{"gene":"ATG9B","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2005,"finding":"ATG9B (APG9L2) localizes primarily to the perinuclear region and also as cytosolic dots that partially colocalize with the autophagosome marker LC3 under starvation conditions, and can functionally complement ATG9A (APG9L1) knockdown to restore starvation-induced autophagosome formation in HeLa cells, establishing it as a functional ortholog of yeast Atg9p.","method":"Transient transfection with fluorescent-tagged constructs, siRNA knockdown of ATG9A, immunofluorescence colocalization with LC3","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization by live imaging tied to functional rescue, single lab, two orthogonal methods (imaging + knockdown rescue)","pmids":["15755735"],"is_preprint":false},{"year":2023,"finding":"Human ATG9B forms a conserved homotrimeric structure (determined by cryo-EM), functions as a lipid scramblase, displays similar subcellular trafficking and steady-state localization to ATG9A, can compensate for ATG9A absence in starvation-induced autophagy, and forms a heteromeric complex with ATG2A.","method":"Single-particle cryo-EM structure determination, lipid scramblase assay, subcellular trafficking/localization analysis, ATG9A knockout complementation assay, co-immunoprecipitation with ATG2A","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus in vitro scramblase assay plus functional complementation plus binding partner identification in a single rigorous study","pmids":["37938170"],"is_preprint":false},{"year":2020,"finding":"siRNA knockdown of Atg9b in cardiomyocyte-derived cells reduces autophagosome formation, and Atg9b protein levels are specifically reduced in aged mouse hearts correlating with decreased autophagic activity, demonstrating Atg9b is required for autophagosome biogenesis in cardiac cells.","method":"siRNA knockdown, autophagosome quantification, gene expression profiling, protein analysis of aged vs. young mouse hearts","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA knockdown with defined autophagosome phenotype, supported by in vivo correlation; single lab","pmids":["32627317"],"is_preprint":false},{"year":2017,"finding":"Atg9b-deficient hepatocytes are vulnerable to ER stress-induced cell death due to accumulation of ubiquitinated proteins, and loss of Atg9b blocks recruitment of p62-associated ubiquitinated proteins to autophagosomes; Atg9b-driven phagophores facilitate docking of both LC3 and p62 to initiate autophagy-associated degradation. Additionally, miR-3091-3p from tumor-derived exosomes suppresses Atg9b expression.","method":"Hepatocarcinogenesis mouse model (CDAA diet), miRNA microarray, PCR profiler array, siRNA knockdown, immunofluorescence for LC3/p62/ubiquitin","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model plus in vitro knockdown with defined molecular phenotype; single lab, multiple complementary methods","pmids":["28740555"],"is_preprint":false},{"year":2021,"finding":"ATG9B promotes colorectal cancer invasion in an autophagy-independent manner: MYH9 directly binds to cytoplasmic residues aa368-411 of ATG9B via its head domain; their interaction stabilizes both proteins by reducing binding to the E3 ubiquitin ligase STUB1, preventing ubiquitin-mediated degradation. ATG9B is transported to the cell edge with MYH9 assistance and accelerates focal adhesion assembly by mediating interaction between endocytosed integrin β1 and Talin-1, promoting integrin β1 activation.","method":"Co-immunoprecipitation, domain mapping, ubiquitination assay, immunofluorescence localization, focal adhesion assembly assay, integrin β1/Talin-1 interaction assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, ubiquitination mechanism, and functional focal adhesion assay; multiple orthogonal methods in a single rigorous study","pmids":["34131310"],"is_preprint":false},{"year":2019,"finding":"HPV16 E7 protein physically interacts with ATG9B (shown by immunoprecipitation), and HPV16 E6 likely transcriptionally regulates ATG9B through the -1750 to -2000 nt region of its promoter (dual-luciferase reporter). Overexpression of ATG9B partially compensates for autophagy blockage caused by 16E6/E7 knockdown.","method":"Immunoprecipitation (16E7–ATG9B interaction), dual-luciferase reporter assay, transcriptome sequencing, gene overexpression rescue experiments","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus reporter assay plus functional rescue; single lab, multiple methods","pmids":["31215164"],"is_preprint":false},{"year":2022,"finding":"miR-7002-5p (from high-glucose macrophage-derived exosomes) directly targets ATG9B, as confirmed by dual-luciferase reporter assay; suppression of ATG9B by miR-7002-5p inhibits autophagy in tubular epithelial cells, inducing dysfunction and inflammation.","method":"Dual-luciferase reporter assay, miRNA sequencing, miR-7002-5p inhibitor experiments in vitro and in vivo","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation plus in vivo confirmation; single lab","pmids":["35971776"],"is_preprint":false},{"year":2022,"finding":"ASCL2 transcriptionally regulates ATG9B expression to maintain stemness properties (self-renewal and tumor-propagation potential) in glioma cells; the ASCL2-ATG9B axis is required for autophagic activity and stemness maintenance.","method":"Transcriptional regulation assay, loss-of-function and gain-of-function experiments for ASCL2 and ATG9B in glioma cells","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined transcriptional regulation with functional stemness readouts; single lab","pmids":["35882624"],"is_preprint":false},{"year":2024,"finding":"ATG9B regulates internalization of various invasive bacteria by controlling actin rearrangement; ATG9B knockdown causes accumulation of actin filaments and phosphorylated LIM kinase and cofilin, indicating ATG9B promotes