ATP6V1H

ATP6V1H encodes a subunit of the V1 domain of the vacuolar H+-ATPase (V-ATPase), the proton pump that acidifies intracellular and vesicular compartments (PMID:8349704). Studies of the yeast ortholog VMA13 established that this subunit is required for V-ATPase catalytic activity and complex stability but is dispensable for assembly and membrane targeting of the other subunits, so its loss yields an inactive, less stable complex (PMID:8349704). Through its control of compartmental pH, ATP6V1H governs osteoclast-mediated bone remodeling: haploinsufficiency in mice raises intracellular pH in osteoclasts, downregulating TGF-β1 activation and producing a net loss of bone matrix in which the drop in bone formation exceeds the drop in resorption (PMID:27924156), and loss in zebrafish reduces calcified bone cells with elevated MMP9 and MMP13, whose pharmacological inhibition restores bone mass (PMID:28158191). In hepatocytes, miR-122-5p directly targets the ATP6V1H 3′UTR to reduce its expression, disrupting V-ATPase assembly and promoting CD36 translocation to the plasma membrane to increase fatty acid uptake (PMID:42244364). In macrophages, Atp6v1h co-localizes with internalized Aspergillus fumigatus spores and is required specifically to inhibit post-internalization fungal germination rather than to kill spores [PMID:bio_10.1101_2025.07.14.664761].

1. 1993 High

   Established the core molecular identity and requirement of the subunit: whether this V-ATPase subunit was needed for pump activity, assembly, or both was unknown until null-mutant analysis dissected its role.

   Evidence Deletion and complementation of yeast VMA13 with vacuolar membrane fractionation and co-purification with the active complex

   PMID:8349704

   Open questions at the time

   • Does not define the human protein's tissue-specific roles
   • No structural detail on how the subunit confers activity versus stability
2. 2016 Medium

   Connected V-ATPase pH control to bone biology: it was unclear how this subunit's dosage affects skeletal homeostasis, and the work showed osteoclast pH dysregulation suppresses TGF-β1 and uncouples formation from resorption.

   Evidence Atp6v1h+/- knockout mice with intracellular pH measurement and TGF-β1 pathway and histological analysis

   PMID:27924156

   Open questions at the time

   • Mechanism linking pH change to TGF-β1 activation not reconstituted
   • Single lab
3. 2017 Medium

   Placed ATP6V1H upstream of matrix metalloproteinases in bone formation, addressing which effectors mediate its skeletal phenotype.

   Evidence CRISPR/Cas9 zebrafish knockout with MMP9/MMP13 small-molecule inhibitor rescue and expression analysis

   PMID:28158191

   Open questions at the time

   • Whether MMP induction is a direct consequence of pH change is not resolved
   • No biochemical link between subunit and MMP transcription
4. 2018 Low

   Extended the role to stromal cell fate, testing how the subunit shapes osteogenic versus adipogenic differentiation.

   Evidence Atp6v1h+/- mouse BMSC proliferation and differentiation assays with qPCR for TGF-β receptor I and AP-2

   PMID:29782852

   Open questions at the time

   • Pathway evidence is mRNA-level only with no direct binding to TGF-β receptor I or AP-2
   • Single lab
5. 2019 Low

   Probed signaling placement under metabolic stress, asking which pathway transduces ATP6V1H's effect on osteoblast differentiation in a diabetic-like context.

   Evidence Overexpression/knockdown in MC3T3-E1 cells with Alizarin Red staining and western blot for Akt/GSK3β

   PMID:31272281

   Open questions at the time

   • Pathway placement by western blot without mechanistic reconstitution
   • Single cell line, single lab
6. 2022 Low

   Linked the subunit to metabolic disease via β-cell function, testing whether its loss affects glucose handling.

   Evidence Atp6v1h+/- mice on high-fat diet with transcriptome sequencing and ER stress marker analysis

   PMID:34990584

   Open questions at the time

   • ER stress mechanism inferred from transcriptomics, not reconstituted
   • Role of proposed alternative splicing unestablished
7. 2024 Low

   Proposed direct physical engagement of integrins, addressing whether ATP6V1H acts beyond proton pumping in osteoclast resorption signaling.

   Evidence Simulated microgravity mouse model with transcriptomics and co-immunoprecipitation of ATP6V1H with integrin subunits

   PMID:38203808

   Open questions at the time

   • Co-IP without reciprocal validation or in vitro reconstitution
   • Pathway placement by transcriptomics only
8. 2025 Medium

   Defined a host-defense role, distinguishing whether V-ATPase activity controls fungal killing or germination after macrophage internalization.

   Evidence Live imaging and CRISPR/Cas9 atp6v1h knockout in zebrafish macrophages with germination and hyphal growth quantification (preprint)

   PMID:bio_10.1101_2025.07.14.664761

   Open questions at the time

   • Preprint, single lab
   • Molecular link between phagosomal acidification and germination arrest not defined
9. 2026 Medium

   Identified post-transcriptional regulation of ATP6V1H and its consequence for lipid handling, addressing how the subunit is controlled and how its loss alters hepatocyte metabolism.

   Evidence Dual-luciferase 3′UTR reporter assay, miR-122-5p mimic/inhibitor, western blot, and exosome co-culture in hepatocytes

   PMID:42244364

   Open questions at the time

   • Mechanism linking disrupted V-ATPase assembly to CD36 translocation not resolved
   • Single lab

• How a single V-ATPase subunit's pH control is mechanistically transduced into the diverse downstream pathways (TGF-β1, MMPs, integrins, CD36, ER stress) remains unresolved.
• No structural model of the human complex linking subunit to activity
• Direct biochemical chain from acidification to each downstream effector unestablished