{"gene":"VMA22","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1995,"finding":"Vma22p (yeast ortholog of VMA22/CCDC115) is a 21-kDa hydrophilic protein associated with ER membranes that is required for V-ATPase assembly; in vma22Δ cells, V1 subunits accumulate in the cytosol and the V0 100-kDa subunit (Vph1p) is rapidly degraded in the ER. Vma22p ER association requires Vma12p.","method":"Genetic deletion, subcellular fractionation, pulse-chase degradation assay, membrane association studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, fractionation experiments, replicated in follow-up studies","pmids":["7673216"],"is_preprint":false},{"year":1998,"finding":"Vma12p and Vma22p form a stable membrane-associated complex in the ER, demonstrated by co-fractionation on density gradients and chemical cross-linking. This Vma12p/Vma22p complex directly and transiently interacts with the V0 subunit Vph1p (half-life ~5 min) to facilitate its assembly; when ER-to-Golgi transport is blocked (sec12 mutant), the Vph1p–Vma12p/Vma22p interaction stabilizes. This represents the first dedicated assembly complex in the ER for an integral membrane protein complex.","method":"Subcellular fractionation, chemical cross-linking, density gradient sedimentation, genetic epistasis with sec12 mutant","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (cross-linking, co-fractionation, density gradient) plus genetic epistasis in a single focused study","pmids":["9660861"],"is_preprint":false},{"year":1993,"finding":"vma22 deletion mutants in yeast are defective in vacuolar ATPase enzyme activity, establishing VMA22 as essential for V-ATPase function; identified in a genetic screen based on inability to grow at neutral pH.","method":"Genetic screen, complementation analysis, V-ATPase enzyme activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic screen with enzymatic activity readout, but VMA22 characterization is secondary to VMA4/VMA5 in this paper","pmids":["8416931"],"is_preprint":false},{"year":2016,"finding":"Human CCDC115 (VMA22 ortholog) localizes primarily to the ERGIC and COPI vesicles (not the ER), distinct from yeast Vma22p. Loss-of-function mutations in CCDC115 in patients cause abnormal N- and O-glycosylation, and defective sialic acid metabolic labeling in fibroblasts is restored by complementation with wild-type CCDC115, indicating CCDC115 is required for Golgi homeostasis and glycosylation.","method":"Immunofluorescence localization, exome sequencing of patients, metabolic labeling of sialic acids, complementation assay in fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment, complementation rescue with functional readout, multiple patient families with orthogonal methods","pmids":["26833332"],"is_preprint":false},{"year":2017,"finding":"CCDC115 functions as a V-ATPase assembly factor; genetic disruption of CCDC115 (or TMEM199) stabilizes HIF1α under aerobic conditions not by preventing lysosomal degradation of HIF1α but by causing intracellular iron depletion, which impairs PHD prolyl hydroxylase activity. Iron supplementation directly restores PHD catalytic activity after V-ATPase disruption.","method":"Genome-wide genetic screen in near-haploid human cells, iron supplementation rescue, HIF1α stabilization assay, PHD activity measurement","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide screen plus targeted rescue experiments with iron supplementation and direct enzymatic activity readout","pmids":["28296633"],"is_preprint":false},{"year":2020,"finding":"CCDC115 and TMEM199 are required for viral entry of influenza A virus and regulation of V-type ATPase assembly, validated in a genome-wide CRISPR screen.","method":"Genome-wide CRISPR/Cas9 screen, functional validation of viral entry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with functional validation, but mechanistic detail limited in the abstract","pmids":["31919360"],"is_preprint":false},{"year":2020,"finding":"CCDC115 is required for transferrin-bound iron (TBI) uptake in human erythroid cells; CCDC115-deficient K562 cells show reduced TBI uptake. CCDC115 is also involved in cellular heme distribution, suggesting a role in endocytic vesicle acidification via its V-ATPase assembly function.","method":"Genome-wide CRISPR screen in human erythroid cells, validation in CCDC115-deficient K562 cells, TBI uptake assay","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus functional validation in KO cells with direct uptake assay, single lab","pmids":["32510613"],"is_preprint":false},{"year":2021,"finding":"Silencing CCDC115 (or TMEM199) in HepG2 hepatocytes causes impaired lysosomal acidification, impaired autophagic capacity, increased lipid droplet accumulation with