{"gene":"ATP5F1B","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2011,"finding":"miR-101 directly binds to the 3'UTR of ATP5B mRNA and negatively regulates ATP5B expression; knockdown of ATP5B significantly inhibited HSV-1 replication, and ectopic overexpression of ATP5B lacking the 3'UTR rescued viral replication suppressed by miR-101, establishing ATP5B as a pro-viral factor regulated by miR-101.","method":"Luciferase reporter assay (3'UTR binding), RNAi knockdown, plaque assay, ectopic overexpression rescue experiment","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, RNAi, rescue) in a single lab","pmids":["21291913"],"is_preprint":false},{"year":2011,"finding":"ATP5B (ectopically localized at the plasma membrane) physically interacts with the calcium channel α2/δ1 subunit in developing myotubes, forming a functional signaling complex at the plasma membrane that accelerates the rate of decline of calcium transients, particularly during repetitive stimulation.","method":"Co-immunoprecipitation, FRET, functional calcium transient measurements in myotubes","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and FRET with functional readout, single lab","pmids":["21490313"],"is_preprint":false},{"year":2012,"finding":"The mRNA-binding export protein REF undergoes deimination (arginine-to-citrulline conversion), and deiminated REF has higher ATP5B mRNA binding strength than non-deiminated REF; impaired deimination of REF in ND4 transgenic mice leads to defective ATP5B mRNA transport to mitochondria and reduced mitochondrial ATP synthase activity.","method":"mRNA binding assays, inhibition of deimination in PC12 cells, transgenic mouse model, mitochondrial ATP synthase activity assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (binding assay, enzymatic activity, mouse model) in a single lab","pmids":["22261716"],"is_preprint":false},{"year":2019,"finding":"ATP5B binds with high affinity to the conserved 3'UTR consensus sequences of rotavirus (RV) RNA; during infection, ATP5B co-localizes with viral RNA and viroplasm; siRNA depletion of ATP5B reduces production of infectious viral progeny without altering intracellular viral RNA levels or translation, indicating ATP5B supports late-stage RV maturation/assembly.","method":"RaPID proteomics-based RNA-protein interaction screen, siRNA knockdown, plaque assay, co-localization imaging, human intestinal enteroids with chemical ATP synthase inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics screen, Co-IP/binding confirmation, RNAi, primary cell model), mechanistic pathway placement established","pmids":["30770472"],"is_preprint":false},{"year":2021,"finding":"ATP5B overexpression in gastric cancer cells elevates intracellular and extracellular ATP levels, activates the FAK/AKT/MMP2 signaling pathway via the plasma membrane P2X7 receptor, and promotes cell migration, invasion, and proliferation; inhibitors of P2X7, FAK, AKT, or MMP2 suppressed these effects.","method":"Overexpression and knockdown experiments, ATP measurement, phospho-protein Western blot, inhibitor treatments, migration/invasion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway components tested with inhibitors and overexpression, single lab","pmids":["33715234"],"is_preprint":false},{"year":2021,"finding":"Inhibition of ATP5B in bone marrow macrophage-derived osteoclasts reduces expression of osteoclast differentiation genes, impairs F-actin formation, decreases adhesion-associated proteins, impairs vacuolar proton secretion and MMP9 secretion, causes mitochondrial dysfunction, and suppresses bone resorption; local ATP5B knockdown in arthritic mice protected joints from destruction.","method":"siRNA/lentiviral knockdown in primary osteoclasts, gene/protein expression, bone resorption assay, F-actin staining, in vivo collagen-induced arthritis model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with multiple functional readouts, single lab","pmids":["33515708"],"is_preprint":false},{"year":2021,"finding":"Ectopic ATP5B at the plasma membrane of MDA-MB-231 breast cancer cells physically co-localizes and co-immunoprecipitates with Caveolin-1 (Cav-1) in caveolar lipid rafts; Cav-1 knockdown reduces migration and invasion, and cholesterol-loading increases ectopic ATP5B levels and promotes invasion, effects blocked by the ATP5B-specific peptide B04.","method":"Co-immunoprecipitation, double immunofluorescence, Cav-1 knockdown, cholesterol loading, peptide inhibition (B04), migration/invasion assays","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with multiple readouts, single lab","pmids":["34009483"],"is_preprint":false},{"year":2022,"finding":"ATP5B is expressed on the cell surface of hepatocellular carcinoma cell lines and binds myristoylated (but not non-myristoylated) HBV preS1 peptide (residues 2-47); ATP5B knockdown in NTCP-expressing HepG2 cells reduces HBV infectivity and cccDNA formation, establishing ATP5B as an essential factor for HBV cell entry.","method":"Cell surface expression analysis, peptide binding assay (myristoylated vs. non-myristoylated preS1), siRNA knockdown, cccDNA quantification, infectivity assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding specificity demonstrated with control peptide, functional knockdown with mechanistic readout, single lab","pmids":["36976868","36076968"],"is_preprint":false},{"year":2023,"finding":"Two ATP5F1B missense variants (p.Thr334Pro and p.Val482Ala) segregate with autosomal dominant early-onset isolated dystonia; functional studies in patient fibroblasts show no decrease in ATP5F1B protein levels but severe reduction in complex V (ATP synthase) activity and impaired mitochondrial membrane potential, consistent with a dominant-negative mechanism.","method":"Genetic segregation analysis, fibroblast functional studies (complex V activity assay, mitochondrial membrane potential measurement)","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell functional assays with two independent families and two orthogonal readouts, single lab","pmids":["36860166"],"is_preprint":false},{"year":2023,"finding":"ATP5B is identified as a direct binding protein of adamantaniline derivative HI-101 (via affinity-based protein profiling); mechanistically, HI-101 promotes the binding of HIF-1α mRNA to ATP5B, thereby inhibiting HIF-1α translation and transcriptional activity, with anti-tumor activity in a xenograft model.","method":"Affinity-based protein profiling (probe HI-102), high-throughput screening, RNA-protein binding assay (HIF-1α mRNA to ATP5B), reporter assays, xenograft mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical probe-based target ID plus RNA-binding functional assay with in vivo validation, single lab","pmids":["37401167"],"is_preprint":false},{"year":2023,"finding":"Under PFOS exposure, ATP5B translocates from the plasma