GO:0048388 endosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review; endosomal lumen acidification is a core biological process downstream of V-ATPase activity at endosomes. Reason: Endosomal acidification is required for receptor-mediated endocytosis completion and nutrient release. V-ATPase is the primary driver; subunit H is a required component.
GO:0051452 intracellular pH reduction	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: NAS from V-ATPase review; intracellular pH reduction is a broader term encompassing all V-ATPase-dependent compartment acidification. Reason: Intracellular pH reduction is a general consequence of V-ATPase activity. More specific annotations to lysosomal and endosomal lumen acidification are already present and are preferable. This broader term is non-core.
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: NAS from V-ATPase review; Golgi lumen acidification is a downstream consequence of V-ATPase activity at Golgi membranes. Reason: Golgi acidification is a non-core downstream function. Lysosomal and endosomal acidification are the primary core contexts.
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from cryo-EM structure paper; proton transmembrane transport is the core molecular function of the V-ATPase complex. Reason: Proton transmembrane transport is the fundamental process of the V-ATPase. Subunit H is essential for this activity.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	ISS GO_REF:0000024	ACCEPT	Summary: ISS manual ortholog transfer; V1 domain membership is experimentally established. Reason: ISS consistent with direct experimental evidence for V1 domain membership.
GO:0005515 protein binding	IPI PMID:25659576 TM9SF4 is a novel V-ATPase-interacting protein that modulate...	MARK AS OVER ANNOTATED	Summary: IPI from TM9SF4/V-ATPase interaction study in colon cancer; TM9SF4 co-immunoprecipitates with ATP6V1H. This is a specific interaction study but the GO:0005515 annotation is still uninformative. Reason: While TM9SF4 interaction with ATP6V1H is documented (PMID:25659576), the protein binding annotation is uninformative. The interaction is in a cancer cell context and the normal physiological relevance is unclear.
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: NAS annotation; the cited paper uses V-ATPase disruption as a tool to impair lysosomal activity. Does not specifically implicate subunit H in macroautophagy regulation. Reason: The cited study does not demonstrate that ATP6V1H specifically regulates macroautophagy; it uses generic V-ATPase disruption to block lysosomal function. This is an over-annotation of a generic downstream consequence of V-ATPase disruption.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	MARK AS OVER ANNOTATED	Summary: HDA from parotid gland exosome proteomics; likely a contaminant in exosome fractions. Reason: Extracellular exosome identification in proteomics is likely contamination. Not a primary localization for a V1 peripheral complex subunit.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: HDA from urinary exosome proteomics; likely a contaminant in exosome fractions. Reason: Extracellular exosome identification in proteomics is likely contamination. Not a primary localization for a V1 subunit.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: HDA from lysosomal membrane proteomics; directly supports lysosomal membrane localization as part of the assembled V-ATPase. Reason: Mass spectrometry in lysosome-enriched fractions directly identifies subunit H at the lysosomal membrane. Supporting Evidence: PMID:17897319 Integral and associated lysosomal membrane proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Reactome TAS annotation; cytosolic localization reflects free V1 complex or V1H in its adaptor role during endocytic events. Reason: Cytosolic localization is well-established for the free V1 complex. Subunit H has a specific regulatory role in the cytosolic free V1 state (inhibiting futile ATP hydrolysis). Multiple independent sources confirm this.
GO:0005829 cytosol	TAS Reactome:R-HSA-167597	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in Nef/CD4 endocytosis context; V1H bridges cytosolic Nef to the AP-2 endocytic complex. Reason: In the Nef endocytosis pathway, V1H functions as a cytosolic adaptor. This is consistent with the documented AP2M1 binding.
GO:0005829 cytosol	TAS Reactome:R-HSA-167601	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in CD4 degradation pathway; consistent. Reason: Cytosolic localization context; consistent with subunit H adaptor function.
GO:0005829 cytosol	TAS Reactome:R-HSA-182171	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in CD8 degradation pathway; consistent. Reason: Cytosolic localization context; consistent with subunit H adaptor function.
GO:0005829 cytosol	TAS Reactome:R-HSA-182198	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in CD8 internalization; consistent. Reason: Cytosolic localization context; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; free V1 complex context. Reason: Cytosolic localization of free V1 complex; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; free V1 complex context. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; free V1 complex context. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9636397	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; Mycobacterium PtpA binds ATP6V1H context. Reason: Cytosolic localization; consistent with free V1 complex.
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in mTORC1 signaling context. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9858916	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Cytosolic localization; consistent.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-167537	KEEP AS NON CORE	Summary: Reactome TAS annotation for plasma membrane in Nef/CD4 complex context; V1H at plasma membrane bridges Nef to AP-2 for CD4 internalization. Reason: Plasma membrane localization in the Nef/CD4 endocytosis context reflects the adaptor function but is non-core relative to lysosomal/endosomal localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-167597	KEEP AS NON CORE	Summary: Reactome TAS for plasma membrane in CD4 internalization context; non-core. Reason: Non-core context; same reasoning as above.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182186	KEEP AS NON CORE	Summary: Reactome TAS for plasma membrane in CD8/Nef complex context; non-core. Reason: Non-core context; plasma membrane in Nef pathway.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-182198	KEEP AS NON CORE	Summary: Reactome TAS for plasma membrane in CD8 internalization context; non-core. Reason: Non-core context.
GO:0005515 protein binding	IPI PMID:11179428 Negative factor from SIV binds to the catalytic subunit of t...	MARK AS OVER ANNOTATED	Summary: IPI from SIV Nef/V-ATPase study; the specific interaction is SIV Nef with subunit H, exploiting the normal AP-2 adaptor function. The protein binding annotation is uninformative. Reason: The SIV Nef-H interaction is documented (PMID:11179428) but the generic protein binding term does not capture the biology. The relevant specific function is the AP-2 medium chain (AP2M1) binding.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	NAS PMID:9442887 Structure, function and regulation of the vacuolar (H+)-ATPa...	ACCEPT	Summary: NAS from Stevens and Forgac review; V1 domain membership is well-established. Reason: The 1997 Stevens and Forgac review is the foundational reference for V-ATPase V1 subunit composition including subunit H. Supporting Evidence: PMID:9442887 The peripheral V1 domain, a 500-kDa complex responsible for ATP hydrolysis, contains at least eight different subunits of molecular weight 70-13 (subunits A-H)
GO:0005515 protein binding	IPI PMID:12032142 Subunit H of the V-ATPase binds to the medium chain of adapt...	MARK AS OVER ANNOTATED	Summary: IPI from Geyer et al. 2002; this study demonstrated specific interaction with AP2M1. The protein binding annotation is uninformative but the underlying interaction is important. Reason: The specific interaction with AP2M1 (mu2 adaptin) is meaningful and well-documented, but GO:0005515 protein binding is uninformative. A more specific annotation to AP-2 adaptor binding or clathrin adaptor binding would be more informative.
GO:0005515 protein binding	IPI PMID:9620685 Interactions between HIV1 Nef and vacuolar ATPase facilitate...	MARK AS OVER ANNOTATED	Summary: IPI from Lu et al. 1998; interaction with HIV-1 Nef documented. Generic protein binding is uninformative. Reason: Generic protein binding annotation; the specific interaction is with HIV-1 Nef (a pathogen protein) and does not reflect normal cellular function.
GO:0006897 endocytosis	IDA PMID:12032142 Subunit H of the V-ATPase binds to the medium chain of adapt...	ACCEPT	Summary: IDA experimental evidence that V1H contributes to endocytosis via AP-2 interaction; this is a legitimate specific function of subunit H. Reason: Geyer et al. 2002 demonstrated that V1H connects to the endocytic machinery through AP2M1 interaction, and V1H-Nef chimeras can drive CD4 internalization. This is genuine experimental evidence for H subunit involvement in clathrin-mediated endocytosis. Supporting Evidence: PMID:12032142 V1H can function as an adaptor for interactions between Nef and AP-2
GO:0007035 vacuolar acidification	NAS PMID:9442887 Structure, function and regulation of the vacuolar (H+)-ATPa...	ACCEPT	Summary: NAS from foundational V-ATPase review; vacuolar acidification is the core biological process. Reason: Vacuolar acidification is a core biological process driven by V-ATPase. The Stevens and Forgac review is a valid reference for this NAS annotation. Supporting Evidence: PMID:9442887 The vacuolar (H+)-ATPases (or V-ATPases) function in the acidification of intracellular compartments in eukaryotic cells
GO:0016887 ATP hydrolysis activity	NAS PMID:9442887 Structure, function and regulation of the vacuolar (H+)-ATPa...	ACCEPT	Summary: NAS from foundational V-ATPase review; subunit H contributes to ATP hydrolysis activity of the V-ATPase complex. Reason: ATP hydrolysis is the biochemical activity of the V1 domain. Subunit H is a regulatory component that modulates this activity. The contributes_to qualifier is appropriate. Supporting Evidence: PMID:9442887 The peripheral V1 domain, a 500-kDa complex responsible for ATP hydrolysis, contains at least eight different subunits of molecular weight 70-13 (subunits A-H)
GO:0030234 enzyme regulator activity	NAS PMID:9442887 Structure, function and regulation of the vacuolar (H+)-ATPa...	ACCEPT	Summary: NAS for enzyme regulator activity; subunit H is the regulatory H subunit that modulates V-ATPase ATP hydrolysis in assembled versus free V1 states. Reason: Subunit H has a documented regulatory function — it inhibits futile ATP hydrolysis in the free V1 complex and activates the pump when assembled with V0. This enzyme regulator activity is a genuinely specific function of the H subunit distinguishing it from other V1 subunits.
GO:1902600 proton transmembrane transport	NAS PMID:9442887 Structure, function and regulation of the vacuolar (H+)-ATPa...	ACCEPT	Summary: NAS from foundational V-ATPase review; proton transmembrane transport is the core function. Reason: Proton transmembrane transport is the core function of the V-ATPase. Subunit H as a regulatory component is appropriately annotated to this process.

Core Functions

ATP6V1H is the regulatory H subunit of the V1 domain of the V-ATPase. It modulates ATPase coupling efficiency: in the free cytosolic V1 complex it inhibits futile ATP hydrolysis, and in the assembled holoenzyme it supports proton-coupled ATP hydrolysis. The H subunit contributes to the rotational mechanism of the V-ATPase by stabilizing the stator in V1, and is essential for regulated disassembly/reassembly of the complex in response to nutrient availability.

Molecular Function:

enzyme regulator activity

Directly Involved In:

lysosomal lumen acidification endosomal lumen acidification

Cellular Locations:

lysosomal membrane cytosol

Supporting Evidence:

file:human/ATP6V1H/ATP6V1H-uniprot.txt
The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H
PMID:9442887
The peripheral V1 domain, a 500-kDa complex responsible for ATP hydrolysis, contains at least eight different subunits of molecular weight 70-13 (subunits A-H)

ATP6V1H (subunit H) directly binds AP2M1 (the mu2 medium chain of AP-2) via armadillo repeat domains spanning residues 133-363, physically connecting the V-ATPase to the clathrin-mediated endocytic machinery. This is an independent function from the proton pump role and is responsible for the involvement of the V-ATPase in clathrin-coated vesicle formation and receptor internalization. HIV-1 and SIV Nef co-opt this interaction to force CD4/CD8 internalization.

Molecular Function:

clathrin-cargo adaptor activity

Directly Involved In:

endocytosis

Cellular Locations:

clathrin-coated vesicle membrane

Supporting Evidence:

PMID:12032142
V1H binds to the C-terminal flexible loop in Nef from HIV-1 and to the medium chain (mu2) of the adaptor protein complex 2 (AP-2) in vitro and in vivo. The interaction sites of V1H and mu2 were mapped to a central region in V1H from positions 133 to 363, which contains 4 armadillo repeats

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:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

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

PMID:11179428

Negative factor from SIV binds to the catalytic subunit of the V-ATPase to internalize CD4 and to increase viral infectivity.