abnormally large lipid droplets colocalizing with lysosomes, and increased apolipoprotein B secretion, indicating CCDC115 is required for lysosomal function and lipophagy.","method":"siRNA knockdown in HepG2 cells, lysosomal acidification assay, autophagy flux assay, lipid droplet imaging and colocalization, apoB secretion measurement","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular phenotype readouts in KD model, single lab","pmids":["34626841"],"is_preprint":false},{"year":2023,"finding":"CCDC115 interacts with the HOPS complex and competes with STX17 for this interaction, thereby inhibiting autophagosome–lysosome fusion. Through this mechanism, CCDC115 inhibits autophagic degradation of YAP (yes-associated protein), promoting cell proliferation under nutrient starvation.","method":"Co-immunoprecipitation, autophagy flux assay, YAP degradation assay, cell proliferation assay under starvation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction with HOPS complex and STX17 competition, multiple functional readouts, single lab","pmids":["36650560"],"is_preprint":false},{"year":2025,"finding":"CCDC115 interacts with IFNGR1/2 and its partner TMEM199, facilitating trafficking of IFN-γ receptors to RAB11A-positive recycling endosomes. CCDC115/TMEM199 also recruits TRAPP II to recycling endosomes and activates RAB11A, enhancing IFNGR1/2 recycling and downstream JAK-STAT signaling leading to PD-L1 upregulation.","method":"Co-immunoprecipitation, receptor trafficking assay, RAB11A activation assay, TRAPP II recruitment assay, PD-L1 expression assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and trafficking assays with multiple downstream functional readouts, single lab","pmids":["41319859"],"is_preprint":false},{"year":2020,"finding":"Swine CCDC115 physically interacts with classical swine fever virus structural glycoprotein E2 during virus replication, as shown by proximity ligation assay. Disruption of this interaction via mutations in E2 reduces viral replication in macrophages and attenuates virulence in swine.","method":"Yeast two-hybrid, proximity ligation assay, recombinant virus with E2 mutations, viral replication assay","journal":"Viruses","confidence":"Low","confidence_rationale":"Tier 3 / Weak — PLA interaction data, swine (non-mammalian model for this context), single lab; functional consequence is for viral rather than host protein mechanism","pmids":["32244508"],"is_preprint":false},{"year":2006,"finding":"Synthetic genetic interactions between erv46Δ and vma22Δ (along with vma12Δ and vma21Δ) in yeast were identified, placing VMA22 in a functional relationship with ER-to-Golgi transport machinery.","method":"Synthetic Genetic Array (SGA) screen for genetic interactions","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic interaction screen, indirect evidence for pathway placement, vma22 is one of many hits","pmids":["17077122"],"is_preprint":false}],"current_model":"VMA22/CCDC115 is a V-ATPase assembly factor that, in yeast, forms a stable ER-resident complex with Vma12p to transiently bind and stabilize the V0 subunit Vph1p during assembly; in humans, CCDC115 localizes to the ERGIC/COPI compartment and is required for Golgi homeostasis, protein glycosylation, lysosomal acidification, and endocytic iron/transferrin trafficking, and additionally regulates autophagosome–lysosome fusion by competing with STX17 for HOPS complex binding (thereby protecting YAP from autophagic degradation) and facilitates IFNGR1/2 recycling via RAB11A-positive endosomes in partnership with TMEM199."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1993,"claim":"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","pmids":["8416931"],"confidence":"Medium","gaps":["Did not distinguish a structural subunit role from an assembly/regulatory role","No subcellular localization or partner defined"]},{"year":1995,"claim":"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","pmids":["7673216"],"confidence":"High","gaps":["Did not show direct physical contact with V0 subunits","Mechanism by which Vma12p anchors Vma22p to the ER unresolved"]},{"year":1998,"claim":"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","pmids":["9660861"],"confidence":"High","gaps":["Structural basis of the Vma12p/Vma22p–Vph1p interaction not determined","Stoichiometry and release step not defined"]},{"year":2006,"claim":"Placed VMA22 in a functional network with ER-to-Golgi transport machinery via synthetic genetic interactions.","evidence":"Synthetic Genetic Array screen in yeast","pmids":["17077122"],"confidence":"Low","gaps":["Genetic interaction is indirect and does not establish a physical or causal link","vma22 was one of many