membrane to mitochondria and physically interacts with TFR2 (transferrin receptor 2); this cooperative translocation drives mitochondrial iron overload, which triggers hepatic insulin resistance. Stabilizing ATP5B on the plasma membrane or ATP5B knockdown prevented TFR2 translocation and reversed mitochondrial iron overload and insulin resistance.","method":"Co-immunoprecipitation, subcellular fractionation, knockdown, pharmacological stabilization of plasma membrane ATP synthase, mitochondrial iron measurement, insulin resistance assays in hepatocytes and mouse liver","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockdown, and gain-of-function with multiple functional readouts in vitro and in vivo, single lab","pmids":["36801541"],"is_preprint":false},{"year":2023,"finding":"Flagellar hook protein FlgE from Pseudomonas aeruginosa directly interacts with ATP5B (identified by pull-down assay); blocking ATP5B attenuates FlgE-induced NF-κB/MAPK signaling, lipid uptake, foam cell formation, and inflammatory responses in macrophages.","method":"Pull-down assay, Western blotting, ATP5B blocking experiments, macrophage functional assays","journal":"Atherosclerosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down assay with blocking experiment, single lab","pmids":["38278062"],"is_preprint":false},{"year":2024,"finding":"Mitochondria-localized lysine acetyltransferase MOF acetylates ATP5B at lysine 201 (K201); SIRT3 deacetylates this site; hyperacetylation of ATP5B at K201 impairs mitochondrial respiration and energy metabolism both in vitro and in vivo, contributing to cardiac dysfunction and heart failure.","method":"Quantitative lysine acetylome analysis, MOF overexpression and SIRT3 knockout mouse models, mitochondrial respiration assays, site-specific mutagenesis (K201 acetylation)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific acetylation identified by acetylome proteomics, validated by writer (MOF) and eraser (SIRT3) genetics, multiple in vitro and in vivo functional readouts","pmids":["39392752"],"is_preprint":false},{"year":2024,"finding":"Under PFOS exposure, ATP5B interacts with both TRPML1 (lysosomal calcium output channel) and VDAC1 (mitochondrial calcium intake channel); ATP5B inhibition or plasma membrane stabilization disrupts the TRPML1-VDAC1 interaction and reverses PFOS-induced mitochondrial calcium overload, worsening lysosomal calcium accumulation, demonstrating ATP5B as a regulator of lysosome-to-mitochondria calcium transmission.","method":"Co-immunoprecipitation, ATP5B knockdown, pharmacological plasma membrane stabilization, calcium measurements in hepatocytes and mouse liver","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional knockdown with mechanistic pathway placement, single lab","pmids":["38626609"],"is_preprint":false},{"year":2024,"finding":"Under PFOS exposure, VDAC1 interacts with ATP5B and undergoes increased oligomerization primarily at mitochondria; ATP5B knockdown or plasma membrane stabilization of ATP5B reduces VDAC1 oligomerization and NLRP3 inflammasome activation, indicating ATP5B facilitates VDAC1 transfer from plasma membrane to mitochondria where it undergoes pro-inflammatory oligomerization.","method":"Co-immunoprecipitation, ATP5B knockdown, pharmacological plasma membrane stabilization, VDAC1 oligomerization assay, NLRP3 inflammasome activation assay","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and gain/loss-of-function with mechanistic pathway placement, single lab","pmids":["38944014"],"is_preprint":false},{"year":2024,"finding":"ATP5B (as TGEV Nsp2 binding partner identified by Co-IP/LC-MS/MS) interacts with TGEV Nsp2 as confirmed by Co-IP and indirect immunofluorescence; downregulation of ATP5B expression promotes TGEV replication, indicating ATP5B functions as a negative regulator of TGEV replication.","method":"Immunoprecipitation/LC-MS/MS, Co-IP, indirect immunofluorescence, ATP5B knockdown with viral replication readout","journal":"Virulence","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP confirmed interaction, single knockdown functional experiment, single lab","pmids":["39239724"],"is_preprint":false},{"year":2020,"finding":"The bovine ATP5B promoter contains functional binding sites for transcription factors MyoD and GATA1; site-directed mutation of these sites and chromatin immunoprecipitation (ChIP) demonstrated that MyoD and GATA1 binding drives basal ATP5B transcription; the proximal minimal promoter was mapped to the region -539/220 relative to the transcriptional start site.","method":"5'-RACE, luciferase reporter assay with 5'-deletion constructs, site-directed mutagenesis, chromatin immunoprecipitation (ChIP)","journal":"Animal biotechnology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct mutagenesis and ChIP establish transcription factor binding, single lab, bovine model","pmids":["33124493"],"is_preprint":false},{"year":2025,"finding":"Cend1 protein physically interacts with Atp5f1b (ATP5F1B) in mitochondria; Cend1 forms dimers via conserved GXXXA motifs in its transmembrane domain to enhance ATP synthesis, and disruption of Cend1 dimerization (G130P mutation) destabilizes Cend1 and abolishes its ATP-enhancing effects; Cend1 KO mice show reduced Complex V activity and worsened ischemia/reperfusion injury.","method":"Co-IP (Cend1-Atp5f1b interaction), Cend1 KO mouse model, site-directed mutagenesis (G130P), mitochondrial membrane potential, mPTP opening, Complex I and V activity assays, infarct volume measurement","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, KO mouse with multiple functional readouts, single lab","pmids":["41469760"],"is_preprint":false}],"current_model":"ATP5F1B (ATP5B) encodes the catalytic β subunit of the mitochondrial F1Fo-ATP synthase (Complex V), where it is the core catalytic component for ATP synthesis; its activity is regulated post-translationally by MOF-catalyzed acetylation at K201 and SIRT3-mediated deacetylation, and its mRNA transport to mitochondria depends on deimination of the carrier protein REF. Beyond its canonical mitochondrial role, ATP5B is ectopically expressed at the plasma membrane where it interacts with partners including Caveolin-1, the calcium channel α2/δ1 subunit, TFR2, and VDAC1 to regulate calcium homeostasis, iron trafficking, and inflammasome activation. ATP5B also serves as a host factor for multiple viruses (HSV-1, rotavirus, HBV, TGEV) through direct RNA or protein interactions, and pathogenic dominant-negative missense variants cause severe Complex V deficiency and isolated dystonia."