SIV Nef binds subunit H of V-ATPase to contact endocytic machinery without direct AP-2 binding; subunit H plays important role in viral infectivity by connecting Nef to endocytic pathway.

PMID:12032142

Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex 2 and connects Nef to the endocytic machinery.

V1H binds AP2M1 (mu2) through armadillo repeats 133-363; V1H functions as an adaptor connecting Nef to AP-2 and the endocytic machinery.

PMID:17897319

Integral and associated lysosomal membrane proteins.

Mass spectrometry identification of ATP6V1H in lysosome-enriched fractions supports lysosomal membrane localization.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

Identification in urinary exosome fraction; likely contamination.

PMID:19199708

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

Identification in parotid gland exosome fraction; likely contamination.

PMID:22982048

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

V-ATPase disruption used as tool to impair lysosomal activity; does not demonstrate specific role of subunit H in macroautophagy regulation.

PMID:25659576

TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells.

TM9SF4 interacts with ATP6V1H in colon cancer cells; TM9SF4 suppression reduces V1/V0 assembly.

PMID:32001091

Structure and Roles of V-type ATPases.

V-ATPases are the primary source of organellar acidification; subunit isoforms are differentially localized; enzymatic activity modulated by regulated reversible disassembly.

PMID:32296183

A reference map of the human binary protein interactome.

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.

Cryo-EM structures of complete human V-ATPase; V1 complex contains regulatory subunits C and H; subunit H is part of the V1 peripheral domain.

PMID:9442887

Structure, function and regulation of the vacuolar (H+)-ATPase.

V1 domain contains eight subunits A-H; subunit H is the regulatory component; V-ATPase functions in acidification of intracellular compartments.

PMID:9620685

Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4.

NBP1 (subunit H) identified as Nef-binding protein; NBP1 is human homolog of yeast Vma13p; connects Nef to endocytic pathway.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-167537

Formation of CD4:Nef:AP-2 Complex:v-ATPase Complex

Reactome:R-HSA-167597

Internalization of the CD4:Nef:AP-2 Complex:v-ATPase Complex

Reactome:R-HSA-167601

Degradation of CD4

Reactome:R-HSA-182171

Degradation of CD8

Reactome:R-HSA-182186

Formation of CD8:Nef:AP-2 Complex:v-ATPase Complex

Reactome:R-HSA-182198

Internalization of the CD8:Nef:AP-2 Complex:v-ATPase Complex

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-9636397

PtpA binds ATP6V1H

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

Reactome:R-HSA-9858916

MITF-M-dependent ATP6V1H gene expression

Suggested Experiments

Experiment: Generate separation-of-function mutations in ATP6V1H that disrupt AP2M1 binding (within residues 133-363) without affecting V1 complex assembly or proton pump activity. Assess clathrin-mediated endocytosis of physiological cargo (transferrin receptor, EGF receptor) in cells expressing mutant versus wild-type H subunit.

Hypothesis: The AP2M1-binding function of subunit H is required for normal clathrin-mediated endocytosis independent of V-ATPase proton pumping.

Type: structure-function mutagenesis and receptor internalization assay

Experiment: Quantify the ratio of V1H in membrane-bound (V-ATPase assembled) versus cytosolic (free V1) fractions under nutrient replete and starved conditions by subcellular fractionation and quantitative proteomics, and measure V1-ATPase activity in each fraction to directly test the inhibitory role of H in the free state.

Hypothesis: Regulated V1/V0 disassembly differentially affects the H subunit regulatory function.

Type: subcellular fractionation and ATPase activity assay

Deep Research

Falcon

(ATP6V1H-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1H (V-type Proton ATPase Subunit H) in Homo sapiens 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: ATP6V1H (V-type Proton ATPase Subunit H) in Homo sapiens

Gene and Protein Identity

The human gene ATP6V1H (UniProt accession Q9UI12) encodes the V-type proton ATPase subunit H, a regulatory component of the vacuolar H+-ATPase (V-ATPase) complex (wang2020structuresofa pages 3-5, forgac1999structureandproperties pages 1-2). V-ATPases are ATP-driven proton pumps that acidify intracellular compartments and, in specialized cell types, export protons across the plasma membrane (forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). The ATP6V1H protein belongs to the V-ATPase H subunit family and contains conserved V-ATPase_H_N and V-ATPase_H_C domains, consistent with its structural role in the enzyme complex.

Structural Organization and Molecular Function

V-ATPase Complex Architecture

V-ATPases are large multisubunit complexes (~830 kDa) composed of two functional domains: the cytosolic V1 domain responsible for ATP hydrolysis, and the membrane-embedded V0 domain that translocates protons (wang2020structuresofa pages 1-3, forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). The human V1 complex contains eight different subunits (A, B, C, D, E, F, G, and H), while the V0 complex comprises subunits a, c, c′, c″, d, e, ATP6AP1, and ATP6AP2 (wang2020structuresofa pages 3-5, chen2024vatpaseincancer pages 1-3).

Position and Role of Subunit H

ATP6V1H is a single-copy V1 subunit located at the V1-V0 interface, where it forms part of a collar structure together with subunit C and the N-terminal domain of subunit a from the V0 complex (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). High-resolution cryo-electron microscopy structures of human V-ATPase at 2.9-3.1 Å resolution reveal that subunit H interacts extensively with peripheral stalk 1 (composed of subunits E and G) and the a-subunit N-terminal domain, bridging the V1 and V0 sectors (wang2020structuresofa pages 3-5).

Feature	ATP6V1H / subunit H summary	Evidence
Gene/protein identity	Human ATP6V1H encodes V-type proton ATPase subunit H, a component of the V1 cytosolic sector of the V-ATPase complex, consistent with the V1 A–H subunit organization described for eukaryotic V-ATPases.	(forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2)
Location within V-ATPase	Subunit H is part of the peripheral/cytosolic V1 domain, not the membrane-embedded V0 proton-translocating domain. In the human cryo-EM structure, H contributes to the bottom collar together with subunit C and the N-terminal domain of subunit a from V0, placing it at the V1–V0 interface.	(wang2020structuresofa pages 3-5, forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2)
Stoichiometry	The V1 sector contains one copy of subunit H per holoenzyme; human V-ATPase structures identify one H together with single copies of C, D, F and three copies each of A, B2, E1 and G1.	(wang2020structuresofa pages 3-5, forgac1999structureandproperties pages 1-2)
Primary biochemical role	ATP6V1H is not the catalytic ATP-hydrolyzing subunit; ATP hydrolysis occurs at A/B interfaces in V1. Instead, subunit H has a structural/regulatory coupling role, helping connect ATP hydrolysis in V1 to proton pumping in V0. Overall enzyme reaction: ATP + H2O powers proton translocation across endomembrane or plasma membranes.	(forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2)
Molecular function in coupling	Structural analysis indicates that subunit H interacts across V1 and V0-linked scaffolding elements and may explain the ability of H to couple V1 ATPase activity to V0 proton pumping activity in the intact enzyme.	(wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Protein interactions	In the human V-ATPase structure, subunit H interacts extensively with peripheral stalk 1 (PS-1; E/G stalk) and the N-terminal domain of subunit a (a-NTD). These contacts bridge the V1 and V0 sectors and help stabilize the collar region.	(wang2020structuresofa pages 3-5)
Structural context	H is positioned in the collar/scaffold region rather than the rotary ATPase head or proton pore. This location is consistent with a role in holding the stator architecture together while the central stalk and c-ring rotate during catalysis.	(wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7, eaton2021theh+atpase(vatpase) pages 1-5)
Role in rotational states	Presence of subunit H in the human structure correlates with stabilization of rotational state 1 relative to other states, suggesting an influence on conformational equilibrium and enzyme mechanics.	(wang2020structuresofa pages 3-5)
Role in regulation	V-ATPase activity can be regulated by reversible V1–V0 disassembly/reassembly. Because H is a V1 subunit located at the V1–V0 interface, its position is consistent with participation in this regulatory architecture; separated V1 and V0 sectors are inactive, preventing futile ATP hydrolysis or proton leak.	(eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9)
Role in assembly	Human structural work identifies H as an essential resolved component of the assembled human holoenzyme and highlights its cross-complex contacts, supporting a role in stabilizing assembled V-ATPase rather than forming the membrane pore or catalytic nucleotide-binding sites directly.	(wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Cellular functional consequences	Through its role in V-ATPase integrity and coupling, ATP6V1H contributes indirectly to organelle acidification, including acidification of endosomes, lysosomes, Golgi-related compartments, and secretory vesicles, and in specialized cells to plasma membrane proton secretion.	(forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2)

Table: This table summarizes where ATP6V1H sits in the V-ATPase complex, how many copies are present, and what structural and regulatory roles subunit H plays. It is useful for distinguishing ATP6V1H from catalytic and membrane proton-translocating subunits while highlighting its coupling and scaffold functions.

Coupling Function and Catalytic Mechanism

While ATP hydrolysis occurs at the interface between the A and B subunits in the V1 head domain, subunit H plays a critical coupling role that connects ATP hydrolysis in V1 to proton pumping through V0 (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7). The V-ATPase operates through a rotary mechanism: ATP hydrolysis drives conformational changes in the A3B3 hexamer, causing rotation of the central stalk (subunits D and F) and the associated c-ring in V0, which translocates protons across the membrane (wang2020structuresofa pages 1-3, forgac1999structureandproperties pages 1-2).

Subunit H stabilizes the assembled holoenzyme and influences the conformational equilibrium between rotational states. Structural analysis indicates that the presence of subunit H correlates with stabilization of rotational state 1 relative to states 2 and 3, suggesting it modulates enzyme mechanics during the catalytic cycle (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7). The extensive interactions of H across V1 and V0 components explain its ability to couple V1's ATPase activity to V0's proton-pumping activity in the intact enzyme (wang2020structuresofa pages 3-5).

Substrate Specificity and Reaction

The V-ATPase complex uses ATP as its substrate, hydrolyzing it to ADP and inorganic phosphate to power proton transport. The overall reaction is:

ATP + H2O + H+cytoplasm → ADP + Pi + H+lumen/extracellular

This reaction establishes both a pH gradient and membrane potential across the targeted membrane (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2).

Subcellular Localization and Functional Compartments

Intracellular Organelles

ATP6V1H-containing V-ATPase complexes localize to multiple intracellular compartments where they maintain organellar pH homeostasis (forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2):

Lysosomes: V-ATPases maintain the acidic lysosomal lumen (pH 4.5-5.0) required for the activity of degradative hydrolases, supporting protein degradation, autophagy, and metabolic recycling (eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2).

Endosomes: Acidification of early and late endosomes facilitates receptor-ligand dissociation, receptor recycling, endocytic trafficking, and formation of endosomal carrier vesicles (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2). Endosomal acidification is also required for pH-dependent viral entry, including influenza and other envelope viruses (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2).

Golgi and Secretory Vesicles: V-ATPases generate luminal acidity within the Golgi and secretory compartments, supporting protein sorting, prohormone processing (e.g., insulin maturation), and vesicle maturation (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2).

Synaptic Vesicles: In neuronal cells, the proton gradient produced by V-ATPases provides the driving force for neurotransmitter uptake into synaptic vesicles via coupled transporters (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2).