actin depolymerization. ULK1 kinase activity regulates ATG9B localization and actin remodeling.","method":"ATG knockout screening, siRNA knockdown in HeLa cells, bacterial internalization assay, immunofluorescence for actin/pLIMK/pCofilin, ULK1 kinase inhibition","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO screen plus mechanistic knockdown with defined molecular readouts; single lab, multiple orthogonal methods","pmids":["38706859"],"is_preprint":false},{"year":2023,"finding":"ATG9b upregulation by propranolol in hepatic stellate cells enhances P62 recruitment to ATG5-ATG12-LC3 compartments and increases co-localization of P62 with ubiquitinated proteins; the PI3K/AKT/mTOR pathway mediates ATG9b-induced autophagic cell death, while p38/JNK is involved in apoptosis.","method":"Co-immunoprecipitation, co-localization immunofluorescence, phospho-antibody microarray, lentiviral ATG9b overexpression, in vivo liver fibrosis model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus co-localization plus pathway inhibitor experiments; single lab, multiple methods","pmids":["37970991"],"is_preprint":false},{"year":2026,"finding":"ATG9B localizes prominently to mitochondria (distinct from ATG9A), where its expression induces aberrant mitochondrial morphology, reduces mitochondrial membrane potential, and promotes mtDNA release and apoptotic cell death. The N-terminal sequence of ATG9B functions as a mitochondrial targeting domain, and expression of this peptide alone is sufficient to induce apoptosis.","method":"Fluorescently tagged ATG9B expression, mitochondrial membrane potential assay, mtDNA release assay, apoptosis indicators, N-terminal domain truncation/expression experiments in tumor cell lines","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, domain mapping, multiple apoptotic readouts; single lab","pmids":["41811769"],"is_preprint":false},{"year":2024,"finding":"A homozygous 11-nucleotide deletion/frameshift mutation in ATG9B (truncating the C-terminal cytosolic domain) causes a rare neurodevelopmental disorder in humans. The truncated ATG9B protein is unstable in cells and localizes only to perinuclear vesicles but not peripheral vesicles (unlike wild-type ATG9B), indicating the C-terminal domain is required for peripheral vesicle trafficking.","method":"Patient genetic analysis, knock-in mouse model generation, cell expression of truncated vs WT ATG9B with subcellular localization analysis, protein stability assay","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model plus cell-based domain analysis; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"ATG9A and ATG9B show distinct subcellular localizations in uterine epithelial cells: ATG9A distributes in a punctate pattern while ATG9B forms elongated tubular shapes in the cytoplasm, suggesting isoform-specific roles in autophagy.","method":"Immunofluorescence staining of primary uterine epithelial and stromal cells, Western blotting","journal":"Clinical and experimental reproductive medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method localization experiment, no functional consequence established beyond descriptive difference","pmids":["38757275"],"is_preprint":false},{"year":2025,"finding":"miR-30c-1-3p directly targets ATG9B (and ATG4B) during M. tuberculosis infection in macrophages; overexpression of ATG9B (alone or with ATG4B) reversed miR-30c-1-3p-mediated autophagy inhibition, demonstrating ATG9B is required for autophagy-mediated antimycobacterial defense.","method":"RNA sequencing, bioinformatics miRNA target prediction, overexpression rescue experiments, Western blot, immunofluorescence, transmission electron microscopy for autophagy levels","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression rescue with multiple orthogonal autophagy readouts; single lab","pmids":["40133377"],"is_preprint":false},{"year":2026,"finding":"ATG9B mediates CBX2-induced autophagy and cisplatin resistance in ovarian cancer; CBX2 stabilizes β-catenin via SIAH2-mediated inhibition of ubiquitin-mediated degradation, and ATG9B inhibition rescues the effects of CBX2-mediated autophagy and drug resistance, placing ATG9B downstream of the Wnt/β-catenin pathway in autophagy regulation.","method":"Co-immunoprecipitation (SIAH2-β-catenin binding), overexpression/silencing plasmid transfection, autophagy flux assays, drug resistance (IC50) assays","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pathway manipulation with functional readouts; single lab","pmids":["41495834"],"is_preprint":false}],"current_model":"ATG9B is a tissue-specific, homotrimeric lipid scramblase (structurally validated by cryo-EM) that is functionally orthologous to yeast Atg9p: it localizes to perinuclear and peripheral vesicles (with its C-terminal domain required for peripheral trafficking), can compensate for ATG9A in starvation-induced autophagy, forms a heteromeric complex with ATG2A, and delivers membrane lipids to the growing autophagosome; beyond canonical autophagy, ATG9B has autophagy-independent roles including MYH9-dependent polarization to the cell edge to promote focal adhesion assembly and cancer invasion, a unique mitochondrial localization (via an N-terminal targeting sequence) that can trigger apoptosis, and regulation of actin depolymerization during bacterial internalization via ULK1-dependent localization control."