},"narrative":{"mechanistic_narrative":"ATP5F1B (ATP5B) encodes the catalytic β subunit of the mitochondrial F1Fo-ATP synthase (Complex V), and its activity is governed by post-translational and trafficking controls: MOF acetylates ATP5B at lysine 201 while SIRT3 reverses this mark, with K201 hyperacetylation impairing mitochondrial respiration and contributing to cardiac dysfunction [PMID:39392752], and dimerization-competent Cend1 binds ATP5F1B in mitochondria to enhance ATP synthesis and protect against ischemia/reperfusion injury [PMID:41469760]. Delivery of ATP5B mRNA to mitochondria depends on the export protein REF, whose deimination increases its ATP5B mRNA-binding strength [PMID:22261716]. Two dominant ATP5F1B missense variants (p.Thr334Pro, p.Val482Ala) cause autosomal-dominant early-onset isolated dystonia through a dominant-negative mechanism, producing severe Complex V deficiency and impaired membrane potential without loss of protein [PMID:36860166]. Beyond the canonical enzyme, ATP5B is ectopically displayed at the plasma membrane, where it forms signaling complexes with the calcium channel α2/δ1 subunit [PMID:21490313] and with Caveolin-1 in caveolar lipid rafts to drive tumor cell migration and invasion [PMID:34009483], and where its extracellular ATP output activates P2X7–FAK/AKT/MMP2 signaling in gastric cancer [PMID:33715234]. ATP5B also acts as an RNA- and protein-binding host factor for multiple viruses, supporting HSV-1 replication [PMID:21291913], rotavirus maturation through binding the viral 3'UTR [PMID:30770472], and HBV entry by binding the myristoylated preS1 peptide [PMID:36976868, PMID:36076968]. Under PFOS exposure ATP5B orchestrates inter-organelle ion and metal transfer, partnering with TFR2 to drive mitochondrial iron overload and insulin resistance [PMID:36801541], with TRPML1 and VDAC1 to relay lysosome-to-mitochondria calcium [PMID:38626609], and promoting VDAC1 oligomerization and NLRP3 inflammasome activation [PMID:38944014].","teleology":[{"year":2011,"claim":"Established that ATP5B has functions beyond bioenergetics — both as a pro-viral host factor under microRNA control and as a plasma-membrane signaling partner.","evidence":"miR-101 3'UTR luciferase/RNAi/rescue for HSV-1 replication; reciprocal Co-IP and FRET with the α2/δ1 calcium channel subunit in myotubes","pmids":["21291913","21490313"],"confidence":"Medium","gaps":["Mechanism by which ATP5B supports HSV-1 replication not defined","How ATP5B reaches the plasma membrane unresolved"]},{"year":2012,"claim":"Answered how nuclear-encoded ATP5B mRNA reaches mitochondria, identifying deimination of the carrier REF as a regulatory switch controlling ATP synthase activity.","evidence":"mRNA binding assays, deimination inhibition in PC12 cells, ND4 transgenic mouse with ATP synthase activity readout","pmids":["22261716"],"confidence":"Medium","gaps":["Whether this transport mechanism operates in human tissues not shown","Enzyme catalyzing REF deimination in this context not identified"]},{"year":2019,"claim":"Defined a specific molecular step for ATP5B in viral RNA biology — direct binding of a conserved viral 3'UTR to support late-stage assembly rather than replication or translation.","evidence":"RaPID RNA-protein interaction screen, siRNA, plaque assay, co-localization, human intestinal enteroids with ATP synthase inhibition","pmids":["30770472"],"confidence":"High","gaps":["Structural basis of ATP5B-viral RNA recognition not determined","Whether RNA binding involves mitochondrial or ectopic ATP5B unclear"]},{"year":2020,"claim":"Identified the transcriptional control of ATP5B, placing MyoD and GATA1 as drivers of basal promoter activity.","evidence":"5'-RACE, deletion/mutagenesis luciferase reporters and ChIP in a bovine model","pmids":["33124493"],"confidence":"Medium","gaps":["Conservation of these regulatory sites in human ATP5B not tested","Tissue-specific regulation not addressed"]},{"year":2021,"claim":"Showed that ectopic plasma-membrane ATP5B drives malignant and osteoclast phenotypes via extracellular ATP signaling and caveolar localization.","evidence":"Overexpression/knockdown, ATP measurement, P2X7/FAK/AKT/MMP2 inhibitors, Cav-1 Co-IP and cholesterol loading, osteoclast and arthritis models","pmids":["33715234","34009483","33515708"],"confidence":"Medium","gaps":["Mechanism of ATP5B trafficking to the cell surface unresolved","Relationship between ectopic and mitochondrial ATP5B pools unclear"]},{"year":2022,"claim":"Established surface ATP5B as an essential HBV entry factor through specific binding to the myristoylated preS1 region.","evidence":"Cell-surface expression, myristoylated vs non-myristoylated preS1 binding, siRNA, cccDNA and infectivity assays in NTCP-HepG2","pmids":["36976868","36076968"],"confidence":"Medium","gaps":["Whether ATP5B acts independently or in concert with NTCP not resolved","Binding interface not mapped structurally"]},{"year":2023,"claim":"Connected ATP5B to dominant human disease and revealed a chemically tractable RNA-binding function controlling oncogenic translation.","evidence":"Genetic segregation and patient-fibroblast Complex V/membrane-potential assays for dystonia; affinity-based target ID of HI-101 with HIF-1α mRNA binding and xenograft","pmids":["36860166","37401167"],"confidence":"Medium","gaps":["Structural explanation for dominant-negative variant effect not defined","Generality of ATP5B mRNA-binding regulation beyond HIF-1α unknown"]},{"year":2023,"claim":"Implicated ATP5B in toxicant-driven inter-organelle metal and ion handling, partnering with TFR2 to cause mitochondrial iron overload and insulin resistance under PFOS.","evidence":"Co-IP, subcellular fractionation, knockdown, plasma-membrane stabilization, iron/insulin-resistance readouts in hepatocytes and mouse liver","pmids":["36801541"],"confidence":"Medium","gaps":["Whether TFR2 cooperation occurs outside PFOS exposure not tested","Trigger for ATP5B translocation not defined"]},{"year":2024,"claim":"Defined the post-translational regulation of catalytic ATP5B activity via the MOF/SIRT3 acetylation axis at K201 and a Cend1 dimerization-dependent enhancement of ATP synthesis.","evidence":"Acetylome proteomics, MOF overexpression, SIRT3 KO, K201 mutagenesis, respiration assays; Cend1 Co-IP, G130P mutant, Cend1 KO mouse with Complex V and infarct readouts","pmids":["39392752","41469760"],"confidence":"High","gaps":["How K201 acetylation alters catalytic mechanism structurally not shown","Whether Cend1 and acetylation pathways intersect unknown"]},{"year":2024,"claim":"Extended the PFOS model to show ATP5B coordinates lysosome-to-mitochondria calcium relay and VDAC1 oligomerization-driven inflammasome activation.","evidence":"Co-IP with TRPML1 and VDAC1, knockdown, plasma-membrane stabilization, calcium measurements, VDAC1 oligomerization and NLRP3 assays","pmids":["38626609","38944014"],"confidence":"Medium","gaps":["Direct versus bridging nature of ATP5B-TRPML1/VDAC1 interactions unclear","Whether these interactions occur in physiological settings not addressed"]},{"year":2024,"claim":"Added bacterial and additional viral binding