{"gene":"ATG2B","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2015,"finding":"Germline overexpression of ATG2B (together with GSKIP) enhances hematopoietic progenitor differentiation, including megakaryocyte differentiation, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during myeloproliferative neoplasm development.","method":"Induced pluripotent stem cell models and primary cells from families carrying a 700-kb germline duplication; functional differentiation assays with TPO stimulation","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC and primary cell models with functional differentiation readout, single lab, two orthogonal cellular systems","pmids":["26280900"],"is_preprint":false},{"year":2021,"finding":"Loss of both Atg2b and Gskip (but not either alone) in mice causes decreased hematopoietic stem cell (HSC) pool size, increased HSC death, and lethality in utero with anemia; mechanistically, double knockout increased expression of oxidative phosphorylation genes without affecting bulk autophagy, indicating a synergistic non-autophagy role for Atg2b and Gskip in HSC maintenance.","method":"Double-knockout mouse model; flow cytometry of HSC populations in fetal liver; gene expression analysis; autophagy flux assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean double-KO mouse with defined cellular phenotype and pathway analysis, single lab, multiple orthogonal methods","pmids":["34748402"],"is_preprint":false},{"year":2012,"finding":"ATG2B is a direct target of miR-130a; miR-130a-mediated downregulation of ATG2B reduces autophagosome formation and inhibits autophagic flux in CLL cells.","method":"miRNA overexpression, RNA interference knockdown of ATG2B, autophagosome formation assay in CLL cell lines and primary CLL cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined autophagy phenotype, validated in primary cells and cell lines, single lab","pmids":["22350415"],"is_preprint":false},{"year":2018,"finding":"miR-143 directly targets ATG2B 3'-UTR; miR-143-mediated suppression of ATG2B inhibits autophagy, reduces IκBα levels, and increases inflammatory responses in intestinal epithelial cells, placing ATG2B upstream of NF-κB signaling in Crohn's disease-associated inflammation.","method":"3'-UTR dual-luciferase reporter assay; immunoblot for LC3 and IκBα; transmission electron microscopy for autophagy; constitutive miR-143 expression and ATG2B depletion in intestinal epithelial cells","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation plus multiple orthogonal functional assays, single lab","pmids":["29562274"],"is_preprint":false},{"year":2020,"finding":"miR-143 directly targets ATG2B and ATG7; co-expression of ATG2B and ATG7 rescues miR-143-suppressed autophagy and attenuates miR-143-enhanced cytarabine cytotoxicity via suppression of caspase-dependent apoptosis in AML cells, establishing ATG2B as a critical component of the autophagic machinery regulating chemosensitivity.","method":"miR-143 overexpression and knockdown; ATG2B and ATG7 co-expression rescue experiments; cell viability assays; caspase apoptosis assays in AML cell lines and primary AML cells","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue co-expression experiment plus primary AML cells, single lab, multiple functional readouts","pmids":["33077697"],"is_preprint":false},{"year":2021,"finding":"miR-130a suppresses VSMC proliferation by targeting ATG2B and inhibiting ATG2B-dependent autophagy; ATG2B overexpression reverses miR-130a-mediated autophagy inhibition and rescues proliferation, placing ATG2B as a pro-autophagic and pro-proliferative effector downstream of miR-130a in vascular smooth muscle cells.","method":"miR-130a overexpression; ATG2B knockdown and rescue plasmid co-transfection; CCK-8/cell cycle assays; LC3 Western blot; rat arteriosclerosis model with immunohistochemistry","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue co-transfection experiment confirmed in vivo in rat model, single lab","pmids":["33611856"],"is_preprint":false},{"year":2016,"finding":"miR-1303 directly targets ATG2B mRNA, negatively regulating ATG2B protein production and thereby downregulating mycobacteria-induced autophagy in macrophages; miR-1303 production is upregulated during BCG infection and regulated by