VMA22

VMA22 (yeast Vma22p; human ortholog CCDC115) is a dedicated assembly factor for the vacuolar H+-ATPase (V-ATPase), required for productive biogenesis of the enzyme rather than for its catalytic cycle (PMID:7673216, PMID:8416931). In yeast, Vma22p is an ER membrane-associated protein that forms a stable complex with Vma12p; this Vma12p/Vma22p complex transiently binds the V0 subunit Vph1p to chaperone its assembly, and in its absence cytosolic V1 subunits fail to assemble while Vph1p is rapidly degraded in the ER (PMID:7673216, PMID:9660861). The human ortholog CCDC115 localizes to the ERGIC/COPI compartment rather than the ER and supports Golgi homeostasis and protein N-/O-glycosylation, with loss-of-function mutations causing a congenital disorder of glycosylation (PMID:26833332). Through its V-ATPase assembly role, CCDC115 controls organellar acidification, which underlies endocytic transferrin/iron uptake and heme distribution, and consequently cellular iron status: its disruption depletes intracellular iron and impairs iron-dependent PHD prolyl hydroxylases, stabilizing HIF1α (PMID:28296633, PMID:32510613). CCDC115 also governs lysosomal acidification and autophagic flux in hepatocytes, where its loss impairs lipophagy (PMID:34626841), and it acts at the autophagosome–lysosome fusion step by competing with STX17 for HOPS complex binding to limit autophagic degradation of YAP (PMID:36650560). In partnership with TMEM199, CCDC115 additionally directs IFN-γ receptor recycling through RAB11A-positive endosomes, recruiting TRAPP II and activating RAB11A to sustain JAK-STAT signaling and PD-L1 expression (PMID:41319859).

1. 1993 Medium

   Established that VMA22 is genetically required for vacuolar ATPase function, before any molecular role was known, by linking its loss to failure of acidification-dependent growth.

   Evidence Genetic screen for neutral-pH growth defects with V-ATPase enzyme activity assay in yeast

   PMID:8416931

   Open questions at the time

   • Did not distinguish a structural subunit role from an assembly/regulatory role
   • No subcellular localization or partner defined
2. 1995 High

   Defined VMA22 as an assembly factor rather than a V-ATPase subunit by showing that its deletion blocks V1 membrane assembly and triggers ER degradation of the V0 subunit Vph1p.

   Evidence Genetic deletion, subcellular fractionation, and pulse-chase degradation assays in yeast

   PMID:7673216

   Open questions at the time

   • Did not show direct physical contact with V0 subunits
   • Mechanism by which Vma12p anchors Vma22p to the ER unresolved
3. 1998 High

   Resolved the molecular mechanism of assembly by showing a stable Vma12p/Vma22p ER complex transiently and directly binds Vph1p to chaperone its incorporation.

   Evidence Cross-linking, co-fractionation, density-gradient sedimentation, and sec12 epistasis in yeast

   PMID:9660861

   Open questions at the time

   • Structural basis of the Vma12p/Vma22p–Vph1p interaction not determined
   • Stoichiometry and release step not defined
4. 2006 Low

   Placed VMA22 in a functional network with ER-to-Golgi transport machinery via synthetic genetic interactions.

   Evidence Synthetic Genetic Array screen in yeast

   PMID:17077122

   Open questions at the time

   • Genetic interaction is indirect and does not establish a physical or causal link
   • vma22 was one of many hits
5. 2016 High

   Translated the yeast assembly-factor role to humans and tied it to disease, showing CCDC115 localizes to ERGIC/COPI and is required for Golgi glycosylation, with patient mutations causing a glycosylation disorder.

   Evidence Immunofluorescence, patient exome sequencing, sialic acid metabolic labeling, and complementation rescue in fibroblasts

   PMID:26833332

   Open questions at the time

   • Why human localization differs from yeast ER residence unexplained
   • Direct demonstration of human V-ATPase assembly defect not shown here
6. 2017 High

   Connected V-ATPase assembly to cellular iron homeostasis, showing CCDC115 loss depletes iron and impairs PHD hydroxylases to stabilize HIF1α, rescued by iron supplementation.

   Evidence Genome-wide genetic screen in haploid human cells with iron rescue and PHD activity readout

   PMID:28296633

   Open questions at the time

   • Direct link from acidification defect to iron depletion at the transporter level not detailed
   • Tissue-specific consequences not addressed
7. 2020 Medium

   Extended the acidification-dependent role to physiological iron uptake, showing CCDC115 is required for transferrin-bound iron uptake and heme distribution in erythroid cells.

   Evidence Genome-wide CRISPR screen and TBI uptake assays in CCDC115-deficient K562 cells

   PMID:32510613

   Open questions at the time

   • Single lab; endocytic acidification mechanism inferred rather than directly measured
   • Heme distribution defect not mechanistically dissected
8. 2020 Medium

   Implicated CCDC115 in viral entry via its V-ATPase assembly function in an unbiased screen.

   Evidence Genome-wide CRISPR/Cas9 screen with influenza A entry validation

   PMID:31919360

   Open questions at the time

   • Mechanistic detail of the entry requirement limited
   • Whether the effect is purely acidification-dependent unresolved
9. 2021 Medium

   Defined a hepatocyte role in lysosomal acidification and lipophagy, with CCDC115 loss impairing autophagic capacity and causing lipid droplet accumulation.

   Evidence siRNA knockdown in HepG2 cells with acidification, autophagy flux, lipid droplet imaging, and apoB secretion assays

   PMID:34626841

   Open questions at the time

   • Knockdown rather than knockout; off-target not excluded
   • Single lab
10. 2023 Medium

    Identified a V-ATPase-independent role at autophagosome–lysosome fusion, with CCDC115 competing with STX17 for HOPS binding to limit autophagic YAP degradation and promote proliferation.

    Evidence Co-immunoprecipitation, autophagy flux, YAP degradation, and proliferation assays under starvation

    PMID:36650560

    Open questions at the time

    • Single lab Co-IP without structural mapping of the HOPS interface
    • How this reconciles with its acidification-promoting role not resolved
11. 2025 Medium

    Revealed a receptor-trafficking function in which CCDC115/TMEM199 routes IFN-γ receptors through RAB11A endosomes via TRAPP II recruitment to sustain JAK-STAT signaling and PD-L1.

    Evidence Co-immunoprecipitation, receptor trafficking, RAB11A activation, TRAPP II recruitment, and PD-L1 assays

    PMID:41319859

    Open questions at the time

    • Single lab; direct vs indirect receptor binding not fully resolved
    • Generality beyond IFN-γ receptors unknown

• How CCDC115 partitions between its conserved V-ATPase assembly function and its V-ATPase-independent roles in HOPS-dependent fusion and RAB11A-mediated receptor recycling remains unresolved.
• No structural model of human CCDC115 or its complexes
• Mechanism partitioning assembly vs trafficking roles undefined
• Whether TMEM199 partnership extends across all functions unknown