partners, framing ATP5B as a broad surface sensor of microbial ligands and a context-dependent regulator of viral replication.","evidence":"Pull-down of FlgE with macrophage signaling readouts; Co-IP/LC-MS/MS of TGEV Nsp2 with knockdown viral replication assay","pmids":["38278062","39239724"],"confidence":"Low","gaps":["Single pull-down/Co-IP without reciprocal validation","Direct versus indirect nature of these interactions not established"]},{"year":null,"claim":"How the same protein partitions between the mitochondrial ATP synthase, ectopic plasma-membrane signaling complexes, and cytosolic RNA-binding roles — and what controls this partitioning — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism for ATP5B trafficking to the cell surface","No unifying structural model linking enzymatic, RNA-binding, and receptor functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[8,12,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,9]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,12,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,6,7]}],"pathway":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[8,12]}],"complexes":["mitochondrial F1Fo-ATP synthase (Complex V)"],"partners":["CACNA2D1","CAV1","TFR2","VDAC1","MCOLN1","CEND1","MOF","SIRT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06576","full_name":"ATP synthase F(1) complex subunit beta, mitochondrial","aliases":["ATP synthase F1 subunit beta"],"length_aa":529,"mass_kda":56.6,"function":"Catalytic subunit beta, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain (Probable) (PubMed:37244256). ATP synthase complex consist of a soluble F(1) head domain - the catalytic core - and a membrane F(1) domain - the membrane proton channel (PubMed:37244256). These two domains are linked by a central stalk rotating inside the F(1) region and a stationary peripheral stalk (PubMed:37244256). During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation (Probable). In vivo, can only synthesize ATP although its ATP hydrolase activity can be activated artificially in vitro (By similarity). With the subunit alpha (ATP5F1A), forms the catalytic core in the F(1) domain (PubMed:37244256)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P06576/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP5F1B","classification":"Common Essential","n_dependent_lines":995,"n_total_lines":1208,"dependency_fraction":0.8236754966887417},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATP5F1B","total_profiled":1310},"omim":[{"mim_id":"621502","title":"DYSTONIA 38, SUSCEPTIBILITY TO; DYT38","url":"https://www.omim.org/entry/621502"},{"mim_id":"620085","title":"HYPERMETABOLISM DUE TO UNCOUPLED MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION 2; HUMOP2","url":"https://www.omim.org/entry/620085"},{"mim_id":"603281","title":"2-PRIME,5-PRIME-@OLIGOADENYLATE SYNTHETASE-LIKE; OASL","url":"https://www.omim.org/entry/603281"},{"mim_id":"603150","title":"ATP SYNTHASE F1, SUBUNIT DELTA; ATP5F1D","url":"https://www.omim.org/entry/603150"},{"mim_id":"300111","title":"PRICKLE PLANAR CELL POLARITY PROTEIN 3; PRICKLE3","url":"https://www.omim.org/entry/300111"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":2427.2},{"tissue":"tongue","ntpm":2993.0}],"url":"https://www.proteinatlas.org/search/ATP5F1B"},"hgnc":{"alias_symbol":[],"prev_symbol":["ATPSB","ATP5B"]},"alphafold":{"accession":"P06576","domains":[{"cath_id":"2.40.10.170","chopping":"59-130","consensus_level":"high","plddt":92.9494,"start":59,"end":130},{"cath_id":"3.40.50.300","chopping":"134-406","consensus_level":"high","plddt":90.4103,"start":134,"end":406},{"cath_id":"1.10.1140.10","chopping":"415-527","consensus_level":"high","plddt":92.9913,"start":415,"end":527}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06576","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06576-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06576-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP5F1B","jax_strain_url":"https://www.jax.org/strain/search?query=ATP5F1B"},"sequence":{"accession":"P06576","fasta_url":"https://rest.uniprot.org/uniprotkb/P06576.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06576/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06576"}},"corpus_meta":[{"pmid":"21291913","id":"PMC_21291913","title":"MiR-101 regulates HSV-1 replication by targeting ATP5B.","date":"2011","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/21291913","citation_count":94,"is_preprint":false},{"pmid":"26526033","id":"PMC_26526033","title":"ATP5A1 and ATP5B are highly expressed in glioblastoma tumor cells and endothelial cells of microvascular proliferation.","date":"2015","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26526033","citation_count":53,"is_preprint":false},{"pmid":"24252137","id":"PMC_24252137","title":"Metabolic markers GAPDH, PKM2, ATP5B and BEC-index in advanced serous ovarian cancer.","date":"2013","source":"BMC clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24252137","citation_count":38,"is_preprint":false},{"pmid":"33715234","id":"PMC_33715234","title":"ATP5B promotes the metastasis and growth of gastric cancer by activating the FAK/AKT/MMP2 pathway.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33715234","citation_count":29,"is_preprint":false},{"pmid":"27525561","id":"PMC_27525561","title":"2,2',4,4'-Tetrabromodiphenyl ether injures cell viability and mitochondrial function of mouse spermatocytes by decreasing mitochondrial proteins Atp5b and Uqcrc1.","date":"2016","source":"Environmental toxicology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27525561","citation_count":28,"is_preprint":false},{"pmid":"30770472","id":"PMC_30770472","title":"Profiling of rotavirus 3'UTR-binding proteins reveals the ATP synthase subunit ATP5B as a host factor that supports late-stage virus replication.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30770472","citation_count":22,"is_preprint":false},{"pmid":"24583174","id":"PMC_24583174","title":"Investigation of the association between ATP2B4 and ATP5B genes with colorectal cancer.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24583174","citation_count":20,"is_preprint":false},{"pmid":"23420545","id":"PMC_23420545","title":"Porcine skeletal muscle differentially expressed gene ATP5B: molecular characterization, expression patterns, and association analysis with meat quality traits.","date":"2013","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/23420545","citation_count":19,"is_preprint":false},{"pmid":"39392752","id":"PMC_39392752","title":"Mitochondrial MOF regulates energy metabolism in heart failure via ATP5B hyperacetylation.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39392752","citation_count":17,"is_preprint":false},{"pmid":"28901394","id":"PMC_28901394","title":"Overexpression of ATP5b promotes cell proliferation in asthma.