Specialized Plasma Membrane Localization

In certain differentiated cell types, V-ATPases are targeted to the plasma membrane for extracellular acidification (forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2):

Osteoclasts: V-ATPases at the ruffled border of osteoclasts secrete protons to acidify the resorption lacuna, dissolving bone mineral matrix during bone remodeling (eaton2021theh+atpase(vatpase) pages 1-5, duan2018vatpasesandosteoclasts pages 1-2, toei2010regulationandisoform pages 1-2).

Renal Intercalated Cells: Plasma membrane V-ATPases in kidney intercalated cells secrete acid into urine, maintaining systemic acid-base balance (forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2).

Epididymal Clear Cells: V-ATPases acidify luminal fluid in the male reproductive tract, creating the low pH environment necessary for sperm maturation and storage (eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2).

Tumor Cells: Some invasive cancers relocalize V-ATPases to the plasma membrane, acidifying the extracellular tumor microenvironment while maintaining an alkaline cytosol, which supports tumor invasion and metastasis (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3).

Localization category	Specific compartment / cell type	ATP6V1H-containing V-ATPase role	Biological processes supported	Recent disease/pathway findings (2023-2025)
Intracellular endomembrane system	Early and late endosomes	ATP-driven proton pumping acidifies endosomal lumen; ATP6V1H is part of the V1 sector that couples ATP hydrolysis to proton transport by the holoenzyme	Receptor-ligand dissociation, receptor recycling, endocytic trafficking, endosomal carrier vesicle formation, entry of pH-dependent viruses and toxins (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2)	V-ATPase remains integrated with nutrient- and stress-signaling networks, including lysosome-linked mTORC1/AMPK control discussed in recent reviews and pathway studies (chen2024vatpaseincancer pages 1-3, duque2025atg16l1controlsmammalian pages 1-3)
Intracellular degradative organelles	Lysosomes	Maintains acidic lysosomal lumen required for hydrolase activity; assembled V-ATPase supports organelle acidification and proteolysis (eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2)	Protein degradation, autophagic cargo turnover, metabolite recycling, lysosomal homeostasis (eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, eaton2021theh+atpase(vatpase) pages 5-9)	TFEB-responsive regulation of Atp6v1h was shown to be necessary for lysosomal acidification and microglial activation in tauopathy; disrupting the CLEAR element in Atp6v1h impaired lysosomal function and altered mTOR/HIF-1-related microglial states (wang2024tfeb–vacuolaratpasesignaling pages 1-7). ATG16L1 was also shown to regulate mammalian V-ATPase assembly/activity and endolysosomal acidification (duque2025atg16l1controlsmammalian pages 1-3)
Secretory and biosynthetic pathway	Golgi-derived vesicles / secretory vesicles	Generates luminal acidity within biosynthetic and secretory compartments (forgac1999structureandproperties pages 1-2, toei2010regulationandisoform pages 1-2)	Protein sorting, prohormone/zymogen processing, vesicle loading and maturation (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2)	Recent literature emphasizes that altered V-ATPase regulation can broadly reshape intracellular pH homeostasis and trafficking in disease states, especially cancer (chen2024vatpaseincancer pages 1-3)
Neurosecretory compartments	Synaptic vesicles and related secretory granules	Proton gradient produced by V-ATPase energizes uptake systems for neurotransmitters and other small molecules (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2)	Neurotransmitter loading and release competence of synaptic vesicles; secretory granule function (forgac1999structureandproperties pages 1-2, jefferies2008functionstructureand pages 1-2)	Brain/tauopathy studies highlight ATP6V1H as a TFEB-regulated lysosomal gene with consequences for neuroimmune responses and neurodegeneration-related lysosome biology (wang2024tfeb–vacuolaratpasesignaling pages 1-7)
Specialized plasma membrane localization	Osteoclast ruffled border / plasma membrane	Exports protons extracellularly to acidify the resorption lacuna; ATP6V1H contributes as a V1 regulatory/coupling subunit in osteoclast V-ATPase complexes (eaton2021theh+atpase(vatpase) pages 1-5, duan2018vatpasesandosteoclasts pages 1-2, toei2010regulationandisoform pages 1-2)	Bone matrix dissolution, bone resorption, bone remodeling (duan2018vatpasesandosteoclasts pages 1-2, toei2010regulationandisoform pages 1-2)	ATP6V1H has been linked to osteoporosis-related phenotypes. A 2024 mouse study reported that Atp6v1h deficiency modulated bone loss under simulated microgravity through Fos-Jun-Src-Integrin pathway changes, reinforcing its relevance to osteoclast biology and osteoporosis mechanisms (zhao2024atp6v1hdeficiencyblocks pages 1-2)
Specialized plasma membrane localization	Renal intercalated cells (kidney)	Plasma membrane V-ATPase secretes protons into urine to maintain systemic acid-base balance (forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2)	Urinary acidification and renal pH homeostasis (forgac1999structureandproperties pages 1-2, toei2010regulationandisoform pages 1-2)	Although ATP6V1H-specific human renal disease evidence is limited here, V-ATPase dysfunction more broadly is central to acidification defects and is a key framework for understanding V-ATPase-linked renal physiology/pathophysiology (eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2)
Specialized plasma membrane localization	Epididymal clear cells / male reproductive tract	Extracellular proton secretion acidifies luminal fluid (eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2)	Sperm maturation and storage in an acidic environment (eaton2021theh+atpase(vatpase) pages 1-5, toei2010regulationandisoform pages 1-2)	Recent reviews continue to cite plasma membrane V-ATPases as crucial examples of tissue-specialized acidification machinery, though ATP6V1H-specific new reproductive findings were not prominent in the retrieved set (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
Specialized plasma membrane localization	Tumor cell plasma membrane / invasive cancer cells	Some cancers relocalize/enhance V-ATPase at the plasma membrane to acidify the extracellular milieu while helping maintain alkaline cytosol (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)	Tumor invasion, metastasis, drug resistance, adaptation to acidic tumor microenvironment (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)	A 2024 review highlighted V-ATPase as a therapeutic target in cancer, linking its activity to proliferation, metastasis, mTORC1/AMPK signaling, non-canonical autophagy, and treatment resistance (chen2024vatpaseincancer pages 1-3)
Immune / CNS lysosome-related compartments	Microglia and endolysosomal immune compartments	Supports lysosomal acidification required for immune-cell degradative and signaling responses (eaton2021theh+atpase(vatpase) pages 1-5, wang2024tfeb–vacuolaratpasesignaling pages 1-7)	Lysosome-dependent immune activation, degradation programs, stress adaptation (wang2024tfeb–vacuolaratpasesignaling pages 1-7, duque2025atg16l1controlsmammalian pages 1-3)	In tauopathy, TFEB-v-ATPase signaling through Atp6v1h regulated lysosomal function and microglial activation; impaired Atp6v1h transcription blunted microglial response while worsening tau pathology (wang2024tfeb–vacuolaratpasesignaling pages 1-7)
Dynamic assembly state rather than fixed compartment	Cytosolic V1 pool associating with endomembranes	ATP6V1H resides in V1, which can reversibly dissociate from and reassemble with membrane V0 sectors; this tunes local proton-pumping activity (eaton2021theh+atpase(vatpase) pages 5-9, duque2025atg16l1controlsmammalian pages 1-3)	Regulation of organelle pH, energy conservation, adaptive control of lysosomal/endosomal acidification (eaton2021theh+atpase(vatpase) pages 5-9, duque2025atg16l1controlsmammalian pages 1-3)	Recent mechanistic work shows mammalian V-ATPase activity is controlled by factors such as ATG16L1 and assembly regulators, linking ATP6V1H-containing V1 to autophagy-associated and nutrient-sensing pathways (duque2025atg16l1controlsmammalian pages 1-3)

Table: This table summarizes where ATP6V1H-containing V-ATPase complexes function in human cells and what biological processes they support. It also highlights recent 2023-2025 findings linking these localizations to lysosomal signaling, osteoporosis, neurodegeneration, autophagy, and cancer.

Biological Processes and Signaling Pathways

Lysosomal Function and Autophagy

ATP6V1H-containing V-ATPases are essential for lysosomal acidification and autophagy, processes central to cellular homeostasis (eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2). Lysosomal acidification enables the activity of acid hydrolases for degradation of proteins, organelles, and other cellular cargo delivered via macroautophagy and other autophagy pathways (eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2).

mTORC1 and Nutrient Sensing

V-ATPase functions as a critical component of the lysosomal nutrient-sensing machinery that regulates mechanistic target of rapamycin complex 1 (mTORC1) (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3). mTORC1 is a master regulator of cellular anabolism and growth that senses amino acid availability at the lysosomal surface. Recent studies demonstrate that mTORC1 activity directly controls V-ATPase assembly and lysosomal acidification: when mTORC1 is active (nutrients abundant), V1 domains including ATP6V1H remain predominantly cytosolic, limiting lysosomal acidification and catabolic activity; when mTORC1 declines (nutrient limitation), V1 assembles with V0 on lysosomes to form active pumps, increasing acidification and protein degradation (chen2024vatpaseincancer pages 1-3).

AMPK and Energy Sensing

V-ATPase participates in lysosome-centered energy sensing networks that coordinate with AMP-activated protein kinase (AMPK), a key cellular energy sensor (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3). The lysosomal surface integrates nutrient and energy cues through V-ATPase interactions with both mTORC1 and AMPK, coordinating catabolic versus anabolic programs in response to metabolic stress (chen2024vatpaseincancer pages 1-3).

TFEB Transcriptional Regulation

ATP6V1H itself is transcriptionally regulated by transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy (wang2024tfeb–vacuolaratpasesignaling pages 1-7). TFEB binds to Coordinated Lysosomal Expression and Regulation (CLEAR) motifs in the promoters of lysosomal genes, including Atp6v1h. A 2024 study in a mouse tauopathy model demonstrated that mutating the CLEAR sequence in the Atp6v1h promoter impaired TFEB-dependent transcriptional induction, resulting in reduced lysosomal acidification, impaired microglial activation, and increased tau pathology (wang2024tfeb–vacuolaratpasesignaling pages 1-7). This work established ATP6V1H as a critical TFEB-responsive node linking transcriptional lysosome programs to functional lysosomal acidification capacity.

ATG16L1 Regulation of V-ATPase

Recent mechanistic studies in 2025 revealed that ATG16L1, a protein primarily known for its role in autophagy, directly binds and regulates V-ATPase activity (duque2025atg16l1controlsmammalian pages 1-3). ATG16L1 knockout elevated V-ATPase activity, increased V1 domain presence on endomembranes, and increased the number of acidified intracellular compartments, indicating that ATG16L1 normally restrains V-ATPase assembly and activity (duque2025atg16l1controlsmammalian pages 1-3). ATG16L1's ability to efficiently bind V-ATPase (including the V1 domain containing ATP6V1H) is required for its inhibitory role in endolysosomal acidification and for control of Mycobacterium tuberculosis infection (duque2025atg16l1controlsmammalian pages 1-3). This expands the ATG16L1-V-ATPase relationship beyond simple recruitment to direct functional control of proton pump activity.

Assembly Regulation by DMXL1/RAVE Complex

V1 domain assembly onto lysosomal V0 is regulated by assembly factors related to the yeast RAVE (Regulator of ATPase of Vacuoles and Endosomes) complex (eaton2021theh+atpase(vatpase) pages 5-9, lee2025dmxl1promotesrecruitment pages 1-2). In 2025, DMXL1 (the mammalian ortholog of yeast Rav1) was identified as a key regulator that assembles with ROGDI and WDR7 and associates with both V0 and V1 subunits (lee2025dmxl1promotesrecruitment pages 1-2). TRPML1 channel activation triggers DMXL1/DMXL2-dependent recruitment of V1 (containing ATP6V1H) to lysosomes, promoting V-ATPase assembly, lumenal acidification, and hydrolytic capacity (lee2025dmxl1promotesrecruitment pages 1-2). This work revealed mammalian assembly-control mechanisms for lysosomal V-ATPase recruitment during stress-responsive remodeling.