},"narrative":{"mechanistic_narrative":"ATG9B is a tissue-specific functional ortholog of yeast Atg9p that drives autophagosome biogenesis by delivering membrane lipids to the growing phagophore [PMID:15755735, PMID:37938170]. It assembles as a conserved homotrimer that functions as a lipid scramblase, recapitulates the subcellular trafficking and steady-state distribution of ATG9A, can compensate for ATG9A loss in starvation-induced autophagy, and forms a heteromeric complex with the lipid-transfer protein ATG2A [PMID:37938170]. In autophagosome formation it acts upstream of cargo docking, facilitating recruitment of LC3 and p62-associated ubiquitinated proteins to nascent phagophores, such that its loss sensitizes cells to ER stress-induced death through accumulation of ubiquitinated substrates [PMID:28740555]. Beyond canonical autophagy, ATG9B has distinct context-dependent roles: it is stabilized by and trafficked with MYH9 to the cell edge, where it accelerates focal adhesion assembly by promoting integrin β1–Talin-1 interaction and integrin β1 activation to drive cancer invasion in an autophagy-independent manner [PMID:34131310]; it controls actin depolymerization during bacterial internalization under ULK1 kinase control, with its loss causing accumulation of actin filaments and phosphorylated LIM kinase and cofilin [PMID:38706859]; and it localizes to mitochondria via an N-terminal targeting sequence, where its expression collapses mitochondrial membrane potential, promotes mtDNA release, and triggers apoptosis [PMID:41811769]. ATG9B expression is set by multiple transcriptional and post-transcriptional inputs, including suppression by several exosomal miRNAs and activation through ASCL2 and Wnt/β-catenin signaling in cancer stemness and drug resistance [PMID:28740555, PMID:35971776, PMID:35882624, PMID:41495834]. A homozygous frameshift truncating the C-terminal cytosolic domain causes a rare human neurodevelopmental disorder, and the truncated protein is unstable and fails to reach peripheral vesicles, defining the C-terminal domain as required for peripheral trafficking.","teleology":[{"year":2005,"claim":"Established that ATG9B is a functional ortholog of yeast Atg9p, answering whether this paralog participates in the autophagy machinery at all.","evidence":"Fluorescent-tagged localization, ATG9A siRNA knockdown rescue, and LC3 colocalization in HeLa cells","pmids":["15755735"],"confidence":"Medium","gaps":["Molecular activity of the protein not defined","No structural information","Direct binding partners unidentified"]},{"year":2017,"claim":"Placed ATG9B upstream of cargo capture by showing its phagophores dock LC3 and p62-associated ubiquitinated proteins, explaining why its loss causes ER stress-induced death.","evidence":"Hepatocarcinogenesis mouse model with siRNA knockdown and LC3/p62/ubiquitin immunofluorescence","pmids":["28740555"],"confidence":"Medium","gaps":["Mechanism of p62/ubiquitin recruitment not defined at molecular level","Single lab"]},{"year":2021,"claim":"Revealed an autophagy-independent function: ATG9B drives focal adhesion assembly and cancer invasion through MYH9-stabilized trafficking and integrin β1 activation.","evidence":"Reciprocal Co-IP, domain mapping (aa368-411), STUB1 ubiquitination assays, and focal adhesion/integrin β1–Talin-1 assays","pmids":["34131310"],"confidence":"High","gaps":["Whether this function requires the scramblase activity unknown","Generality beyond colorectal cancer untested"]},{"year":2023,"claim":"Defined the biochemical activity and quaternary structure of ATG9B, establishing it as a homotrimeric lipid scramblase that binds ATG2A and compensates for ATG9A.","evidence":"Single-particle cryo-EM, in vitro lipid scramblase assay, ATG9A knockout complementation, and ATG2A co-immunoprecipitation","pmids":["37938170"],"confidence":"High","gaps":["Stoichiometry/architecture of the ATG9B-ATG2A complex not resolved structurally","Tissue context of scramblase function untested in vivo"]},{"year":2024,"claim":"Connected ATG9B to cytoskeletal control during infection, showing it promotes actin depolymerization under ULK1 regulation to govern bacterial internalization.","evidence":"ATG knockout screen, siRNA knockdown, bacterial internalization assays, actin/pLIMK/pCofilin immunofluorescence, ULK1 inhibition in HeLa cells","pmids":["38706859"],"confidence":"Medium","gaps":["Direct effectors linking ATG9B to LIMK/cofilin unknown","Whether ULK1 phosphorylates ATG9B directly untested"]},{"year":2024,"claim":"Linked ATG9B to human disease and mapped a trafficking determinant, showing a C-terminal frameshift causes neurodevelopmental disease and abolishes peripheral vesicle targeting.","evidence":"Patient genetics, knock-in mouse model, and cell-based localization/stability comparison of truncated vs WT protein (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Mechanistic basis of neurodevelopmental phenotype not established","How the C-terminal domain mediates peripheral trafficking unknown"]},{"year":2026,"claim":"Uncovered a pro-apoptotic mitochondrial role distinct from ATG9A, mediated by an N-terminal mitochondrial targeting sequence.","evidence":"Tagged ATG9B expression, mitochondrial membrane potential and mtDNA release assays, apoptosis readouts, and N-terminal domain truncation in tumor cell lines","pmids":["41811769"],"confidence":"Medium","gaps":["Whether endogenous ATG9B localizes to mitochondria physiologically unclear","Mechanism of membrane potential collapse undefined","Single lab"]},{"year":null,"claim":"How ATG9B's single scramblase activity is partitioned across its diverse autophagic, focal-adhesion, actin-remodeling, and mitochondrial-apoptotic functions, and how its trafficking is switched between these fates, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking scramblase activity to autophagy-independent roles","Regulators selecting perinuclear vs peripheral vs mitochondrial localization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]}],"complexes":["ATG9B-ATG2A complex"],"partners":["ATG2A","MYH9","STUB1","ULK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q674R7","full_name":"Autophagy-related protein 9B","aliases":["APG9-like 2","Nitric oxide synthase 3-overlapping antisense gene protein","Protein sONE"],"length_aa":924,"mass_kda":101.0,"function":"Phospholipid scramblase involved in autophagy by