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28901394","citation_count":17,"is_preprint":false},{"pmid":"36801541","id":"PMC_36801541","title":"Mitochondrial iron overload mediated by cooperative transfer of plasma membrane ATP5B and TFR2 to mitochondria triggers hepatic insulin resistance under PFOS exposure.","date":"2023","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/36801541","citation_count":17,"is_preprint":false},{"pmid":"33515708","id":"PMC_33515708","title":"Targeted inhibition of ATP5B gene prevents bone erosion in collagen-induced arthritis by inhibiting osteoclastogenesis.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33515708","citation_count":15,"is_preprint":false},{"pmid":"21490313","id":"PMC_21490313","title":"The calcium channel α2/δ1 subunit interacts with ATP5b in the plasma membrane of developing muscle cells.","date":"2011","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21490313","citation_count":15,"is_preprint":false},{"pmid":"36860166","id":"PMC_36860166","title":"Variants in ATP5F1B are associated with dominantly inherited dystonia.","date":"2023","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36860166","citation_count":14,"is_preprint":false},{"pmid":"37401167","id":"PMC_37401167","title":"Adamantaniline Derivatives Target ATP5B to Inhibit Translation of Hypoxia Inducible Factor-1α.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37401167","citation_count":10,"is_preprint":false},{"pmid":"25192831","id":"PMC_25192831","title":"Determining ACTB, ATP5B and RPL32 as optimal reference genes for quantitative RT-PCR studies of cryopreserved stallion semen.","date":"2014","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/25192831","citation_count":9,"is_preprint":false},{"pmid":"38626609","id":"PMC_38626609","title":"Autophagy-dependent lysosomal calcium overload and the ATP5B-regulated lysosomes-mitochondria calcium transmission induce liver insulin resistance under perfluorooctane sulfonate exposure.","date":"2024","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/38626609","citation_count":9,"is_preprint":false},{"pmid":"38944014","id":"PMC_38944014","title":"The VDAC1 oligomerization regulated by ATP5B leads to the NLRP3 inflammasome activation in the liver cells under PFOS exposure.","date":"2024","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/38944014","citation_count":9,"is_preprint":false},{"pmid":"34009483","id":"PMC_34009483","title":"The function of Cav-1 in MDA-MB-231 breast cancer cell migration and invasion induced by ectopic ATP5B.","date":"2021","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34009483","citation_count":8,"is_preprint":false},{"pmid":"22261716","id":"PMC_22261716","title":"The role of deimination in ATP5b mRNA transport in a transgenic mouse model of multiple sclerosis.","date":"2012","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/22261716","citation_count":7,"is_preprint":false},{"pmid":"36076968","id":"PMC_36076968","title":"ATP5B Is an Essential Factor for Hepatitis B Virus Entry.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36076968","citation_count":6,"is_preprint":false},{"pmid":"27840937","id":"PMC_27840937","title":"ATP5B and ETFB metabolic markers in children with congenital hydronephrosis.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27840937","citation_count":4,"is_preprint":false},{"pmid":"38278062","id":"PMC_38278062","title":"Flagellar hook protein FlgE promotes macrophage activation and atherosclerosis by targeting ATP5B.","date":"2023","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/38278062","citation_count":3,"is_preprint":false},{"pmid":"33124493","id":"PMC_33124493","title":"Characterization of the promoter region of bovine ATP5B: roles of MyoD and GATA1 in the regulation of basal transcription.","date":"2020","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33124493","citation_count":1,"is_preprint":false},{"pmid":"41469760","id":"PMC_41469760","title":"Targeting Cend1-Atp5f1b interaction rescues mitochondrial dysfunction and ameliorates ischemic brain injury.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41469760","citation_count":0,"is_preprint":false},{"pmid":"39239724","id":"PMC_39239724","title":"ATP synthase subunit ATP5B interacts with TGEV Nsp2 and acts as a negative regulator of TGEV replication.","date":"2024","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/39239724","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14426,"output_tokens":4560,"usd":0.055839,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12834,"output_tokens":3929,"usd":0.081198,"stage2_stop_reason":"end_turn"},"total_usd":0.137037,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-101 directly binds to the 3'UTR of ATP5B mRNA and negatively regulates ATP5B expression; knockdown of ATP5B significantly inhibited HSV-1 replication, and ectopic overexpression of ATP5B lacking the 3'UTR rescued viral replication suppressed by miR-101, establishing ATP5B as a pro-viral factor regulated by miR-101.\",\n      \"method\": \"Luciferase reporter assay (3'UTR binding), RNAi knockdown, plaque assay, ectopic overexpression rescue experiment\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, RNAi, rescue) in a single lab\",\n      \"pmids\": [\"21291913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATP5B (ectopically localized at the plasma membrane) physically interacts with the calcium channel α2/δ1 subunit in developing myotubes, forming a functional signaling complex at the plasma membrane that accelerates the rate of decline of calcium transients, particularly during repetitive stimulation.\",\n      \"method\": \"Co-immunoprecipitation, FRET, functional calcium transient measurements in myotubes\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and FRET with functional readout, single lab\",\n      \"pmids\": [\"21490313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The mRNA-binding export protein REF undergoes deimination (arginine-to-citrulline conversion), and deiminated REF has higher ATP5B mRNA binding strength than non-deiminated REF; impaired deimination of REF in ND4 transgenic mice leads to defective ATP5B mRNA transport to mitochondria and reduced mitochondrial ATP synthase activity.\",\n      \"method\": \"mRNA binding assays, inhibition of deimination in PC12 cells, transgenic mouse model, mitochondrial ATP synthase activity assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (binding assay, enzymatic activity, mouse model) in a single lab\",\n      \"pmids\": [\"22261716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATP5B binds with high affinity to the conserved 3'UTR consensus sequences of rotavirus (RV) RNA; during infection, ATP5B co-localizes with viral RNA and viroplasm; siRNA depletion of ATP5B reduces production of infectious viral progeny without altering intracellular viral RNA levels or translation, indicating ATP5B supports late-stage RV maturation/assembly.