Reversible V1-V0 Disassembly

A unique regulatory mechanism for V-ATPase is reversible disassembly, wherein the V1 and V0 domains dissociate in response to environmental signals such as glucose deprivation (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9). When dissociated, both V1 and V0 are inactive: V1 lacks ATPase activity without V0, and V0 does not conduct protons without V1, preventing futile ATP hydrolysis and proton leak (eaton2021theh+atpase(vatpase) pages 5-9). ATP6V1H, as a V1 subunit positioned at the V1-V0 interface in the collar region, participates in this reversible assembly architecture (wang2020structuresofa pages 3-5, eaton2021theh+atpase(vatpase) pages 5-9). Assembly and disassembly regulate V-ATPase activity in mammalian cells during the lysosome regeneration cycle, aging, and metabolic adaptation (eaton2021theh+atpase(vatpase) pages 5-9).

Pathway / regulatory mechanism	Role of ATP6V1H-containing V-ATPase	Mechanistic summary	Key recent findings (2022-2025)	Evidence
mTORC1 nutrient sensing	V-ATPase acts as a lysosomal platform and activity switch that helps determine lysosomal acidification status and thereby regulates mTORC1-dependent catabolic versus anabolic states	When nutrients are sufficient, mTORC1 activity suppresses V1 recruitment/assembly on lysosomes, limiting acidification and catabolic activity; when mTORC1 declines, V1 domains assemble with V0 on lysosomes to form active pumps, lowering lysosomal pH and increasing degradation. V-ATPase is also described as part of the lysosomal nutrient-sensing machinery that communicates amino acid status to mTORC1 (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)	Direct control of lysosomal catabolism by mTORC1 through V-ATPase assembly was shown in 2022, establishing that mTORC1 can rapidly regulate lysosomal acidification by controlling V1-V0 assembly. Recent reviews in 2024 continue to place V-ATPase at the center of lysosomal mTORC1 signaling in cancer and metabolism (chen2024vatpaseincancer pages 1-3)	(eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
AMPK energy sensing	V-ATPase participates in lysosome-centered nutrient/energy sensing networks that coordinate with AMPK	Reviews of V-ATPase signaling note that the lysosomal surface integrates nutrient cues through V-ATPase with AMPK and mTORC1. In stress or nutrient limitation states, V-ATPase-dependent acidification and assembly state influence the signaling environment that supports AMPK-linked catabolic adaptation (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)	Recent pathway-focused reviews from 2024 emphasize V-ATPase interactions with AMPK as part of the metabolic regulatory machinery in cancer and other disease settings, although ATP6V1H-specific biochemical steps remain less directly resolved than for TFEB or ATG16L1 (chen2024vatpaseincancer pages 1-3)	(eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
TFEB transcriptional regulation	ATP6V1H itself is TFEB-responsive, linking transcriptional lysosome programs to V-ATPase abundance and lysosomal competence	TFEB binds CLEAR-regulated lysosomal gene programs. In a 2024 tauopathy study, mutating the CLEAR sequence of Atp6v1h reduced the TFEB response, impairing lysosomal acidification and lysosomal activity. This demonstrates that ATP6V1H is not only a structural V-ATPase component but also a transcriptionally regulated node in lysosomal adaptation (wang2024tfeb–vacuolaratpasesignaling pages 1-7)	In 2024, endogenous disruption of TFEB-dependent Atp6v1h regulation in mice impaired lysosomal function, reduced microglial activation, and increased tau pathology, providing unusually direct in vivo evidence for ATP6V1H in TFEB-lysosome signaling (wang2024tfeb–vacuolaratpasesignaling pages 1-7)	(wang2024tfeb–vacuolaratpasesignaling pages 1-7)
Autophagy and lysosomal homeostasis	ATP6V1H-containing V-ATPase is required for lysosomal acidification that underpins autophagic degradation and broader lysosomal homeostasis	V-ATPase acidifies lysosomes, enabling hydrolase activity, cargo degradation, and autophagic flux. Disrupting ATP6V1H-dependent V-ATPase regulation impairs lysosomal function. Reviews also describe V-ATPase as a signaling hub, not merely a proton pump, in endolysosomal and autophagic pathways (eaton2021theh+atpase(vatpase) pages 1-5, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2)	The 2024 TFEB-Atp6v1h study tied altered ATP6V1H expression to defective lysosomal acidification in vivo. Recent reviews and mechanistic studies likewise emphasize lysosomal homeostasis as a central disease-relevant output of V-ATPase regulation (chen2024vatpaseincancer pages 1-3, wang2024tfeb–vacuolaratpasesignaling pages 1-7)	(eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3, jefferies2008functionstructureand pages 1-2, toei2010regulationandisoform pages 1-2, wang2024tfeb–vacuolaratpasesignaling pages 1-7)
ATG16L1 interaction axis	ATG16L1 binds V-ATPase and regulates its activity; ATP6V1H-containing V1 is part of the regulated assembly state	ATG16L1, best known from autophagy, directly interfaces with V-ATPase. ATG16L1 knockout increases V-ATPase activity, increases V1 presence on endomembranes, and increases acidified compartments, indicating that ATG16L1 normally restrains V-ATPase assembly/activity in mammalian cells (duque2025atg16l1controlsmammalian pages 1-3)	A 2025 study showed that ATG16L1 controls mammalian V-ATPase and endolysosomal acidification, expanding the ATG16L1-V-ATPase relationship beyond recruitment during noncanonical autophagy to direct control of proton pump function (duque2025atg16l1controlsmammalian pages 1-3)	(duque2025atg16l1controlsmammalian pages 1-3)
DMXL1 / assembly-factor regulation	ATP6V1H-containing V1 assembly on lysosomes is regulated by DMXL1/DMXL2-containing machinery related to yeast RAVE	DMXL1 assembles with ROGDI and WDR7 and associates with V0 and V1 subunits. Upon TRPML1 activation, DMXL1/DMXL2 promote recruitment of V1 to lysosomes, supporting V-ATPase assembly, lumen acidification, and hydrolytic capacity (lee2025dmxl1promotesrecruitment pages 1-2)	The 2025 DMXL1 study identified a mammalian assembly-control module for lysosomal V-ATPase recruitment, helping explain how V1-containing complexes, including ATP6V1H, are dynamically targeted to lysosomes during stress-responsive remodeling (lee2025dmxl1promotesrecruitment pages 1-2)	(lee2025dmxl1promotesrecruitment pages 1-2)
Reversible V1-V0 assembly/disassembly	ATP6V1H, as a V1 subunit at the V1-V0 interface, participates in the reversible assembly architecture that controls pump activation	V-ATPase activity is regulated by reversible dissociation of cytosolic V1 from membrane V0. Separated sectors are inactive, preventing futile ATP hydrolysis or proton leak. Subunit H sits in the collar/interface region and helps couple V1 ATPase activity to V0 proton pumping in assembled holoenzyme, making it structurally relevant to assembly-dependent regulation (wang2020structuresofa pages 3-5, eaton2021theh+atpase(vatpase) pages 5-9)	Recent mammalian studies and reviews continue to show that assembly/disassembly is a major control point for lysosomal pH regulation. Structural work on human V-ATPase highlights subunit H as part of the interdomain coupling apparatus that stabilizes the assembled state (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7, eaton2021theh+atpase(vatpase) pages 5-9)	(wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7, eaton2021theh+atpase(vatpase) pages 5-9)
Disease-linked signaling outputs	ATP6V1H-dependent V-ATPase regulation feeds into neurodegeneration, cancer, bone biology, and metabolic disease pathways	Because V-ATPase controls lysosomal pH, nutrient signaling, and autophagy, perturbation of ATP6V1H can affect microglial state, tumor adaptation, osteoclast activity, and diabetes-associated expression programs. ATP6V1H has been implicated in bone homeostasis and in altered expression associated with type 2 diabetes (zhao2024atp6v1hdeficiencyblocks pages 1-2, molina2011decreasedexpressionof pages 1-3)	2024 work connected Atp6v1h to osteoclast-linked bone loss pathways under simulated microgravity, while 2024 cancer review literature emphasized V-ATPase as a therapeutic target in tumor metabolism, invasion, and drug resistance. Earlier human expression work also reported reduced ATP6V1H expression with diabetes progression (chen2024vatpaseincancer pages 1-3, zhao2024atp6v1hdeficiencyblocks pages 1-2, molina2011decreasedexpressionof pages 1-3)	(chen2024vatpaseincancer pages 1-3, zhao2024atp6v1hdeficiencyblocks pages 1-2, molina2011decreasedexpressionof pages 1-3)

Table: This table summarizes the main signaling pathways and regulatory mechanisms involving ATP6V1H-containing V-ATPase complexes, emphasizing lysosomal nutrient sensing, transcriptional control, autophagy, and dynamic assembly regulation. It is useful for linking ATP6V1H’s structural role in the proton pump to current disease-relevant pathway biology.

Recent Developments (2023-2025)

Cancer Biology

A 2024 comprehensive review highlighted V-ATPase as a critical player in cancer cell biology and a promising therapeutic target (chen2024vatpaseincancer pages 1-3). Enhanced V-ATPase activity in cancer cells is closely associated with tumor cell proliferation, metastasis, and adaptation to the acidic tumor microenvironment (chen2024vatpaseincancer pages 1-3). V-ATPase promotes tumor invasion by regulating extracellular pH and supports drug resistance through its interactions with mTORC1, AMPK, and non-canonical autophagy pathways (chen2024vatpaseincancer pages 1-3). Multiple V-ATPase inhibitors are being evaluated as potential anticancer agents.

Neurodegeneration and Tauopathy

The 2024 study by Wang and colleagues demonstrated that TFEB-dependent regulation of Atp6v1h is essential for lysosomal function and microglial activation in Alzheimer's disease-related tauopathy (wang2024tfeb–vacuolaratpasesignaling pages 1-7). Mice with disrupted TFEB-Atp6v1h signaling exhibited impaired lysosomal acidification, reduced microglial response, and increased tau pathology (wang2024tfeb–vacuolaratpasesignaling pages 1-7). This work positioned ATP6V1H within the TFEB-V-ATPase-lysosome axis as a critical node in neuroinflammatory and neurodegenerative processes.

Bone Biology and Osteoporosis

A 2024 study investigated Atp6v1h deficiency in a mouse model of simulated microgravity-induced bone loss (zhao2024atp6v1hdeficiencyblocks pages 1-2). Atp6v1h heterozygous knockout mice displayed bone loss due to reduced V-ATPase function but did not show aggravated bone loss under microgravity conditions (zhao2024atp6v1hdeficiencyblocks pages 1-2). Transcriptomic analysis revealed that Atp6v1h levels influence bone remodeling through the Fos-Jun-Src-Integrin pathway, affecting osteoclast activity and bone resorption (zhao2024atp6v1hdeficiencyblocks pages 1-2). These findings position ATP6V1H as a potential therapeutic target for osteoporosis and environmental bone loss.

Metabolic Disease

Earlier longitudinal studies in humans reported decreased ATP6V1H mRNA expression in peripheral blood during progression from impaired fasting glucose to overt type 2 diabetes (molina2011decreasedexpressionof pages 1-3). The downregulation of ATP6V1H was statistically significant within individuals as diabetes developed, suggesting a role for V-ATPase dysfunction in diabetes-associated metabolic changes (molina2011decreasedexpressionof pages 1-3).