mediating autophagosomal membrane expansion. Cycles between the preautophagosomal structure/phagophore assembly site (PAS) and the cytoplasmic vesicle pool and supplies membrane for the growing autophagosome. Lipid scramblase activity plays a key role in preautophagosomal structure/phagophore assembly by distributing the phospholipids that arrive through ATG2 (ATG2A or ATG2B) from the cytoplasmic to the luminal leaflet of the bilayer, thereby driving autophagosomal membrane expansion (By similarity). In addition to autophagy, also plays a role in necrotic cell death (By similarity)","subcellular_location":"Preautophagosomal structure membrane","url":"https://www.uniprot.org/uniprotkb/Q674R7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATG9B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATG9B","total_profiled":1310},"omim":[{"mim_id":"616226","title":"AUTOPHAGY-RELATED 2B; ATG2B","url":"https://www.omim.org/entry/616226"},{"mim_id":"612205","title":"AUTOPHAGY-RELATED 9B; ATG9B","url":"https://www.omim.org/entry/612205"},{"mim_id":"612204","title":"AUTOPHAGY-RELATED 9A; ATG9A","url":"https://www.omim.org/entry/612204"},{"mim_id":"604261","title":"AUTOPHAGY-RELATED 5; ATG5","url":"https://www.omim.org/entry/604261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":9.9},{"tissue":"pituitary gland","ntpm":5.9},{"tissue":"testis","ntpm":6.9}],"url":"https://www.proteinatlas.org/search/ATG9B"},"hgnc":{"alias_symbol":["FLJ14885","APG9L2","SONE"],"prev_symbol":["NOS3AS"]},"alphafold":{"accession":"Q674R7","domains":[{"cath_id":"-","chopping":"186-248_259-352","consensus_level":"medium","plddt":88.88,"start":186,"end":352},{"cath_id":"-","chopping":"354-479_627-670","consensus_level":"medium","plddt":89.383,"start":354,"end":670},{"cath_id":"-","chopping":"676-746_764-775_790-806_822-847","consensus_level":"medium","plddt":80.4072,"start":676,"end":847}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q674R7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q674R7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q674R7-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATG9B","jax_strain_url":"https://www.jax.org/strain/search?query=ATG9B"},"sequence":{"accession":"Q674R7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q674R7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q674R7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q674R7"}},"corpus_meta":[{"pmid":"19197948","id":"PMC_19197948","title":"Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability.","date":"2009","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19197948","citation_count":229,"is_preprint":false},{"pmid":"15755735","id":"PMC_15755735","title":"Endothelial nitric-oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15755735","citation_count":102,"is_preprint":false},{"pmid":"34131310","id":"PMC_34131310","title":"MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/34131310","citation_count":69,"is_preprint":false},{"pmid":"32627317","id":"PMC_32627317","title":"Aging is associated with a decline in Atg9b-mediated autophagosome formation and appearance of enlarged mitochondria in the heart.","date":"2020","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/32627317","citation_count":61,"is_preprint":false},{"pmid":"30968427","id":"PMC_30968427","title":"The long noncoding RNA sONE represses triple-negative breast cancer aggressiveness through inducing the expression of miR-34a, miR-15a, miR-16, and let-7a.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30968427","citation_count":58,"is_preprint":false},{"pmid":"30081213","id":"PMC_30081213","title":"A novel role of sONE/NOS3/NO signaling cascade in mediating hydrogen sulphide bilateral effects on triple negative breast cancer progression.","date":"2018","source":"Nitric oxide : biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30081213","citation_count":57,"is_preprint":false},{"pmid":"28740555","id":"PMC_28740555","title":"Atg9b Deficiency Suppresses Autophagy and Potentiates Endoplasmic Reticulum Stress-Associated Hepatocyte Apoptosis in Hepatocarcinogenesis.","date":"2017","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/28740555","citation_count":56,"is_preprint":false},{"pmid":"27265029","id":"PMC_27265029","title":"Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27265029","citation_count":36,"is_preprint":false},{"pmid":"26261587","id":"PMC_26261587","title":"Anti-hypertensive effect of Lycium barbarum L. with down-regulated expression of renal endothelial lncRNA sONE in a rat model of salt-sensitive hypertension.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26261587","citation_count":36,"is_preprint":false},{"pmid":"31215164","id":"PMC_31215164","title":"Human papillomavirus 16E6/E7 activates autophagy via Atg9B and LAMP1 in cervical cancer cells.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31215164","citation_count":35,"is_preprint":false},{"pmid":"35971776","id":"PMC_35971776","title":"Exosomal miR-7002-5p derived from highglucose-induced macrophages suppresses autophagy in tubular epithelial cells by targeting Atg9b.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35971776","citation_count":30,"is_preprint":false},{"pmid":"30128915","id":"PMC_30128915","title":"Role of long non-coding RNAs expression (ANRIL, NOS3-AS, and APOA1-AS) in development of atherosclerosis in Egyptian systemic lupus erythematosus patients.","date":"2018","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30128915","citation_count":24,"is_preprint":false},{"pmid":"35882624","id":"PMC_35882624","title":"ASCL2 Maintains Stemness Phenotype through ATG9B and Sensitizes Gliomas to Autophagy Inhibitor.