\",\n      \"method\": \"RaPID proteomics-based RNA-protein interaction screen, siRNA knockdown, plaque assay, co-localization imaging, human intestinal enteroids with chemical ATP synthase inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics screen, Co-IP/binding confirmation, RNAi, primary cell model), mechanistic pathway placement established\",\n      \"pmids\": [\"30770472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATP5B overexpression in gastric cancer cells elevates intracellular and extracellular ATP levels, activates the FAK/AKT/MMP2 signaling pathway via the plasma membrane P2X7 receptor, and promotes cell migration, invasion, and proliferation; inhibitors of P2X7, FAK, AKT, or MMP2 suppressed these effects.\",\n      \"method\": \"Overexpression and knockdown experiments, ATP measurement, phospho-protein Western blot, inhibitor treatments, migration/invasion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway components tested with inhibitors and overexpression, single lab\",\n      \"pmids\": [\"33715234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Inhibition of ATP5B in bone marrow macrophage-derived osteoclasts reduces expression of osteoclast differentiation genes, impairs F-actin formation, decreases adhesion-associated proteins, impairs vacuolar proton secretion and MMP9 secretion, causes mitochondrial dysfunction, and suppresses bone resorption; local ATP5B knockdown in arthritic mice protected joints from destruction.\",\n      \"method\": \"siRNA/lentiviral knockdown in primary osteoclasts, gene/protein expression, bone resorption assay, F-actin staining, in vivo collagen-induced arthritis model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with multiple functional readouts, single lab\",\n      \"pmids\": [\"33515708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ectopic ATP5B at the plasma membrane of MDA-MB-231 breast cancer cells physically co-localizes and co-immunoprecipitates with Caveolin-1 (Cav-1) in caveolar lipid rafts; Cav-1 knockdown reduces migration and invasion, and cholesterol-loading increases ectopic ATP5B levels and promotes invasion, effects blocked by the ATP5B-specific peptide B04.\",\n      \"method\": \"Co-immunoprecipitation, double immunofluorescence, Cav-1 knockdown, cholesterol loading, peptide inhibition (B04), migration/invasion assays\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"34009483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATP5B is expressed on the cell surface of hepatocellular carcinoma cell lines and binds myristoylated (but not non-myristoylated) HBV preS1 peptide (residues 2-47); ATP5B knockdown in NTCP-expressing HepG2 cells reduces HBV infectivity and cccDNA formation, establishing ATP5B as an essential factor for HBV cell entry.\",\n      \"method\": \"Cell surface expression analysis, peptide binding assay (myristoylated vs. non-myristoylated preS1), siRNA knockdown, cccDNA quantification, infectivity assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding specificity demonstrated with control peptide, functional knockdown with mechanistic readout, single lab\",\n      \"pmids\": [\"36976868\", \"36076968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two ATP5F1B missense variants (p.Thr334Pro and p.Val482Ala) segregate with autosomal dominant early-onset isolated dystonia; functional studies in patient fibroblasts show no decrease in ATP5F1B protein levels but severe reduction in complex V (ATP synthase) activity and impaired mitochondrial membrane potential, consistent with a dominant-negative mechanism.\",\n      \"method\": \"Genetic segregation analysis, fibroblast functional studies (complex V activity assay, mitochondrial membrane potential measurement)\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell functional assays with two independent families and two orthogonal readouts, single lab\",\n      \"pmids\": [\"36860166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATP5B is identified as a direct binding protein of adamantaniline derivative HI-101 (via affinity-based protein profiling); mechanistically, HI-101 promotes the binding of HIF-1α mRNA to ATP5B, thereby inhibiting HIF-1α translation and transcriptional activity, with anti-tumor activity in a xenograft model.\",\n      \"method\": \"Affinity-based protein profiling (probe HI-102), high-throughput screening, RNA-protein binding assay (HIF-1α mRNA to ATP5B), reporter assays, xenograft mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical probe-based target ID plus RNA-binding functional assay with in vivo validation, single lab\",\n      \"pmids\": [\"37401167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Under PFOS exposure, ATP5B translocates from the plasma membrane to mitochondria and physically interacts with TFR2 (transferrin receptor 2); this cooperative translocation drives mitochondrial iron overload, which triggers hepatic insulin resistance. Stabilizing ATP5B on the plasma membrane or ATP5B knockdown prevented TFR2 translocation and reversed mitochondrial iron overload and insulin resistance.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, knockdown, pharmacological stabilization of plasma membrane ATP synthase, mitochondrial iron measurement, insulin resistance assays in hepatocytes and mouse liver\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockdown, and gain-of-function with multiple functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"36801541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Flagellar hook protein FlgE from Pseudomonas aeruginosa directly interacts with ATP5B (identified by pull-down assay); blocking ATP5B attenuates FlgE-induced NF-κB/MAPK signaling, lipid uptake, foam cell formation, and inflammatory responses in macrophages.\",\n      \"method\": \"Pull-down assay, Western blotting, ATP5B blocking experiments, macrophage functional assays\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down assay with blocking experiment, single lab\",\n      \"pmids\": [\"38278062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mitochondria-localized lysine acetyltransferase MOF acetylates ATP5B at lysine 201 (K201); SIRT3 deacetylates this site; hyperacetylation of ATP5B at K201 impairs mitochondrial respiration and energy metabolism both in vitro and in vivo, contributing to cardiac dysfunction and heart failure.