hits"]},{"year":2016,"claim":"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","pmids":["26833332"],"confidence":"High","gaps":["Why human localization differs from yeast ER residence unexplained","Direct demonstration of human V-ATPase assembly defect not shown here"]},{"year":2017,"claim":"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","pmids":["28296633"],"confidence":"High","gaps":["Direct link from acidification defect to iron depletion at the transporter level not detailed","Tissue-specific consequences not addressed"]},{"year":2020,"claim":"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","pmids":["32510613"],"confidence":"Medium","gaps":["Single lab; endocytic acidification mechanism inferred rather than directly measured","Heme distribution defect not mechanistically dissected"]},{"year":2020,"claim":"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","pmids":["31919360"],"confidence":"Medium","gaps":["Mechanistic detail of the entry requirement limited","Whether the effect is purely acidification-dependent unresolved"]},{"year":2021,"claim":"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","pmids":["34626841"],"confidence":"Medium","gaps":["Knockdown rather than knockout; off-target not excluded","Single lab"]},{"year":2023,"claim":"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","pmids":["36650560"],"confidence":"Medium","gaps":["Single lab Co-IP without structural mapping of the HOPS interface","How this reconciles with its acidification-promoting role not resolved"]},{"year":2025,"claim":"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","pmids":["41319859"],"confidence":"Medium","gaps":["Single lab; direct vs indirect receptor binding not fully resolved","Generality beyond IFN-γ receptors unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human CCDC115 or its complexes","Mechanism partitioning assembly vs trafficking roles undefined","Whether TMEM199 partnership extends across all functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]}],"complexes":["Vma12p/Vma22p ER assembly complex"],"partners":["VMA12","VPH1","TMEM199","STX17","HOPS COMPLEX","IFNGR1","IFNGR2","RAB11A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96NT0","full_name":"Vacuolar ATPase assembly protein VMA22","aliases":["Coiled-coil domain-containing protein 115"],"length_aa":180,"mass_kda":19.8,"function":"Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis. In aerobic conditions, required for intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. Necessary for endolysosomal acidification and lysosomal degradation (PubMed:28296633). May be involved in Golgi homeostasis (PubMed:26833332)","subcellular_location":"Endosome; Lysosome; Endoplasmic reticulum-Golgi intermediate compartment; Cytoplasmic vesicle, COPI-coated vesicle; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q96NT0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/VMA22","classification":"Common Essential","n_dependent_lines":1033,"n_total_lines":1208,"dependency_fraction":0.8551324503311258},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATP6V0A2","stoichiometry":0.2},{"gene":"ATP6V1F","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VMA22","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"CCDC115","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC115"},"hgnc":{"alias_symbol":["MGC12981","FLJ30131","ccp1"],"prev_symbol":["CCDC115"]},"alphafold":{"accession":"Q96NT0","domains":[{"cath_id":"1.10.287.3240","chopping":"1-55_66-87_129-174","consensus_level":"medium","plddt":93.085,"start":1,"end":174}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NT0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NT0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NT0-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VMA22","jax_strain_url":"https://www.jax.org/strain/search?query=VMA22"},"sequence":{"accession":"Q96NT0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NT0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NT0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NT0"}},"corpus_meta":[{"pmid":"31919360","id":"PMC_31919360","title":"Genome-wide 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accumulate in the cytosol and the V0 100-kDa subunit (Vph1p) is rapidly degraded in the ER. Vma22p ER association requires Vma12p.\",\n      \"method\": \"Genetic deletion, subcellular fractionation, pulse-chase degradation assay, membrane association studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, fractionation experiments, replicated in follow-up studies\",\n      \"pmids\": [\"7673216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Vma12p and Vma22p form a stable membrane-associated complex in the ER, demonstrated by co-fractionation on density gradients and chemical cross-linking. This Vma12p/Vma22p complex directly and transiently interacts with the V0 subunit Vph1p (half-life ~5 min) to facilitate its assembly; when ER-to-Golgi transport is blocked (sec12 mutant), the Vph1p–Vma12p/Vma22p interaction stabilizes. This represents the first dedicated assembly complex in the ER for an integral membrane protein complex.