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35882624","citation_count":14,"is_preprint":false},{"pmid":"33023330","id":"PMC_33023330","title":"Lnc-ATG9B-4 aggravates progress of hepatocellular carcinoma through cell proliferation and migration by upregulating CDK5.","date":"2020","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/33023330","citation_count":14,"is_preprint":false},{"pmid":"28923830","id":"PMC_28923830","title":"The role of CRP and ATG9B expression in clear cell renal cell carcinoma.","date":"2017","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/28923830","citation_count":12,"is_preprint":false},{"pmid":"37938170","id":"PMC_37938170","title":"ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37938170","citation_count":11,"is_preprint":false},{"pmid":"28868266","id":"PMC_28868266","title":"Evaluation of Placental mir-155-5p and Long Non-coding RNA sONE Expression in Patients with Severe Pre-eclampsia.","date":"2017","source":"International journal of molecular and cellular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28868266","citation_count":9,"is_preprint":false},{"pmid":"38706859","id":"PMC_38706859","title":"ATG9B regulates bacterial internalization via actin rearrangement.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38706859","citation_count":6,"is_preprint":false},{"pmid":"36643035","id":"PMC_36643035","title":"125I Radioactive Particles Drive Protective Autophagy in Hepatocellular Carcinoma by Upregulating ATG9B.","date":"2022","source":"Journal of clinical and translational hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/36643035","citation_count":5,"is_preprint":false},{"pmid":"37970991","id":"PMC_37970991","title":"Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis.","date":"2023","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37970991","citation_count":4,"is_preprint":false},{"pmid":"40133377","id":"PMC_40133377","title":"Has-miR-30c-1-3p inhibits macrophage autophagy and promotes Mycobacterium tuberculosis survival by targeting ATG4B and ATG9B.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40133377","citation_count":4,"is_preprint":false},{"pmid":"27263291","id":"PMC_27263291","title":"[Expressions and Clinical Significance of Autophagy-related Genes ATG2B, ATG4D, ATG9B in Breast Carcinoma].","date":"2016","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/27263291","citation_count":4,"is_preprint":false},{"pmid":"31384404","id":"PMC_31384404","title":"Association of the ATG9B gene polymorphisms with coronary artery disease susceptibility: A case-control study.","date":"2019","source":"Journal of cardiovascular and thoracic research","url":"https://pubmed.ncbi.nlm.nih.gov/31384404","citation_count":3,"is_preprint":false},{"pmid":"38757275","id":"PMC_38757275","title":"The differential expression patterns of Atg9a and Atg9b in cells of the reproductive organs.","date":"2024","source":"Clinical and experimental reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38757275","citation_count":2,"is_preprint":false},{"pmid":"38526029","id":"PMC_38526029","title":"Depletion of CPNE7 sensitizes colorectal cancer to 5-fluorouracil by downregulating ATG9B expression.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38526029","citation_count":2,"is_preprint":false},{"pmid":"36262348","id":"PMC_36262348","title":"Unveiling the Noncanonical Autophagy-Independent Role of ATG7 and ATG9B in Head and Neck Squamous Cell Carcinoma (HNSCC).","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36262348","citation_count":2,"is_preprint":false},{"pmid":"40258750","id":"PMC_40258750","title":"ATG9B-4 accelerates the proliferation and migration of liver cancer cells in an ARNTL-CDK5 pathway-dependent manner: A case-control study.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40258750","citation_count":2,"is_preprint":false},{"pmid":"36966459","id":"PMC_36966459","title":"Contribution of NOS3AS Variants to Susceptibility to Essential Hypertension: A Study in Kermanshah Province, Western Iran.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36966459","citation_count":1,"is_preprint":false},{"pmid":"40123635","id":"PMC_40123635","title":"Exon Sequence Analysis of the ATG5, ATG12, ATG9B Genes in Colorectal Cancer Patients During Radiotherapy.","date":"2024","source":"Indian journal of clinical biochemistry : IJCB","url":"https://pubmed.ncbi.nlm.nih.gov/40123635","citation_count":1,"is_preprint":false},{"pmid":"41811769","id":"PMC_41811769","title":"ATG9B regulates mitochondrial integrity and apoptotic tumor cell death.","date":"2026","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/41811769","citation_count":0,"is_preprint":false},{"pmid":"41495834","id":"PMC_41495834","title":"CBX2 promotes cisplatin resistance in ovarian cancer via SIAH2-mediated β-catenin stabilization and ATG9B-dependent autophagy activation.","date":"2026","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/41495834","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.24.684263","title":"<i>ATG</i>  gene duplication in vertebrates: evolutionary divergence and its functional implications","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.24.684263","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.28.620020","title":"Characterization of a novel neurodevelopmental rare disease caused by a mutation within the autophagy gene  <i>ATG9B</i>","date":"2024-10-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.28.620020","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19558,"output_tokens":3807,"usd":0.05789,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11619,"output_tokens":2919,"usd":0.065535,"stage2_stop_reason":"end_turn"},"total_usd":0.123425,"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\": 2005,\n      \"finding\": \"ATG9B (APG9L2) localizes primarily to the perinuclear region and also as cytosolic dots that partially colocalize with the autophagosome marker LC3 under starvation conditions, and can functionally complement ATG9A (APG9L1) knockdown to restore starvation-induced autophagosome formation in HeLa cells, establishing it as a functional ortholog of yeast Atg9p.