\",\n      \"method\": \"Quantitative lysine acetylome analysis, MOF overexpression and SIRT3 knockout mouse models, mitochondrial respiration assays, site-specific mutagenesis (K201 acetylation)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific acetylation identified by acetylome proteomics, validated by writer (MOF) and eraser (SIRT3) genetics, multiple in vitro and in vivo functional readouts\",\n      \"pmids\": [\"39392752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under PFOS exposure, ATP5B interacts with both TRPML1 (lysosomal calcium output channel) and VDAC1 (mitochondrial calcium intake channel); ATP5B inhibition or plasma membrane stabilization disrupts the TRPML1-VDAC1 interaction and reverses PFOS-induced mitochondrial calcium overload, worsening lysosomal calcium accumulation, demonstrating ATP5B as a regulator of lysosome-to-mitochondria calcium transmission.\",\n      \"method\": \"Co-immunoprecipitation, ATP5B knockdown, pharmacological plasma membrane stabilization, calcium measurements in hepatocytes and mouse liver\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional knockdown with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"38626609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under PFOS exposure, VDAC1 interacts with ATP5B and undergoes increased oligomerization primarily at mitochondria; ATP5B knockdown or plasma membrane stabilization of ATP5B reduces VDAC1 oligomerization and NLRP3 inflammasome activation, indicating ATP5B facilitates VDAC1 transfer from plasma membrane to mitochondria where it undergoes pro-inflammatory oligomerization.\",\n      \"method\": \"Co-immunoprecipitation, ATP5B knockdown, pharmacological plasma membrane stabilization, VDAC1 oligomerization assay, NLRP3 inflammasome activation assay\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and gain/loss-of-function with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"38944014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP5B (as TGEV Nsp2 binding partner identified by Co-IP/LC-MS/MS) interacts with TGEV Nsp2 as confirmed by Co-IP and indirect immunofluorescence; downregulation of ATP5B expression promotes TGEV replication, indicating ATP5B functions as a negative regulator of TGEV replication.\",\n      \"method\": \"Immunoprecipitation/LC-MS/MS, Co-IP, indirect immunofluorescence, ATP5B knockdown with viral replication readout\",\n      \"journal\": \"Virulence\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP confirmed interaction, single knockdown functional experiment, single lab\",\n      \"pmids\": [\"39239724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The bovine ATP5B promoter contains functional binding sites for transcription factors MyoD and GATA1; site-directed mutation of these sites and chromatin immunoprecipitation (ChIP) demonstrated that MyoD and GATA1 binding drives basal ATP5B transcription; the proximal minimal promoter was mapped to the region -539/220 relative to the transcriptional start site.\",\n      \"method\": \"5'-RACE, luciferase reporter assay with 5'-deletion constructs, site-directed mutagenesis, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Animal biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct mutagenesis and ChIP establish transcription factor binding, single lab, bovine model\",\n      \"pmids\": [\"33124493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cend1 protein physically interacts with Atp5f1b (ATP5F1B) in mitochondria; Cend1 forms dimers via conserved GXXXA motifs in its transmembrane domain to enhance ATP synthesis, and disruption of Cend1 dimerization (G130P mutation) destabilizes Cend1 and abolishes its ATP-enhancing effects; Cend1 KO mice show reduced Complex V activity and worsened ischemia/reperfusion injury.\",\n      \"method\": \"Co-IP (Cend1-Atp5f1b interaction), Cend1 KO mouse model, site-directed mutagenesis (G130P), mitochondrial membrane potential, mPTP opening, Complex I and V activity assays, infarct volume measurement\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, KO mouse with multiple functional readouts, single lab\",\n      \"pmids\": [\"41469760\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP5F1B (ATP5B) encodes the catalytic β subunit of the mitochondrial F1Fo-ATP synthase (Complex V), where it is the core catalytic component for ATP synthesis; its activity is regulated post-translationally by MOF-catalyzed acetylation at K201 and SIRT3-mediated deacetylation, and its mRNA transport to mitochondria depends on deimination of the carrier protein REF. Beyond its canonical mitochondrial role, ATP5B is ectopically expressed at the plasma membrane where it interacts with partners including Caveolin-1, the calcium channel α2/δ1 subunit, TFR2, and VDAC1 to regulate calcium homeostasis, iron trafficking, and inflammasome activation. ATP5B also serves as a host factor for multiple viruses (HSV-1, rotavirus, HBV, TGEV) through direct RNA or protein interactions, and pathogenic dominant-negative missense variants cause severe Complex V deficiency and isolated dystonia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP5F1B (ATP5B) encodes the catalytic β subunit of the mitochondrial F1Fo-ATP synthase (Complex V), and its activity is governed by post-translational and trafficking controls: MOF acetylates ATP5B at lysine 201 while SIRT3 reverses this mark, with K201 hyperacetylation impairing mitochondrial respiration and contributing to cardiac dysfunction [#12], and dimerization-competent Cend1 binds ATP5F1B in mitochondria to enhance ATP synthesis and protect against ischemia/reperfusion injury [#17]. Delivery of ATP5B mRNA to mitochondria depends on the export protein REF, whose deimination increases its ATP5B mRNA-binding strength [#2]. Two dominant ATP5F1B missense variants (p.Thr334Pro, p.Val482Ala) cause autosomal-dominant early-onset isolated dystonia through a dominant-negative mechanism, producing severe Complex V deficiency and impaired membrane potential without loss of protein [#8]. Beyond the canonical enzyme, ATP5B is ectopically displayed at the plasma membrane, where it forms signaling complexes with the calcium channel α2/δ1 subunit [#1] and with Caveolin-1 in caveolar lipid rafts to drive tumor cell migration and invasion [#6], and where its extracellular ATP output activates P2X7–FAK/AKT/MMP2 signaling in gastric cancer [#4]. ATP5B also acts as an RNA- and protein-binding host factor for multiple viruses, supporting HSV-1 replication [#0], rotavirus maturation through binding the viral 3'UTR [#3], and HBV entry by binding the myristoylated preS1 peptide [#7]. Under PFOS exposure ATP5B orchestrates inter-organelle ion and metal transfer, partnering with TFR2 to drive mitochondrial iron overload and insulin resistance [#10], with TRPML1 and VDAC1 to relay lysosome-to-mitochondria calcium [#13], and promoting VDAC1 oligomerization and NLRP3 inflammasome activation [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that ATP5B has functions beyond bioenergetics — both as a pro-viral host factor under microRNA control and as a plasma-membrane signaling partner.