\",\n      \"method\": \"Subcellular fractionation, chemical cross-linking, density gradient sedimentation, genetic epistasis with sec12 mutant\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (cross-linking, co-fractionation, density gradient) plus genetic epistasis in a single focused study\",\n      \"pmids\": [\"9660861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"vma22 deletion mutants in yeast are defective in vacuolar ATPase enzyme activity, establishing VMA22 as essential for V-ATPase function; identified in a genetic screen based on inability to grow at neutral pH.\",\n      \"method\": \"Genetic screen, complementation analysis, V-ATPase enzyme activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic screen with enzymatic activity readout, but VMA22 characterization is secondary to VMA4/VMA5 in this paper\",\n      \"pmids\": [\"8416931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human CCDC115 (VMA22 ortholog) localizes primarily to the ERGIC and COPI vesicles (not the ER), distinct from yeast Vma22p. Loss-of-function mutations in CCDC115 in patients cause abnormal N- and O-glycosylation, and defective sialic acid metabolic labeling in fibroblasts is restored by complementation with wild-type CCDC115, indicating CCDC115 is required for Golgi homeostasis and glycosylation.\",\n      \"method\": \"Immunofluorescence localization, exome sequencing of patients, metabolic labeling of sialic acids, complementation assay in fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment, complementation rescue with functional readout, multiple patient families with orthogonal methods\",\n      \"pmids\": [\"26833332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CCDC115 functions as a V-ATPase assembly factor; genetic disruption of CCDC115 (or TMEM199) stabilizes HIF1α under aerobic conditions not by preventing lysosomal degradation of HIF1α but by causing intracellular iron depletion, which impairs PHD prolyl hydroxylase activity. Iron supplementation directly restores PHD catalytic activity after V-ATPase disruption.\",\n      \"method\": \"Genome-wide genetic screen in near-haploid human cells, iron supplementation rescue, HIF1α stabilization assay, PHD activity measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide screen plus targeted rescue experiments with iron supplementation and direct enzymatic activity readout\",\n      \"pmids\": [\"28296633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCDC115 and TMEM199 are required for viral entry of influenza A virus and regulation of V-type ATPase assembly, validated in a genome-wide CRISPR screen.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, functional validation of viral entry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with functional validation, but mechanistic detail limited in the abstract\",\n      \"pmids\": [\"31919360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCDC115 is required for transferrin-bound iron (TBI) uptake in human erythroid cells; CCDC115-deficient K562 cells show reduced TBI uptake. CCDC115 is also involved in cellular heme distribution, suggesting a role in endocytic vesicle acidification via its V-ATPase assembly function.\",\n      \"method\": \"Genome-wide CRISPR screen in human erythroid cells, validation in CCDC115-deficient K562 cells, TBI uptake assay\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus functional validation in KO cells with direct uptake assay, single lab\",\n      \"pmids\": [\"32510613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing CCDC115 (or TMEM199) in HepG2 hepatocytes causes impaired lysosomal acidification, impaired autophagic capacity, increased lipid droplet accumulation with abnormally large lipid droplets colocalizing with lysosomes, and increased apolipoprotein B secretion, indicating CCDC115 is required for lysosomal function and lipophagy.\",\n      \"method\": \"siRNA knockdown in HepG2 cells, lysosomal acidification assay, autophagy flux assay, lipid droplet imaging and colocalization, apoB secretion measurement\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular phenotype readouts in KD model, single lab\",\n      \"pmids\": [\"34626841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC115 interacts with the HOPS complex and competes with STX17 for this interaction, thereby inhibiting autophagosome–lysosome fusion. Through this mechanism, CCDC115 inhibits autophagic degradation of YAP (yes-associated protein), promoting cell proliferation under nutrient starvation.