\",\n      \"method\": \"Transient transfection with fluorescent-tagged constructs, siRNA knockdown of ATG9A, immunofluorescence colocalization with LC3\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization by live imaging tied to functional rescue, single lab, two orthogonal methods (imaging + knockdown rescue)\",\n      \"pmids\": [\"15755735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human ATG9B forms a conserved homotrimeric structure (determined by cryo-EM), functions as a lipid scramblase, displays similar subcellular trafficking and steady-state localization to ATG9A, can compensate for ATG9A absence in starvation-induced autophagy, and forms a heteromeric complex with ATG2A.\",\n      \"method\": \"Single-particle cryo-EM structure determination, lipid scramblase assay, subcellular trafficking/localization analysis, ATG9A knockout complementation assay, co-immunoprecipitation with ATG2A\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus in vitro scramblase assay plus functional complementation plus binding partner identification in a single rigorous study\",\n      \"pmids\": [\"37938170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"siRNA knockdown of Atg9b in cardiomyocyte-derived cells reduces autophagosome formation, and Atg9b protein levels are specifically reduced in aged mouse hearts correlating with decreased autophagic activity, demonstrating Atg9b is required for autophagosome biogenesis in cardiac cells.\",\n      \"method\": \"siRNA knockdown, autophagosome quantification, gene expression profiling, protein analysis of aged vs. young mouse hearts\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA knockdown with defined autophagosome phenotype, supported by in vivo correlation; single lab\",\n      \"pmids\": [\"32627317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Atg9b-deficient hepatocytes are vulnerable to ER stress-induced cell death due to accumulation of ubiquitinated proteins, and loss of Atg9b blocks recruitment of p62-associated ubiquitinated proteins to autophagosomes; Atg9b-driven phagophores facilitate docking of both LC3 and p62 to initiate autophagy-associated degradation. Additionally, miR-3091-3p from tumor-derived exosomes suppresses Atg9b expression.\",\n      \"method\": \"Hepatocarcinogenesis mouse model (CDAA diet), miRNA microarray, PCR profiler array, siRNA knockdown, immunofluorescence for LC3/p62/ubiquitin\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model plus in vitro knockdown with defined molecular phenotype; single lab, multiple complementary methods\",\n      \"pmids\": [\"28740555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG9B promotes colorectal cancer invasion in an autophagy-independent manner: MYH9 directly binds to cytoplasmic residues aa368-411 of ATG9B via its head domain; their interaction stabilizes both proteins by reducing binding to the E3 ubiquitin ligase STUB1, preventing ubiquitin-mediated degradation. ATG9B is transported to the cell edge with MYH9 assistance and accelerates focal adhesion assembly by mediating interaction between endocytosed integrin β1 and Talin-1, promoting integrin β1 activation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assay, immunofluorescence localization, focal adhesion assembly assay, integrin β1/Talin-1 interaction assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, ubiquitination mechanism, and functional focal adhesion assay; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"34131310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HPV16 E7 protein physically interacts with ATG9B (shown by immunoprecipitation), and HPV16 E6 likely transcriptionally regulates ATG9B through the -1750 to -2000 nt region of its promoter (dual-luciferase reporter). Overexpression of ATG9B partially compensates for autophagy blockage caused by 16E6/E7 knockdown.\",\n      \"method\": \"Immunoprecipitation (16E7–ATG9B interaction), dual-luciferase reporter assay, transcriptome sequencing, gene overexpression rescue experiments\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus reporter assay plus functional rescue; single lab, multiple methods\",\n      \"pmids\": [\"31215164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-7002-5p (from high-glucose macrophage-derived exosomes) directly targets ATG9B, as confirmed by dual-luciferase reporter assay; suppression of ATG9B by miR-7002-5p inhibits autophagy in tubular epithelial cells, inducing dysfunction and inflammation.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA sequencing, miR-7002-5p inhibitor experiments in vitro and in vivo\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation plus in vivo confirmation; single lab\",\n      \"pmids\": [\"35971776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ASCL2 transcriptionally regulates ATG9B expression to maintain stemness properties (self-renewal and tumor-propagation potential) in glioma cells; the ASCL2-ATG9B axis is required for autophagic activity and stemness maintenance.\",\n      \"method\": \"Transcriptional regulation assay, loss-of-function and gain-of-function experiments for ASCL2 and ATG9B in glioma cells\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined transcriptional regulation with functional stemness readouts; single lab\",\n      \"pmids\": [\"35882624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATG9B regulates internalization of various invasive bacteria by controlling actin rearrangement; ATG9B knockdown causes accumulation of actin filaments and phosphorylated LIM kinase and cofilin, indicating ATG9B promotes actin depolymerization. ULK1 kinase activity regulates ATG9B localization and actin remodeling.