\",\n      \"evidence\": \"miR-101 3'UTR luciferase/RNAi/rescue for HSV-1 replication; reciprocal Co-IP and FRET with the α2/δ1 calcium channel subunit in myotubes\",\n      \"pmids\": [\"21291913\", \"21490313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ATP5B supports HSV-1 replication not defined\", \"How ATP5B reaches the plasma membrane unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Answered how nuclear-encoded ATP5B mRNA reaches mitochondria, identifying deimination of the carrier REF as a regulatory switch controlling ATP synthase activity.\",\n      \"evidence\": \"mRNA binding assays, deimination inhibition in PC12 cells, ND4 transgenic mouse with ATP synthase activity readout\",\n      \"pmids\": [\"22261716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this transport mechanism operates in human tissues not shown\", \"Enzyme catalyzing REF deimination in this context not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a specific molecular step for ATP5B in viral RNA biology — direct binding of a conserved viral 3'UTR to support late-stage assembly rather than replication or translation.\",\n      \"evidence\": \"RaPID RNA-protein interaction screen, siRNA, plaque assay, co-localization, human intestinal enteroids with ATP synthase inhibition\",\n      \"pmids\": [\"30770472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ATP5B-viral RNA recognition not determined\", \"Whether RNA binding involves mitochondrial or ectopic ATP5B unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the transcriptional control of ATP5B, placing MyoD and GATA1 as drivers of basal promoter activity.\",\n      \"evidence\": \"5'-RACE, deletion/mutagenesis luciferase reporters and ChIP in a bovine model\",\n      \"pmids\": [\"33124493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of these regulatory sites in human ATP5B not tested\", \"Tissue-specific regulation not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that ectopic plasma-membrane ATP5B drives malignant and osteoclast phenotypes via extracellular ATP signaling and caveolar localization.\",\n      \"evidence\": \"Overexpression/knockdown, ATP measurement, P2X7/FAK/AKT/MMP2 inhibitors, Cav-1 Co-IP and cholesterol loading, osteoclast and arthritis models\",\n      \"pmids\": [\"33715234\", \"34009483\", \"33515708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ATP5B trafficking to the cell surface unresolved\", \"Relationship between ectopic and mitochondrial ATP5B pools unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established surface ATP5B as an essential HBV entry factor through specific binding to the myristoylated preS1 region.\",\n      \"evidence\": \"Cell-surface expression, myristoylated vs non-myristoylated preS1 binding, siRNA, cccDNA and infectivity assays in NTCP-HepG2\",\n      \"pmids\": [\"36976868\", \"36076968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATP5B acts independently or in concert with NTCP not resolved\", \"Binding interface not mapped structurally\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected ATP5B to dominant human disease and revealed a chemically tractable RNA-binding function controlling oncogenic translation.\",\n      \"evidence\": \"Genetic segregation and patient-fibroblast Complex V/membrane-potential assays for dystonia; affinity-based target ID of HI-101 with HIF-1α mRNA binding and xenograft\",\n      \"pmids\": [\"36860166\", \"37401167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural explanation for dominant-negative variant effect not defined\", \"Generality of ATP5B mRNA-binding regulation beyond HIF-1α unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated ATP5B in toxicant-driven inter-organelle metal and ion handling, partnering with TFR2 to cause mitochondrial iron overload and insulin resistance under PFOS.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, knockdown, plasma-membrane stabilization, iron/insulin-resistance readouts in hepatocytes and mouse liver\",\n      \"pmids\": [\"36801541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TFR2 cooperation occurs outside PFOS exposure not tested\", \"Trigger for ATP5B translocation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the post-translational regulation of catalytic ATP5B activity via the MOF/SIRT3 acetylation axis at K201 and a Cend1 dimerization-dependent enhancement of ATP synthesis.\",\n      \"evidence\": \"Acetylome proteomics, MOF overexpression, SIRT3 KO, K201 mutagenesis, respiration assays; Cend1 Co-IP, G130P mutant, Cend1 KO mouse with Complex V and infarct readouts\",\n      \"pmids\": [\"39392752\", \"41469760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How K201 acetylation alters catalytic mechanism structurally not shown\", \"Whether Cend1 and acetylation pathways intersect unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the PFOS model to show ATP5B coordinates lysosome-to-mitochondria calcium relay and VDAC1 oligomerization-driven inflammasome activation.\",\n      \"evidence\": \"Co-IP with TRPML1 and VDAC1, knockdown, plasma-membrane stabilization, calcium measurements, VDAC1 oligomerization and NLRP3 assays\",\n      \"pmids\": [\"38626609\", \"38944014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus bridging nature of ATP5B-TRPML1/VDAC1 interactions unclear\", \"Whether these interactions occur in physiological settings not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added bacterial and additional viral binding partners, framing ATP5B as a broad surface sensor of microbial ligands and a context-dependent regulator of viral replication.\",\n      \"evidence\": \"Pull-down of FlgE with macrophage signaling readouts; Co-IP/LC-MS/MS of TGEV Nsp2 with knockdown viral replication assay\",\n      \"pmids\": [\"38278062\", \"39239724\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pull-down/Co-IP without reciprocal validation\", \"Direct versus indirect nature of these interactions not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same protein partitions between the mitochondrial ATP synthase, ectopic plasma-membrane signaling complexes, and cytosolic RNA-binding roles — and what controls this partitioning — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism for ATP5B trafficking to the cell surface\", \"No unifying structural model linking enzymatic, RNA-binding, and receptor functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [8, 12, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 12, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"complexes\": [\"mitochondrial F1Fo-ATP synthase (Complex V)\"],\n    \"partners\": [\"CACNA2D1\", \"CAV1\", \"TFR2\", \"VDAC1\", \"MCOLN1\", \"CEND1\", \"MOF\", \"SIRT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"ATP5F1B","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 36976868"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}