\",\n      \"method\": \"Co-immunoprecipitation, autophagy flux assay, YAP degradation assay, cell proliferation assay under starvation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction with HOPS complex and STX17 competition, multiple functional readouts, single lab\",\n      \"pmids\": [\"36650560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC115 interacts with IFNGR1/2 and its partner TMEM199, facilitating trafficking of IFN-γ receptors to RAB11A-positive recycling endosomes. CCDC115/TMEM199 also recruits TRAPP II to recycling endosomes and activates RAB11A, enhancing IFNGR1/2 recycling and downstream JAK-STAT signaling leading to PD-L1 upregulation.\",\n      \"method\": \"Co-immunoprecipitation, receptor trafficking assay, RAB11A activation assay, TRAPP II recruitment assay, PD-L1 expression assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and trafficking assays with multiple downstream functional readouts, single lab\",\n      \"pmids\": [\"41319859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Swine CCDC115 physically interacts with classical swine fever virus structural glycoprotein E2 during virus replication, as shown by proximity ligation assay. Disruption of this interaction via mutations in E2 reduces viral replication in macrophages and attenuates virulence in swine.\",\n      \"method\": \"Yeast two-hybrid, proximity ligation assay, recombinant virus with E2 mutations, viral replication assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — PLA interaction data, swine (non-mammalian model for this context), single lab; functional consequence is for viral rather than host protein mechanism\",\n      \"pmids\": [\"32244508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Synthetic genetic interactions between erv46Δ and vma22Δ (along with vma12Δ and vma21Δ) in yeast were identified, placing VMA22 in a functional relationship with ER-to-Golgi transport machinery.\",\n      \"method\": \"Synthetic Genetic Array (SGA) screen for genetic interactions\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic interaction screen, indirect evidence for pathway placement, vma22 is one of many hits\",\n      \"pmids\": [\"17077122\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VMA22/CCDC115 is a V-ATPase assembly factor that, in yeast, forms a stable ER-resident complex with Vma12p to transiently bind and stabilize the V0 subunit Vph1p during assembly; in humans, CCDC115 localizes to the ERGIC/COPI compartment and is required for Golgi homeostasis, protein glycosylation, lysosomal acidification, and endocytic iron/transferrin trafficking, and additionally regulates autophagosome–lysosome fusion by competing with STX17 for HOPS complex binding (thereby protecting YAP from autophagic degradation) and facilitates IFNGR1/2 recycling via RAB11A-positive endosomes in partnership with TMEM199.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2]. 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 [#0, #1]. 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 [#3]. 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 HIF1\\u03b1 [#4, #6]. CCDC115 also governs lysosomal acidification and autophagic flux in hepatocytes, where its loss impairs lipophagy [#7], and it acts at the autophagosome\\u2013lysosome fusion step by competing with STX17 for HOPS complex binding to limit autophagic degradation of YAP [#8]. In partnership with TMEM199, CCDC115 additionally directs IFN-\\u03b3 receptor recycling through RAB11A-positive endosomes, recruiting TRAPP II and activating RAB11A to sustain JAK-STAT signaling and PD-L1 expression [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic screen for neutral-pH growth defects with V-ATPase enzyme activity assay in yeast\",\n      \"pmids\": [\"8416931\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not distinguish a structural subunit role from an assembly/regulatory role\", \"No subcellular localization or partner defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic deletion, subcellular fractionation, and pulse-chase degradation assays in yeast\",\n      \"pmids\": [\"7673216\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not show direct physical contact with V0 subunits\", \"Mechanism by which Vma12p anchors Vma22p to the ER unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved the molecular mechanism of assembly by showing a stable Vma12p/Vma22p ER complex transiently and directly binds Vph1p to chaperone its incorporation.