\",\n      \"method\": \"ATG knockout screening, siRNA knockdown in HeLa cells, bacterial internalization assay, immunofluorescence for actin/pLIMK/pCofilin, ULK1 kinase inhibition\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO screen plus mechanistic knockdown with defined molecular readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38706859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATG9b upregulation by propranolol in hepatic stellate cells enhances P62 recruitment to ATG5-ATG12-LC3 compartments and increases co-localization of P62 with ubiquitinated proteins; the PI3K/AKT/mTOR pathway mediates ATG9b-induced autophagic cell death, while p38/JNK is involved in apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, co-localization immunofluorescence, phospho-antibody microarray, lentiviral ATG9b overexpression, in vivo liver fibrosis model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus co-localization plus pathway inhibitor experiments; single lab, multiple methods\",\n      \"pmids\": [\"37970991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATG9B localizes prominently to mitochondria (distinct from ATG9A), where its expression induces aberrant mitochondrial morphology, reduces mitochondrial membrane potential, and promotes mtDNA release and apoptotic cell death. The N-terminal sequence of ATG9B functions as a mitochondrial targeting domain, and expression of this peptide alone is sufficient to induce apoptosis.\",\n      \"method\": \"Fluorescently tagged ATG9B expression, mitochondrial membrane potential assay, mtDNA release assay, apoptosis indicators, N-terminal domain truncation/expression experiments in tumor cell lines\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, domain mapping, multiple apoptotic readouts; single lab\",\n      \"pmids\": [\"41811769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A homozygous 11-nucleotide deletion/frameshift mutation in ATG9B (truncating the C-terminal cytosolic domain) causes a rare neurodevelopmental disorder in humans. The truncated ATG9B protein is unstable in cells and localizes only to perinuclear vesicles but not peripheral vesicles (unlike wild-type ATG9B), indicating the C-terminal domain is required for peripheral vesicle trafficking.\",\n      \"method\": \"Patient genetic analysis, knock-in mouse model generation, cell expression of truncated vs WT ATG9B with subcellular localization analysis, protein stability assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model plus cell-based domain analysis; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATG9A and ATG9B show distinct subcellular localizations in uterine epithelial cells: ATG9A distributes in a punctate pattern while ATG9B forms elongated tubular shapes in the cytoplasm, suggesting isoform-specific roles in autophagy.\",\n      \"method\": \"Immunofluorescence staining of primary uterine epithelial and stromal cells, Western blotting\",\n      \"journal\": \"Clinical and experimental reproductive medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method localization experiment, no functional consequence established beyond descriptive difference\",\n      \"pmids\": [\"38757275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-30c-1-3p directly targets ATG9B (and ATG4B) during M. tuberculosis infection in macrophages; overexpression of ATG9B (alone or with ATG4B) reversed miR-30c-1-3p-mediated autophagy inhibition, demonstrating ATG9B is required for autophagy-mediated antimycobacterial defense.\",\n      \"method\": \"RNA sequencing, bioinformatics miRNA target prediction, overexpression rescue experiments, Western blot, immunofluorescence, transmission electron microscopy for autophagy levels\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression rescue with multiple orthogonal autophagy readouts; single lab\",\n      \"pmids\": [\"40133377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATG9B mediates CBX2-induced autophagy and cisplatin resistance in ovarian cancer; CBX2 stabilizes β-catenin via SIAH2-mediated inhibition of ubiquitin-mediated degradation, and ATG9B inhibition rescues the effects of CBX2-mediated autophagy and drug resistance, placing ATG9B downstream of the Wnt/β-catenin pathway in autophagy regulation.\",\n      \"method\": \"Co-immunoprecipitation (SIAH2-β-catenin binding), overexpression/silencing plasmid transfection, autophagy flux assays, drug resistance (IC50) assays\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pathway manipulation with functional readouts; single lab\",\n      \"pmids\": [\"41495834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATG9B is a tissue-specific, homotrimeric lipid scramblase (structurally validated by cryo-EM) that is functionally orthologous to yeast Atg9p: it localizes to perinuclear and peripheral vesicles (with its C-terminal domain required for peripheral trafficking), can compensate for ATG9A in starvation-induced autophagy, forms a heteromeric complex with ATG2A, and delivers membrane lipids to the growing autophagosome; beyond canonical autophagy, ATG9B has autophagy-independent roles including MYH9-dependent polarization to the cell edge to promote focal adhesion assembly and cancer invasion, a unique mitochondrial localization (via an N-terminal targeting sequence) that can trigger apoptosis, and regulation of actin depolymerization during bacterial internalization via ULK1-dependent localization control.