Disease-Associated Mutations

A 2023 review cataloged disease-associated mutations in V-ATPase subunits across different isoforms (duan2018vatpasesandosteoclasts pages 1-2). While most disease mutations have been identified in other V-ATPase subunits (particularly subunit a isoforms causing renal tubular acidosis and osteopetrosis), emerging evidence continues to link ATP6V1H dysregulation to bone density disorders and metabolic disease (duan2018vatpasesandosteoclasts pages 1-2, zhao2024atp6v1hdeficiencyblocks pages 1-2).

Current Understanding and Applications

Experimental Evidence Base

The functional characterization of ATP6V1H is supported by multiple experimental approaches:

Structural studies: High-resolution cryo-EM structures of human V-ATPase (2020) defined ATP6V1H's position, interactions, and role in coupling V1 and V0 (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Genetic studies: Knockout and knockin mouse models demonstrated ATP6V1H's roles in bone homeostasis, lysosomal function, and microglial activation (wang2024tfeb–vacuolaratpasesignaling pages 1-7, zhao2024atp6v1hdeficiencyblocks pages 1-2)
Biochemical studies: Assembly/disassembly regulation, mTORC1 control, and ATG16L1 interactions were characterized through biochemical and cell biological approaches (eaton2021theh+atpase(vatpase) pages 5-9, lee2025dmxl1promotesrecruitment pages 1-2, duque2025atg16l1controlsmammalian pages 1-3)
Expression studies: Human transcriptomic and proteomic analyses linked ATP6V1H expression changes to diabetes and cancer (chen2024vatpaseincancer pages 1-3, molina2011decreasedexpressionof pages 1-3)

Evolutionary and Bioinformatic Context

V-ATPases are evolutionarily conserved from yeast to humans, sharing structural and mechanistic features with F-type ATP synthases (forgac1999structureandproperties pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). Subunit H is present across eukaryotes, though its precise sequence varies. The conservation of subunit H's coupling function across species underscores its fundamental importance in V-ATPase biology (forgac1999structureandproperties pages 1-2, toei2010regulationandisoform pages 1-2).

Expert Perspectives and Future Directions

Current expert opinion positions V-ATPase as both a fundamental housekeeping enzyme and an emerging therapeutic target (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3). The 2021 comprehensive review by Eaton and colleagues emphasized that V-ATPases are "central players in many normal and pathophysiological processes that directly influence human health in many different and sometimes unexpected ways," including cancer, neurodegeneration, diabetes, and sensory perception (eaton2021theh+atpase(vatpase) pages 1-5).

Recent reviews highlight several key future research directions:

Isoform-specific targeting: Development of V-ATPase inhibitors or modulators that selectively target disease-relevant subunit isoforms or subcellular V-ATPase populations (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
Assembly regulation therapeutics: Exploiting reversible V1-V0 assembly as a regulatory mechanism for therapeutic intervention (eaton2021theh+atpase(vatpase) pages 5-9)
Lysosomal signaling: Further elucidating how V-ATPase integrates with mTORC1, AMPK, TFEB, and autophagy pathways to coordinate cellular metabolism and stress responses (chen2024vatpaseincancer pages 1-3, wang2024tfeb–vacuolaratpasesignaling pages 1-7, duque2025atg16l1controlsmammalian pages 1-3)
Precision medicine applications: Using ATP6V1H expression or V-ATPase activity as biomarkers for disease stratification or treatment response in cancer, neurodegeneration, and metabolic disease (chen2024vatpaseincancer pages 1-3, wang2024tfeb–vacuolaratpasesignaling pages 1-7, molina2011decreasedexpressionof pages 1-3)

Summary

ATP6V1H encodes the V-type proton ATPase subunit H, a single-copy regulatory component of the V1 cytosolic domain that couples ATP hydrolysis to proton transport through the V0 membrane sector. Structurally positioned at the V1-V0 interface, subunit H stabilizes the assembled holoenzyme and influences rotational mechanics during the catalytic cycle. The V-ATPase complex acidifies endosomes, lysosomes, Golgi compartments, and secretory vesicles, and in specialized cells functions at the plasma membrane for bone resorption, renal acidification, and tumor invasion. ATP6V1H-containing V-ATPases participate in critical signaling pathways including mTORC1/AMPK nutrient sensing, TFEB-regulated lysosomal biogenesis, autophagy, and reversible assembly regulation. Recent 2023-2025 research has established ATP6V1H as a TFEB-responsive gene essential for lysosomal function in neurodegeneration, a regulator of bone homeostasis linked to osteoporosis mechanisms, and a component controlled by ATG16L1 and DMXL1-mediated assembly machinery. These findings position ATP6V1H within an expanding understanding of V-ATPase as both a fundamental proton pump and a signaling hub with broad implications for human health and disease.

References

(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(forgac1999structureandproperties pages 1-2): Michael Forgac. Structure and properties of the vacuolar (h+)-atpases*. The Journal of Biological Chemistry, 274:12951-12954, May 1999. URL: https://doi.org/10.1074/jbc.274.19.12951, doi:10.1074/jbc.274.19.12951. This article has 417 citations.
(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.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(chen2024vatpaseincancer pages 1-3): Tingting Chen, Xiaotan Lin, Shuo Lu, and Bo Li. V-atpase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling : CCS, Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9, doi:10.1186/s12964-024-01998-9. This article has 25 citations.
(toei2010regulationandisoform pages 1-2): Masashi Toei, Regina Saum, and Michael Forgac. Regulation and isoform function of the v-atpases. Biochemistry, 49 23:4715-23, Jun 2010. URL: https://doi.org/10.1021/bi100397s, doi:10.1021/bi100397s. This article has 503 citations and is from a peer-reviewed journal.
(jefferies2008functionstructureand pages 1-2): Kevin C. Jefferies, Daniel J. Cipriano, and Michael Forgac. Function, structure and regulation of the vacuolar (h+)-atpases. Archives of biochemistry and biophysics, 476 1:33-42, Aug 2008. URL: https://doi.org/10.1016/j.abb.2008.03.025, doi:10.1016/j.abb.2008.03.025. This article has 345 citations and is from a peer-reviewed journal.
(wang2020structuresofa pages 5-7): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 5-9): 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.
(duan2018vatpasesandosteoclasts pages 1-2): Xiaohong Duan, Shaoqing Yang, Lei Zhang, and Tielin Yang. V-atpases and osteoclasts: ambiguous future of v-atpases inhibitors in osteoporosis. Theranostics, 8:5379-5399, Oct 2018. URL: https://doi.org/10.7150/thno.28391, doi:10.7150/thno.28391. This article has 86 citations and is from a domain leading peer-reviewed journal.
(duque2025atg16l1controlsmammalian pages 1-3): Thabata L.A. Duque, Masroor Paddar, Einar Trosdal, Ruheena Javed, Lee Allers, Michal H. Mudd, Prithvi Akepati, Soumya R. Mishra, Michelle Salemi, Brett Phinney, Shawn B. Bratton, Thomas Wileman, and Vojo Deretic. Atg16l1 controls mammalian vacuolar proton atpase. Sep 2025. URL: https://doi.org/10.1083/jcb.202503166, doi:10.1083/jcb.202503166. This article has 2 citations and is from a highest quality peer-reviewed journal.
(wang2024tfeb–vacuolaratpasesignaling pages 1-7): Baiping Wang, Heidi Martini-Stoica, Chuangye Qi, Tzu-Chiao Lu, Shuo Wang, Wen Xiong, Yanyan Qi, Yin Xu, Marco Sardiello, Hongjie Li, and Hui Zheng. Tfeb–vacuolar atpase signaling regulates lysosomal function and microglial activation in tauopathy. Nature neuroscience, 27:48-62, Nov 2024. URL: https://doi.org/10.1038/s41593-023-01494-2, doi:10.1038/s41593-023-01494-2. This article has 81 citations and is from a highest quality peer-reviewed journal.
(zhao2024atp6v1hdeficiencyblocks pages 1-2): Zanyan Zhao, Xiangpu Wang, Yu Ma, and Xiaohong Duan. Atp6v1h deficiency blocks bone loss in simulated microgravity mice through the fos-jun-src-integrin pathway. International Journal of Molecular Sciences, 25:637, Jan 2024. URL: https://doi.org/10.3390/ijms25010637, doi:10.3390/ijms25010637. This article has 4 citations.
(lee2025dmxl1promotesrecruitment pages 1-2): Chan Lee, Matthew J. G. Eldridge, Miguel A. Gonzalez-Lozano, Thomas Bresnahan, Zachary Niday, Donato Del Camino, Tao Fu, Joao A. Paulo, Magdalene M. Moran, Sophie Helaine, and J. Wade Harper. Dmxl1 promotes recruitment of v1-atpase to lysosomes upon trpml1 activation. Nature structural & molecular biology, Jun 2025. URL: https://doi.org/10.1038/s41594-025-01581-x, doi:10.1038/s41594-025-01581-x. This article has 14 citations and is from a highest quality peer-reviewed journal.
(molina2011decreasedexpressionof pages 1-3): Melanie F. Molina, Hui-Qi Qu, Anne R. Rentfro, Saraswathy Nair, Yang Lu, Craig L. Hanis, Joseph B. McCormick, and Susan P. Fisher-Hoch. Decreased expression of atp6v1h in type 2 diabetes: a pilot report on the diabetes risk study in mexican americans. Biochemical and biophysical research communications, 412 4:728-31, Sep 2011. URL: https://doi.org/10.1016/j.bbrc.2011.08.041, doi:10.1016/j.bbrc.2011.08.041. This article has 29 citations and is from a peer-reviewed journal.

📚 Additional Documentation

Notes

(ATP6V1H-notes.md)

ATP6V1H Research Notes

Gene overview

ATP6V1H (UniProt Q9UI12) encodes V-type proton ATPase subunit H (483 amino acids, ~57 kDa), the regulatory subunit H of the V1 peripheral complex of the vacuolar H+-ATPase (V-ATPase). The protein is also known as NBP1 (Nef-binding protein 1) and VMA13 homolog.

There are two isoforms: isoform 1 (canonical, 483 AA) and isoform 2 (Q9UI12-2, differs at residues 176-193 due to VSP_012274).

V-ATPase complex structure

The V-ATPase is a multi-subunit complex split into the cytoplasmic V1 domain (ATP hydrolysis) and the membrane-embedded V0 domain (proton translocation).

PMID:9442887

PMID:33065002

Role of subunit H specifically

Subunit H is a regulatory subunit of V1, present as one copy. It is essential for V-ATPase activity but not assembly in yeast (VMA13). It is important for regulating the coupling of ATP hydrolysis to proton transport.

UniProt states: "Regulatory subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase). The H subunit activates ATPase activity of the V1 subcomplex when dissociated from V0. It has been proposed to inhibit the non-productive hydrolysis of ATP when V1 is in a free state in the cytoplasm."

The H subunit (VMA13/Subunit H) has a unique regulatory role: in the free V1 complex (dissociated from V0), H inhibits futile ATP hydrolysis. When reassociated with V0, it activates the pump. This regulatory switch is important for the regulated disassembly mechanism.

Interaction with AP-2 and endocytic machinery

A key non-V-ATPase function: subunit H (identified as NBP1) binds directly to AP-2 (specifically the medium chain mu2, AP2M1), connecting the V-ATPase to the clathrin-mediated endocytic machinery.

PMID:12032142

The biological significance of the V1H-AP2M1 interaction is established: it is not merely a pathogen-hijacking mechanism. The interaction occurs under normal cellular conditions and is part of the endocytic function of the V-ATPase complex on clathrin-coated vesicles.

HIV Nef interaction

Subunit H (NBP1) was originally identified as the binding partner for HIV-1 Nef.