\",\n      \"evidence\": \"Cross-linking, co-fractionation, density-gradient sedimentation, and sec12 epistasis in yeast\",\n      \"pmids\": [\"9660861\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of the Vma12p/Vma22p\\u2013Vph1p interaction not determined\", \"Stoichiometry and release step not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed VMA22 in a functional network with ER-to-Golgi transport machinery via synthetic genetic interactions.\",\n      \"evidence\": \"Synthetic Genetic Array screen in yeast\",\n      \"pmids\": [\"17077122\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Genetic interaction is indirect and does not establish a physical or causal link\", \"vma22 was one of many hits\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunofluorescence, patient exome sequencing, sialic acid metabolic labeling, and complementation rescue in fibroblasts\",\n      \"pmids\": [\"26833332\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Why human localization differs from yeast ER residence unexplained\", \"Direct demonstration of human V-ATPase assembly defect not shown here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected V-ATPase assembly to cellular iron homeostasis, showing CCDC115 loss depletes iron and impairs PHD hydroxylases to stabilize HIF1\\u03b1, rescued by iron supplementation.\",\n      \"evidence\": \"Genome-wide genetic screen in haploid human cells with iron rescue and PHD activity readout\",\n      \"pmids\": [\"28296633\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct link from acidification defect to iron depletion at the transporter level not detailed\", \"Tissue-specific consequences not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the acidification-dependent role to physiological iron uptake, showing CCDC115 is required for transferrin-bound iron uptake and heme distribution in erythroid cells.\",\n      \"evidence\": \"Genome-wide CRISPR screen and TBI uptake assays in CCDC115-deficient K562 cells\",\n      \"pmids\": [\"32510613\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; endocytic acidification mechanism inferred rather than directly measured\", \"Heme distribution defect not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated CCDC115 in viral entry via its V-ATPase assembly function in an unbiased screen.\",\n      \"evidence\": \"Genome-wide CRISPR/Cas9 screen with influenza A entry validation\",\n      \"pmids\": [\"31919360\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic detail of the entry requirement limited\", \"Whether the effect is purely acidification-dependent unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a hepatocyte role in lysosomal acidification and lipophagy, with CCDC115 loss impairing autophagic capacity and causing lipid droplet accumulation.\",\n      \"evidence\": \"siRNA knockdown in HepG2 cells with acidification, autophagy flux, lipid droplet imaging, and apoB secretion assays\",\n      \"pmids\": [\"34626841\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Knockdown rather than knockout; off-target not excluded\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a V-ATPase-independent role at autophagosome\\u2013lysosome fusion, with CCDC115 competing with STX17 for HOPS binding to limit autophagic YAP degradation and promote proliferation.\",\n      \"evidence\": \"Co-immunoprecipitation, autophagy flux, YAP degradation, and proliferation assays under starvation\",\n      \"pmids\": [\"36650560\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab Co-IP without structural mapping of the HOPS interface\", \"How this reconciles with its acidification-promoting role not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a receptor-trafficking function in which CCDC115/TMEM199 routes IFN-\\u03b3 receptors through RAB11A endosomes via TRAPP II recruitment to sustain JAK-STAT signaling and PD-L1.\",\n      \"evidence\": \"Co-immunoprecipitation, receptor trafficking, RAB11A activation, TRAPP II recruitment, and PD-L1 assays\",\n      \"pmids\": [\"41319859\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; direct vs indirect receptor binding not fully resolved\", \"Generality beyond IFN-\\u03b3 receptors unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of human CCDC115 or its complexes\", \"Mechanism partitioning assembly vs trafficking roles undefined\", \"Whether TMEM199 partnership extends across all functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Vma12p/Vma22p ER assembly complex\"\n    ],\n    \"partners\": [\n      \"VMA12\",\n      \"VPH1\",\n      \"TMEM199\",\n      \"STX17\",\n      \"HOPS complex\",\n      \"IFNGR1\",\n      \"IFNGR2\",\n      \"RAB11A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}