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATG9B is a tissue-specific functional ortholog of yeast Atg9p that drives autophagosome biogenesis by delivering membrane lipids to the growing phagophore [#0, #1]. It assembles as a conserved homotrimer that functions as a lipid scramblase, recapitulates the subcellular trafficking and steady-state distribution of ATG9A, can compensate for ATG9A loss in starvation-induced autophagy, and forms a heteromeric complex with the lipid-transfer protein ATG2A [#1]. In autophagosome formation it acts upstream of cargo docking, facilitating recruitment of LC3 and p62-associated ubiquitinated proteins to nascent phagophores, such that its loss sensitizes cells to ER stress-induced death through accumulation of ubiquitinated substrates [#3]. Beyond canonical autophagy, ATG9B has distinct context-dependent roles: it is stabilized by and trafficked with MYH9 to the cell edge, where it accelerates focal adhesion assembly by promoting integrin \\u03b21\\u2013Talin-1 interaction and integrin \\u03b21 activation to drive cancer invasion in an autophagy-independent manner [#4]; it controls actin depolymerization during bacterial internalization under ULK1 kinase control, with its loss causing accumulation of actin filaments and phosphorylated LIM kinase and cofilin [#8]; and it localizes to mitochondria via an N-terminal targeting sequence, where its expression collapses mitochondrial membrane potential, promotes mtDNA release, and triggers apoptosis [#10]. ATG9B expression is set by multiple transcriptional and post-transcriptional inputs, including suppression by several exosomal miRNAs and activation through ASCL2 and Wnt/\\u03b2-catenin signaling in cancer stemness and drug resistance [#3, #6, #7, #14]. A homozygous frameshift truncating the C-terminal cytosolic domain causes a rare human neurodevelopmental disorder, and the truncated protein is unstable and fails to reach peripheral vesicles, defining the C-terminal domain as required for peripheral trafficking [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that ATG9B is a functional ortholog of yeast Atg9p, answering whether this paralog participates in the autophagy machinery at all.\",\n      \"evidence\": \"Fluorescent-tagged localization, ATG9A siRNA knockdown rescue, and LC3 colocalization in HeLa cells\",\n      \"pmids\": [\"15755735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular activity of the protein not defined\", \"No structural information\", \"Direct binding partners unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed ATG9B upstream of cargo capture by showing its phagophores dock LC3 and p62-associated ubiquitinated proteins, explaining why its loss causes ER stress-induced death.\",\n      \"evidence\": \"Hepatocarcinogenesis mouse model with siRNA knockdown and LC3/p62/ubiquitin immunofluorescence\",\n      \"pmids\": [\"28740555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of p62/ubiquitin recruitment not defined at molecular level\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an autophagy-independent function: ATG9B drives focal adhesion assembly and cancer invasion through MYH9-stabilized trafficking and integrin \\u03b21 activation.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping (aa368-411), STUB1 ubiquitination assays, and focal adhesion/integrin \\u03b21\\u2013Talin-1 assays\",\n      \"pmids\": [\"34131310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this function requires the scramblase activity unknown\", \"Generality beyond colorectal cancer untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the biochemical activity and quaternary structure of ATG9B, establishing it as a homotrimeric lipid scramblase that binds ATG2A and compensates for ATG9A.\",\n      \"evidence\": \"Single-particle cryo-EM, in vitro lipid scramblase assay, ATG9A knockout complementation, and ATG2A co-immunoprecipitation\",\n      \"pmids\": [\"37938170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/architecture of the ATG9B-ATG2A complex not resolved structurally\", \"Tissue context of scramblase function untested in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ATG9B to cytoskeletal control during infection, showing it promotes actin depolymerization under ULK1 regulation to govern bacterial internalization.\",\n      \"evidence\": \"ATG knockout screen, siRNA knockdown, bacterial internalization assays, actin/pLIMK/pCofilin immunofluorescence, ULK1 inhibition in HeLa cells\",\n      \"pmids\": [\"38706859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effectors linking ATG9B to LIMK/cofilin unknown\", \"Whether ULK1 phosphorylates ATG9B directly untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ATG9B to human disease and mapped a trafficking determinant, showing a C-terminal frameshift causes neurodevelopmental disease and abolishes peripheral vesicle targeting.\",\n      \"evidence\": \"Patient genetics, knock-in mouse model, and cell-based localization/stability comparison of truncated vs WT protein (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Mechanistic basis of neurodevelopmental phenotype not established\", \"How the C-terminal domain mediates peripheral trafficking unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Uncovered a pro-apoptotic mitochondrial role distinct from ATG9A, mediated by an N-terminal mitochondrial targeting sequence.\",\n      \"evidence\": \"Tagged ATG9B expression, mitochondrial membrane potential and mtDNA release assays, apoptosis readouts, and N-terminal domain truncation in tumor cell lines\",\n      \"pmids\": [\"41811769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous ATG9B localizes to mitochondria physiologically unclear\", \"Mechanism of membrane potential collapse undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATG9B's single scramblase activity is partitioned across its diverse autophagic, focal-adhesion, actin-remodeling, and mitochondrial-apoptotic functions, and how its trafficking is switched between these fates, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking scramblase activity to autophagy-independent roles\", \"Regulators selecting perinuclear vs peripheral vs mitochondrial localization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"ATG9B-ATG2A complex\"],\n    \"partners\": [\"ATG2A\", \"MYH9\", \"STUB1\", \"ULK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}