PMID:9620685

PMID:11179428

The Nef-H interaction hijacks the normal V1H-AP2 endocytic function to force CD4 internalization. This is a consequence of H's role as an adaptor connecting V-ATPase to AP-2.

Subcellular localization

Subunit H is detected:
- At lysosomal membrane (HDA, PMID:17897319) — part of assembled V-ATPase
- In cytosol (IDA, GO_REF:0000052 immunofluorescence) — free V1 complex
- At Golgi, endosome, plasma membrane (NAS, PMID:32001091) — assembled V-ATPase at various membranes
- At clathrin-coated vesicle membrane (IEA, UniProt mapping) — consistent with AP-2 interaction

Endocytosis annotation

GO:0006897 endocytosis (IDA, PMID:12032142) — the evidence is that V1H binds AP2M1 and Nef-V1H chimeras can internalize CD4. This demonstrates that V1H contributes to endocytosis via AP-2 interaction. This is a legitimate specific annotation beyond generic "protein binding."

Regulation of macroautophagy (NAS, PMID:22982048)

As for ATP6V1G1, this annotation is an over-annotation. The cited paper uses V-ATPase disruption to impair lysosomal activity; it does not show that H subunit specifically regulates macroautophagy.

Reactome annotations: Nef pathway

Multiple Reactome entries refer to the HIV Nef / CD4 internalization pathway via V-ATPase subunit H. These are placed at the cytosol because V1H bridges cytosolic Nef to AP-2. The localization to cytosol in these entries reflects the V1H function in this endocytic context, not primary V-ATPase localization.

Vacuolar acidification / proton transport annotations

Multiple NAS annotations to vacuolar acidification, endosomal lumen acidification, Golgi lumen acidification, intracellular pH reduction, and proton transmembrane transport from PMID:32001091 and PMID:9442887. These are general review-based annotations for V-ATPase function and are appropriate as NAS.

Summary

ATP6V1H is both a regulatory subunit of the V1 complex (directly modulating ATPase activity in free V1 versus assembled holoenzyme contexts) and a structural adaptor connecting the V-ATPase complex to the AP-2 endocytic machinery via armadillo repeat-mediated AP2M1 binding. The endocytic adaptor function is a legitimate core function of subunit H, distinct from generic V-ATPase proton pumping, and is exploited by HIV/SIV Nef.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1H/ATP6V1H-deep-research-falcon.md,
21 citations). It corroborates the regulatory-subunit-H core above and adds
assembly-regulation and disease detail; no change to annotation calls.

Core confirmed / sharpened. H is a single-copy V1 subunit at the V1–V0
interface, forming the bottom collar with subunit C and the V0 a-subunit
N-terminal domain, and contacting the EG peripheral stalk. It couples V1 ATP
hydrolysis to V0 proton pumping and stabilizes rotational state 1;
structural/regulatory, not catalytic. Consistent with the known inhibition of
futile ATP hydrolysis by free V1 (H-dependent). No change to calls.
Assembly regulation (proteostasis-relevant). V-ATPase assembly involving H
is modulated by the DMXL1/RAVE complex and by ATG16L1, and by reversible
V1–V0 disassembly — regulatory inputs for the PN regulation branch.
TFEB–ATP6V1H axis (Wang 2024). TFEB-dependent Atp6v1h expression is required
for lysosomal acidification and microglial activation; its disruption worsens tau
pathology — positioning H in the TFEB–V-ATPase–lysosome feedback loop (non-core,
disease context).
Bone/metabolic disease. Atp6v1h deficiency reduces V-ATPase function and
causes bone loss via a Fos-Jun-Src-Integrin/osteoclast pathway (Zhao 2024);
reduced ATP6V1H expression is associated with type-2-diabetes progression
(Molina 2011). Non-core disease context. (H is also NBP1/Nef-binding protein.)

Net: no change to calls — H is the single-copy regulatory V1 subunit at the V1–V0
collar, coupling ATP hydrolysis to proton pumping and gating V-ATPase assembly.

Pn Notes

(ATP6V1H-pn-notes.md)

ATP6V1H PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UI12
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1H/ATP6V1H-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1H/ATP6V1H-ai-review.html
Gene notes: present - genes/human/ATP6V1H/ATP6V1H-notes.md
GOA TSV: present - genes/human/ATP6V1H/ATP6V1H-goa.tsv
UniProt record: present - genes/human/ATP6V1H/ATP6V1H-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1H.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1H.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: ATP6V1H encodes V-type proton ATPase subunit H (483 amino acids, ~57 kDa), the regulatory subunit H of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase). Subunit H is present as a single copy in the V1 complex and has a dual regulatory role: in the assembled V-ATPase holoenzyme it supports proton pump activity, while in the free cytosolic V1 complex (dissociated from V0 during regulated disassembly) it inhibits futile ATP hydrolysis. Beyond its structural role in the V-ATPase, subunit H directly binds to AP2M1 (the medium chain mu2 of adaptor protein complex 2) through armadillo repeat domains spanning residues 133-363, physically connecting the V-ATPase to the clathrin-mediated endocytic machinery. The protein was originally identified as Nef-binding protein 1 (NBP1) and is the human ortholog of yeast Vma13p. HIV-1 and SIV Nef exploit the subunit H-AP2M1 interaction to forcibly internalize CD4 from infected cell surfaces, but this reflects co-option of a normal cellular endocytic function. Two isoforms exist (Q9UI12-1 and Q9UI12-2); isoform 2 differs at residues 176-193. The protein localizes to lysosomal and endosomal membranes (as part of assembled V-ATPase), to the cytosol (as part of free V1 complex), and at clathrin-coated vesicle membranes. ATP6V1H is ubiquitously expressed.
Existing/core annotation action counts: ACCEPT: 22; KEEP_AS_NON_CORE: 29; MARK_AS_OVER_ANNOTATED: 9; MODIFY: 2

PN Consistency Summary

Consistency: Consistent on the core V-ATPase regulatory-subunit role. PN treats H purely as a "V1 proton-pump component"; the review adds a well-supported SECOND function (AP2M1/AP-2 binding → clathrin-mediated endocytosis, GO:0006897 / GO:0035615 clathrin-cargo adaptor; PMID:12032142) that the PN node does not represent. Not a contradiction, but the PN row under-describes H.
PN story / NEW pressure: Projected terms VERIFIED real. GO:0046612 (lysosomal V1) is a lysosome-specific sibling of the review's vacuolar GO:0000221 — already captured at function level. GO:0007042 lysosomal lumen acidification IS already in the review (IBA + 2× NAS, ACCEPT) → "already_in_goa_exact," correctly. GO:0033176 already present (ACCEPT/entailed). No NEW pressure from the PN node; if anything the gene's endocytic-adaptor function is the under-captured story, and that is project-orthogonal (not part of the ALP V-ATPase row).
Evidence alignment: As with G1, PN cites review-article titles (mTORC1/V-ATPase/neurodegeneration) absent from the review's PMID set; review is anchored on PMID:9442887 (Forgac review), PMID:33065002 (cryo-EM), PMID:12032142 (AP2M1). Same V-ATPase biology; the endocytic-adaptor literature is unique to the review.
Verdict: Consistent, already captured (all three projected terms present or covered by siblings). No edits needed for the PN row; note that H's AP-2/endocytosis function lies outside the PN node and is fully handled in the review.

Full Consistency Review

UniProt: Q9UI12 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (very thorough; dual-function review, 60+ annotations)
PN placement: Autophagy-Lysosome Pathway two rows — …|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component and …|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 …component ; PN-node mapping: subtype→GO:0046612 (lysosomal V1 domain, mapped/ok); subtype→GO:0033176 (V-ATPase complex, mapped/ok); type→GO:0007042 (lysosomal lumen acidification, mapped/ok); class→GO:0010506 context_only/too_broad.
Consistency: Consistent on the core V-ATPase regulatory-subunit role. PN treats H purely as a "V1 proton-pump component"; the review adds a well-supported SECOND function (AP2M1/AP-2 binding → clathrin-mediated endocytosis, GO:0006897 / GO:0035615 clathrin-cargo adaptor; PMID:12032142) that the PN node does not represent. Not a contradiction, but the PN row under-describes H.
PN story / NEW pressure: Projected terms VERIFIED real. GO:0046612 (lysosomal V1) is a lysosome-specific sibling of the review's vacuolar GO:0000221 — already captured at function level. GO:0007042 lysosomal lumen acidification IS already in the review (IBA + 2× NAS, ACCEPT) → "already_in_goa_exact," correctly. GO:0033176 already present (ACCEPT/entailed). No NEW pressure from the PN node; if anything the gene's endocytic-adaptor function is the under-captured story, and that is project-orthogonal (not part of the ALP V-ATPase row).
Mapping strategy: No change to node mapping warranted from this gene. Projected CC terms are at/below review specificity; no broader-than-review over-reach.
Evidence alignment: As with G1, PN cites review-article titles (mTORC1/V-ATPase/neurodegeneration) absent from the review's PMID set; review is anchored on PMID:9442887 (Forgac review), PMID:33065002 (cryo-EM), PMID:12032142 (AP2M1). Same V-ATPase biology; the endocytic-adaptor literature is unique to the review.
Verdict: Consistent, already captured (all three projected terms present or covered by siblings). No edits needed for the PN row; note that H's AP-2/endocytosis function lies outside the PN node and is fully handled in the review.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1H/ATP6V1H-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: Q9UI12
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: Q9UI12
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=already_in_goa_exact | 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: Q9UI12
gene_symbol: ATP6V1H
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATP6V1H encodes V-type proton ATPase subunit H (483 amino acids, ~57 kDa),
  the regulatory subunit H of the V1 peripheral domain of the vacuolar-type
  H+-ATPase (V-ATPase). Subunit H is present as a single copy in the V1
  complex and has a dual regulatory role: in the assembled V-ATPase holoenzyme
  it supports proton pump activity, while in the free cytosolic V1 complex
  (dissociated from V0 during regulated disassembly) it inhibits futile ATP
  hydrolysis. Beyond its structural role in the V-ATPase, subunit H directly
  binds to AP2M1 (the medium chain mu2 of adaptor protein complex 2) through
  armadillo repeat domains spanning residues 133-363, physically connecting the
  V-ATPase to the clathrin-mediated endocytic machinery. The protein was
  originally identified as Nef-binding protein 1 (NBP1) and is the human
  ortholog of yeast Vma13p. HIV-1 and SIV Nef exploit the subunit H-AP2M1
  interaction to forcibly internalize CD4 from infected cell surfaces, but this
  reflects co-option of a normal cellular endocytic function. Two isoforms
  exist (Q9UI12-1 and Q9UI12-2); isoform 2 differs at residues 176-193. The
  protein localizes to lysosomal and endosomal membranes (as part of assembled
  V-ATPase), to the cytosol (as part of free V1 complex), and at
  clathrin-coated vesicle membranes. ATP6V1H is ubiquitously expressed.
alternative_products:
- name: '1'
  id: Q9UI12-1
- name: '2'
  id: Q9UI12-2
  sequence_note: VSP_012274
existing_annotations:
- 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: Subunit H is a genuine V1 domain component confirmed by cryo-EM and
      biochemical characterization.
    action: ACCEPT
    reason: V1 domain membership is well established. Subunit H is a regulatory
      component of the V1 complex, one copy per holoenzyme (PMID:33065002, PMID:9442887).

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA phylogenetic transfer; lysosomal acidification is the core biological
      output of the assembled V-ATPase containing subunit H.
    action: ACCEPT
    reason: Lysosomal lumen acidification is the primary downstream consequence
      of V-ATPase proton pumping. As a regulatory subunit essential for V-ATPase
      activity, H is rightly annotated as involved in this process.

- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA transfer for synaptic vesicle lumen acidification; non-core neuronal
      context for this ubiquitously expressed subunit.
    action: KEEP_AS_NON_CORE
    reason: Neuronal synaptic vesicle acidification is a non-core context for this
      ubiquitous regulatory subunit.

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: IEA from InterPro; V1 domain membership is experimentally established.
    action: ACCEPT
    reason: V1 domain membership is supported by structural and functional data.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: IEA ARBA for membrane localization; overly general term but consistent
      with lysosomal/endosomal/plasma membrane localization.
    action: MODIFY
    reason: Generic membrane is too imprecise. The more specific terms lysosomal
      membrane (HDA), endosome membrane (NAS), and plasma membrane (NAS) already
      exist in the annotation set. The IDA annotation to GO:0016020 from PMID:33065002
      directly contextualizes which membrane is meant.
    proposed_replacement_terms:
    - id: GO:0005765
      label: lysosomal membrane

- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: IEA from UniProt subcellular location mapping; consistent with the
      documented AP-2 (clathrin adaptor) interaction of subunit H.
    action: ACCEPT
    reason: Subunit H directly binds AP2M1 (PMID:12032142), which is a component
      of clathrin-coated vesicle machinery. Localization at clathrin-coated vesicle
      membrane is consistent with this interaction.
    supported_by:
    - reference_id: PMID:12032142
      supporting_text: V1H binds to the C-terminal flexible loop in Nef from HIV-1
        and to the medium chain (mu2) of the adaptor protein complex 2 (AP-2) in vitro
        and in vivo

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: IEA from InterPro; proton-transporting ATPase rotational mechanism is
      the molecular activity of the V-ATPase complex.
    action: ACCEPT
    reason: The V-ATPase uses a rotational mechanism for proton translocation. Subunit
      H contributes to this complex activity as a regulatory component.

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: IEA from InterPro; proton transmembrane transport is the core biological
      process of the V-ATPase.
    action: ACCEPT
    reason: Proton transmembrane transport is the fundamental function of the V-ATPase
      complex. Subunit H is essential for this activity as a regulatory component.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from binary interactome reference map; uninformative
      over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome dataset. The specific informative interaction
      is with AP2M1 (PMID:12032142), not the generic protein binding term.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein binding from neurodegenerative disease interactome;
      uninformative over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome dataset; protein binding does not describe
      specific molecular function of subunit H.

- 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: IEA Ensembl Compara transfer; non-core neuronal context for this ubiquitous
      subunit.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle context is non-core for this ubiquitously expressed
      regulatory subunit.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: IDA from immunofluorescence curation; cytosolic localization reflects
      the free V1 complex state.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is a genuine functional state for subunit H.
      The free V1 complex is present in the cytosol when dissociated from V0, and
      subunit H specifically inhibits futile ATP hydrolysis in this context.

- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review; Golgi membrane localization is mentioned
      for V-ATPase generally. Not specific to subunit H but consistent with the
      review's description of V-ATPase distribution.
    action: KEEP_AS_NON_CORE
    reason: Golgi membrane localization is supported only by NAS from a general
      V-ATPase review. While V-ATPase does localize to Golgi, this is not a core
      context for the H subunit.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review; lysosomal membrane localization is the core
      localization for the assembled V-ATPase holoenzyme.
    action: ACCEPT
    reason: Lysosomal membrane localization is well supported and is the primary
      localization of the assembled V-ATPase. Also supported by HDA mass spectrometry
      (PMID:17897319).

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review; plasma membrane V-ATPase in specialized cell
      types (e.g., kidney intercalated cells).
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is a non-core context for this ubiquitous
      subunit; it occurs in specialized cells. The more relevant localization is
      lysosomal/endosomal.

- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review; vacuolar acidification is the core biological
      process downstream of V-ATPase proton pumping.
    action: ACCEPT
    reason: Vacuolar acidification is the primary biological function of V-ATPase
      activity. Subunit H as a regulatory component of the V-ATPase is appropriately
      annotated to this process.

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review; lysosomal lumen acidification is the core
      functional output of lysosome-localized V-ATPase.
    action: ACCEPT
    reason: Lysosomal lumen acidification is the primary biological process driven
      by the V-ATPase at the lysosomal membrane. Subunit H is a required regulatory
      component of this activity.

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: NAS from cryo-EM structure paper; lysosomal lumen acidification is
      the core function of the V-ATPase complex.
    action: ACCEPT
    reason: The structure paper describes V-ATPase function in intracellular acidification.
      Lysosomal lumen acidification is a core function.

- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review; endosome membrane localization of assembled
      V-ATPase is well established.
    action: ACCEPT
    reason: Endosomal membrane localization of V-ATPase is well established and
      important for receptor-mediated endocytosis and iron release from transferrin.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: located_in
  review:
    summary: IDA from cryo-EM structure study; this directly shows subunit H as
      part of the membrane-associated V-ATPase holoenzyme.
    action: MODIFY
    reason: The cryo-EM structure places subunit H in the V-ATPase complex at membranes.
      The generic membrane term is less informative than lysosomal membrane. Suggest
      retaining but noting more specific terms are preferred.
    proposed_replacement_terms:
    - id: GO:0005765
      label: lysosomal membrane

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: NAS from cryo-EM structure paper; V-ATPase complex membership is well
      established.
    action: ACCEPT
    reason: Subunit H is a confirmed component of the V-ATPase holoenzyme complex.

- term:
    id: GO:0048388
    label: endosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review; endosomal lumen acidification is a core
      biological process downstream of V-ATPase activity at endosomes.
    action: ACCEPT
    reason: Endosomal acidification is required for receptor-mediated endocytosis
      completion and nutrient release. V-ATPase is the primary driver; subunit H
      is a required component.

- term:
    id: GO:0051452
    label: intracellular pH reduction
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review; intracellular pH reduction is a broader
      term encompassing all V-ATPase-dependent compartment acidification.
    action: KEEP_AS_NON_CORE
    reason: Intracellular pH reduction is a general consequence of V-ATPase activity.
      More specific annotations to lysosomal and endosomal lumen acidification are
      already present and are preferable. This broader term is non-core.

- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review; Golgi lumen acidification is a downstream
      consequence of V-ATPase activity at Golgi membranes.
    action: KEEP_AS_NON_CORE
    reason: Golgi acidification is a non-core downstream function. Lysosomal and
      endosomal acidification are the primary core contexts.

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: NAS from cryo-EM structure paper; proton transmembrane transport is
      the core molecular function of the V-ATPase complex.
    action: ACCEPT
    reason: Proton transmembrane transport is the fundamental process of the V-ATPase.
      Subunit H is essential for this activity.

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: ISS manual ortholog transfer; V1 domain membership is experimentally
      established.
    action: ACCEPT
    reason: ISS consistent with direct experimental evidence for V1 domain membership.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25659576
  qualifier: enables
  review:
    summary: IPI from TM9SF4/V-ATPase interaction study in colon cancer; TM9SF4
      co-immunoprecipitates with ATP6V1H. This is a specific interaction study but
      the GO:0005515 annotation is still uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: While TM9SF4 interaction with ATP6V1H is documented (PMID:25659576),
      the protein binding annotation is uninformative. The interaction is in a cancer
      cell context and the normal physiological relevance is unclear.

- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: NAS annotation; the cited paper uses V-ATPase disruption as a tool
      to impair lysosomal activity. Does not specifically implicate subunit H in
      macroautophagy regulation.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited study does not demonstrate that ATP6V1H specifically regulates
      macroautophagy; it uses generic V-ATPase disruption to block lysosomal function.
      This is an over-annotation of a generic downstream consequence of V-ATPase
      disruption.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: HDA from parotid gland exosome proteomics; likely a contaminant in
      exosome fractions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Extracellular exosome identification in proteomics is likely contamination.
      Not a primary localization for a V1 peripheral complex subunit.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: HDA from urinary exosome proteomics; likely a contaminant in exosome
      fractions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Extracellular exosome identification in proteomics is likely contamination.
      Not a primary localization for a V1 subunit.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: HDA from lysosomal membrane proteomics; directly supports lysosomal
      membrane localization as part of the assembled V-ATPase.
    action: ACCEPT
    reason: Mass spectrometry in lysosome-enriched fractions directly identifies
      subunit H at the lysosomal membrane.
    supported_by:
    - reference_id: PMID:17897319
      supporting_text: Integral and associated lysosomal membrane proteins

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Reactome TAS annotation; cytosolic localization reflects free V1 complex
      or V1H in its adaptor role during endocytic events.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is well-established for the free V1 complex.
      Subunit H has a specific regulatory role in the cytosolic free V1 state
      (inhibiting futile ATP hydrolysis). Multiple independent sources confirm this.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167597
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in Nef/CD4 endocytosis context;
      V1H bridges cytosolic Nef to the AP-2 endocytic complex.
    action: KEEP_AS_NON_CORE
    reason: In the Nef endocytosis pathway, V1H functions as a cytosolic adaptor.
      This is consistent with the documented AP2M1 binding.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167601
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in CD4 degradation pathway; consistent.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; consistent with subunit H adaptor function.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-182171
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in CD8 degradation pathway; consistent.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; consistent with subunit H adaptor function.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-182198
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in CD8 internalization; consistent.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; free V1 complex context.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization of free V1 complex; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; free V1 complex context.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; free V1 complex context.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9636397
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; Mycobacterium PtpA binds ATP6V1H
      context.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent with free V1 complex.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in mTORC1 signaling context.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858916
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization; consistent.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167537
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for plasma membrane in Nef/CD4 complex context;
      V1H at plasma membrane bridges Nef to AP-2 for CD4 internalization.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization in the Nef/CD4 endocytosis context reflects
      the adaptor function but is non-core relative to lysosomal/endosomal localization.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-167597
  qualifier: located_in
  review:
    summary: Reactome TAS for plasma membrane in CD4 internalization context; non-core.
    action: KEEP_AS_NON_CORE
    reason: Non-core context; same reasoning as above.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-182186
  qualifier: located_in
  review:
    summary: Reactome TAS for plasma membrane in CD8/Nef complex context; non-core.
    action: KEEP_AS_NON_CORE
    reason: Non-core context; plasma membrane in Nef pathway.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-182198
  qualifier: located_in
  review:
    summary: Reactome TAS for plasma membrane in CD8 internalization context; non-core.
    action: KEEP_AS_NON_CORE
    reason: Non-core context.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11179428
  qualifier: enables
  review:
    summary: IPI from SIV Nef/V-ATPase study; the specific interaction is SIV Nef
      with subunit H, exploiting the normal AP-2 adaptor function. The protein binding
      annotation is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The SIV Nef-H interaction is documented (PMID:11179428) but the generic
      protein binding term does not capture the biology. The relevant specific function
      is the AP-2 medium chain (AP2M1) binding.

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: NAS
  original_reference_id: PMID:9442887
  qualifier: part_of
  review:
    summary: NAS from Stevens and Forgac review; V1 domain membership is
      well-established.
    action: ACCEPT
    reason: The 1997 Stevens and Forgac review is the foundational reference for
      V-ATPase V1 subunit composition including subunit H.
    supported_by:
    - reference_id: PMID:9442887
      supporting_text: The peripheral V1 domain, a 500-kDa complex responsible for
        ATP hydrolysis, contains at least eight different subunits of molecular weight
        70-13 (subunits A-H)

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12032142
  qualifier: enables
  review:
    summary: IPI from Geyer et al. 2002; this study demonstrated specific interaction
      with AP2M1. The protein binding annotation is uninformative but the underlying
      interaction is important.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific interaction with AP2M1 (mu2 adaptin) is meaningful and
      well-documented, but GO:0005515 protein binding is uninformative. A more specific
      annotation to AP-2 adaptor binding or clathrin adaptor binding would be more
      informative.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9620685
  qualifier: enables
  review:
    summary: IPI from Lu et al. 1998; interaction with HIV-1 Nef documented. Generic
      protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding annotation; the specific interaction is with
      HIV-1 Nef (a pathogen protein) and does not reflect normal cellular function.

- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IDA
  original_reference_id: PMID:12032142
  qualifier: involved_in
  review:
    summary: IDA experimental evidence that V1H contributes to endocytosis via AP-2
      interaction; this is a legitimate specific function of subunit H.
    action: ACCEPT
    reason: Geyer et al. 2002 demonstrated that V1H connects to the endocytic machinery
      through AP2M1 interaction, and V1H-Nef chimeras can drive CD4 internalization.
      This is genuine experimental evidence for H subunit involvement in clathrin-mediated
      endocytosis.
    supported_by:
    - reference_id: PMID:12032142
      supporting_text: V1H can function as an adaptor for interactions between Nef
        and AP-2

- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:9442887
  qualifier: involved_in
  review:
    summary: NAS from foundational V-ATPase review; vacuolar acidification is the
      core biological process.
    action: ACCEPT
    reason: Vacuolar acidification is a core biological process driven by V-ATPase.
      The Stevens and Forgac review is a valid reference for this NAS annotation.
    supported_by:
    - reference_id: PMID:9442887
      supporting_text: The vacuolar (H+)-ATPases (or V-ATPases) function in the acidification
        of intracellular compartments in eukaryotic cells

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: NAS
  original_reference_id: PMID:9442887
  qualifier: contributes_to
  review:
    summary: NAS from foundational V-ATPase review; subunit H contributes to ATP
      hydrolysis activity of the V-ATPase complex.
    action: ACCEPT
    reason: ATP hydrolysis is the biochemical activity of the V1 domain. Subunit
      H is a regulatory component that modulates this activity. The contributes_to
      qualifier is appropriate.
    supported_by:
    - reference_id: PMID:9442887
      supporting_text: The peripheral V1 domain, a 500-kDa complex responsible for
        ATP hydrolysis, contains at least eight different subunits of molecular weight
        70-13 (subunits A-H)

- term:
    id: GO:0030234
    label: enzyme regulator activity
  evidence_type: NAS
  original_reference_id: PMID:9442887
  qualifier: enables
  review:
    summary: NAS for enzyme regulator activity; subunit H is the regulatory H subunit
      that modulates V-ATPase ATP hydrolysis in assembled versus free V1 states.
    action: ACCEPT
    reason: Subunit H has a documented regulatory function — it inhibits futile ATP
      hydrolysis in the free V1 complex and activates the pump when assembled with
      V0. This enzyme regulator activity is a genuinely specific function of the H
      subunit distinguishing it from other V1 subunits.

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:9442887
  qualifier: involved_in
  review:
    summary: NAS from foundational V-ATPase review; proton transmembrane transport
      is the core function.
    action: ACCEPT
    reason: Proton transmembrane transport is the core function of the V-ATPase.
      Subunit H as a regulatory component is appropriately annotated to this process.

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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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: PMID:11179428
  title: Negative factor from SIV binds to the catalytic subunit of the V-ATPase to
    internalize CD4 and to increase viral infectivity.
  findings:
  - statement: SIV Nef binds subunit H of V-ATPase to contact endocytic machinery
      without direct AP-2 binding; subunit H plays important role in viral infectivity
      by connecting Nef to endocytic pathway.
- id: PMID:12032142
  title: Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex
    2 and connects Nef to the endocytic machinery.
  findings:
  - statement: >-
      V1H binds AP2M1 (mu2) through armadillo repeats 133-363; V1H functions as
      an adaptor connecting Nef to AP-2 and the endocytic machinery.
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings:
  - statement: Mass spectrometry identification of ATP6V1H in lysosome-enriched
      fractions supports lysosomal membrane localization.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: Identification in urinary exosome fraction; likely contamination.
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings:
  - statement: Identification in parotid gland exosome fraction; likely contamination.
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: V-ATPase disruption used as tool to impair lysosomal activity; does
      not demonstrate specific role of subunit H in macroautophagy regulation.
- id: PMID:25659576
  title: TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations
    associated with drug resistance and invasiveness of colon cancer cells.
  findings:
  - statement: TM9SF4 interacts with ATP6V1H in colon cancer cells; TM9SF4 suppression
      reduces V1/V0 assembly.
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings:
  - statement: >-
      V-ATPases are the primary source of organellar acidification; subunit isoforms
      are differentially localized; enzymatic activity modulated by regulated
      reversible disassembly.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  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:
  - statement: Cryo-EM structures of complete human V-ATPase; V1 complex contains
      regulatory subunits C and H; subunit H is part of the V1 peripheral domain.
- id: PMID:9442887
  title: Structure, function and regulation of the vacuolar (H+)-ATPase.
  findings:
  - statement: >-
      V1 domain contains eight subunits A-H; subunit H is the regulatory component;
      V-ATPase functions in acidification of intracellular compartments.
- id: PMID:9620685
  title: Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization
    of CD4.
  findings:
  - statement: NBP1 (subunit H) identified as Nef-binding protein; NBP1 is human
      homolog of yeast Vma13p; connects Nef to endocytic pathway.
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-167537
  title: Formation of CD4:Nef:AP-2 Complex:v-ATPase Complex
  findings: []
- id: Reactome:R-HSA-167597
  title: Internalization of the CD4:Nef:AP-2 Complex:v-ATPase Complex
  findings: []
- id: Reactome:R-HSA-167601
  title: Degradation of CD4
  findings: []
- id: Reactome:R-HSA-182171
  title: Degradation of CD8
  findings: []
- id: Reactome:R-HSA-182186
  title: Formation of CD8:Nef:AP-2 Complex:v-ATPase Complex
  findings: []
- id: Reactome:R-HSA-182198
  title: Internalization of the CD8:Nef:AP-2 Complex:v-ATPase Complex
  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-9636397
  title: PtpA binds ATP6V1H
  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: []
- id: Reactome:R-HSA-9858916
  title: MITF-M-dependent ATP6V1H gene expression
  findings: []

core_functions:
- description: >-
    ATP6V1H is the regulatory H subunit of the V1 domain of the V-ATPase. It
    modulates ATPase coupling efficiency: in the free cytosolic V1 complex it
    inhibits futile ATP hydrolysis, and in the assembled holoenzyme it supports
    proton-coupled ATP hydrolysis. The H subunit contributes to the rotational
    mechanism of the V-ATPase by stabilizing the stator in V1, and is essential
    for regulated disassembly/reassembly of the complex in response to nutrient
    availability.
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  molecular_function:
    id: GO:0030234
    label: enzyme regulator activity
  directly_involved_in:
  - id: GO:0007042
    label: lysosomal lumen acidification
  - id: GO:0048388
    label: endosomal lumen acidification
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/ATP6V1H/ATP6V1H-uniprot.txt
    supporting_text: "The V1 complex consists of three catalytic AB heterodimers that
      form a heterohexamer, three peripheral stalks each consisting of EG heterodimers,
      one central rotor including subunits D and F, and the regulatory subunits C
      and H"
  - reference_id: PMID:9442887
    supporting_text: The peripheral V1 domain, a 500-kDa complex responsible for
      ATP hydrolysis, contains at least eight different subunits of molecular weight
      70-13 (subunits A-H)

- description: >-
    ATP6V1H (subunit H) directly binds AP2M1 (the mu2 medium chain of AP-2) via
    armadillo repeat domains spanning residues 133-363, physically connecting the
    V-ATPase to the clathrin-mediated endocytic machinery. This is an independent
    function from the proton pump role and is responsible for the involvement of
    the V-ATPase in clathrin-coated vesicle formation and receptor internalization.
    HIV-1 and SIV Nef co-opt this interaction to force CD4/CD8 internalization.
  molecular_function:
    id: GO:0035615
    label: clathrin-cargo adaptor activity
  directly_involved_in:
  - id: GO:0006897
    label: endocytosis
  locations:
  - id: GO:0030665
    label: clathrin-coated vesicle membrane
  supported_by:
  - reference_id: PMID:12032142
    supporting_text: V1H binds to the C-terminal flexible loop in Nef from HIV-1
      and to the medium chain (mu2) of the adaptor protein complex 2 (AP-2) in vitro
      and in vivo. The interaction sites of V1H and mu2 were mapped to a central
      region in V1H from positions 133 to 363, which contains 4 armadillo repeats

suggested_questions:
- question: Does the AP2M1-binding function of subunit H reflect a conserved role
    of V-ATPase in clathrin-coated vesicle biogenesis, or is the H subunit unusually
    specialized for this endocytic adaptor role compared to other V1 subunits?
  experts:
  - Geyer M
  - Peterlin BM
- question: How does the regulatory switch of subunit H work mechanistically — what
    structural changes occur in H between the free V1 state (ATP hydrolysis inhibited)
    and the assembled holoenzyme state (ATP hydrolysis activated)?
  experts:
  - Forgac M
  - Rubinstein JL

suggested_experiments:
- hypothesis: The AP2M1-binding function of subunit H is required for normal
    clathrin-mediated endocytosis independent of V-ATPase proton pumping.
  description: >-
    Generate separation-of-function mutations in ATP6V1H that disrupt AP2M1 binding
    (within residues 133-363) without affecting V1 complex assembly or proton pump
    activity. Assess clathrin-mediated endocytosis of physiological cargo (transferrin
    receptor, EGF receptor) in cells expressing mutant versus wild-type H subunit.
  experiment_type: structure-function mutagenesis and receptor internalization assay
- hypothesis: Regulated V1/V0 disassembly differentially affects the H subunit
    regulatory function.
  description: >-
    Quantify the ratio of V1H in membrane-bound (V-ATPase assembled) versus
    cytosolic (free V1) fractions under nutrient replete and starved conditions by
    subcellular fractionation and quantitative proteomics, and measure V1-ATPase
    activity in each fraction to directly test the inhibitory role of H in the
    free state.
  experiment_type: subcellular fractionation and ATPase activity assay

ATP6V1H

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1H (V-type Proton ATPase Subunit H) in Homo sapiens

Gene and Protein Identity

Structural Organization and Molecular Function

V-ATPase Complex Architecture

Position and Role of Subunit H

Coupling Function and Catalytic Mechanism

Substrate Specificity and Reaction

Subcellular Localization and Functional Compartments

Intracellular Organelles

Specialized Plasma Membrane Localization

Biological Processes and Signaling Pathways

Lysosomal Function and Autophagy

mTORC1 and Nutrient Sensing

AMPK and Energy Sensing

TFEB Transcriptional Regulation

ATG16L1 Regulation of V-ATPase

Assembly Regulation by DMXL1/RAVE Complex

Reversible V1-V0 Disassembly

Recent Developments (2023-2025)

Cancer Biology

Neurodegeneration and Tauopathy

Bone Biology and Osteoporosis

Metabolic Disease

Disease-Associated Mutations

Current Understanding and Applications

Experimental Evidence Base

Evolutionary and Bioinformatic Context

Expert Perspectives and Future Directions

Summary

📚 Additional Documentation

Notes

ATP6V1H Research Notes

Gene overview

V-ATPase complex structure

Role of subunit H specifically

Interaction with AP-2 and endocytic machinery

HIV Nef interaction

Subcellular localization

Endocytosis annotation

Regulation of macroautophagy (NAS, PMID:22982048)

Reactome annotations: Nef pathway

Vacuolar acidification / proton transport annotations

Summary

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1H 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