PI3K and NF-κB signaling.","method":"Luciferase reporter assay targeting ATG2B 3'-UTR; miR-1303 overexpression; autophagy measurement in BCG-infected cells; PI3K/NF-κB pathway inhibitors","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter plus single-method autophagy readout, single lab","pmids":["26771516"],"is_preprint":false},{"year":2024,"finding":"The E3 ubiquitin ligase RNF5 mediates ubiquitin-dependent degradation of ATG2B; the circular RNA circDHX8 directly binds RNF5 and inhibits RNF5-mediated degradation, thereby stabilizing ATG2B protein and promoting autophagy and gastric cancer malignancy. Additionally, ATG2B is an acetylated protein subjected to SIRT1-mediated deacetylation, which enhances its binding to RNF5.","method":"RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation; Western blotting for ubiquitination; circDHX8 interference in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus MS identification plus RIP, single lab, multiple orthogonal biochemical methods","pmids":["38866787"],"is_preprint":false},{"year":2024,"finding":"SIRT1 mediates deacetylation of ATG2B (and ATG5), and this deacetylation activates autophagy in ovarian cancer cells; the ACSS2/SIRT1/ATG2B axis links acetate metabolism and glycolysis to autophagy regulation.","method":"CUT&TAG; co-immunoprecipitation; ACSS2 knockdown; stable-isotope labeling; Seahorse metabolic assays; in vitro and in vivo tumor models","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&TAG and co-IP for deacetylation mechanism, confirmed in vivo, single lab","pmids":["39362518"],"is_preprint":false},{"year":2009,"finding":"ATG2B harbors a mononucleotide repeat susceptible to frameshift mutations in microsatellite instability-high (MSI-H) gastric and colorectal cancers; frameshift mutations were detected in 10 MSI-H cancers, suggesting ATG2B loss-of-function mutations may deregulate autophagy in these tumors.","method":"Single-strand conformation polymorphism (SSCP) analysis of mononucleotide repeats in tumor samples","journal":"The Journal of pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mutation detection only, no functional validation of ATG2B-specific mechanism, single study","pmids":["19197948"],"is_preprint":false},{"year":2021,"finding":"ATG2B upregulated in LPS-pretreated BMSC-derived exosomes (L-Exo) attenuates septic liver injury by enhancing mitophagy and inhibiting release of mitochondrial DNA into the cytosol, thereby suppressing macrophage STING signaling.","method":"In vivo cecal ligation and puncture sepsis model; in vitro macrophage experiments; exosome ultracentrifugation; mitophagy assays; mtDNA cytosolic release measurement; STING pathway analysis","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ATG2B identified as major factor but mechanistic specificity relies on correlative exosome cargo analysis; single lab, limited direct ATG2B manipulation","pmids":["36857936"],"is_preprint":false}],"current_model":"ATG2B is an autophagy-related protein that promotes autophagosome formation and autophagic flux; it is post-translationally regulated by SIRT1-mediated deacetylation (which activates it) and RNF5-mediated ubiquitin-dependent degradation (which destabilizes it), and is transcriptionally/post-transcriptionally repressed by multiple miRNAs (miR-130a, miR-143, miR-375, miR-1303, miR-1278, miR-181a, miR-320a); in hematopoiesis, ATG2B cooperates with GSKIP to maintain HSC pool size and, when overexpressed, enhances progenitor sensitivity to TPO to predispose to myeloid malignancies."},"narrative":{"mechanistic_narrative":"ATG2B is a component of the core autophagic machinery that promotes autophagosome formation and sustains autophagic flux across multiple cell types [PMID:22350415, PMID:33077697]. Its function is gated by opposing post-translational controls: SIRT1-mediated deacetylation activates ATG2B-dependent autophagy and links acetate metabolism and glycolysis to autophagy through an ACSS2/SIRT1/ATG2B axis [PMID:39362518], while the same deacetylation enhances ATG2B binding to the E3 ubiquitin ligase RNF5, which drives its ubiquitin-dependent degradation; the circular RNA circDHX8 antagonizes RNF5 to stabilize ATG2B and promote autophagy [PMID:38866787]. ATG2B is additionally repressed at the post-transcriptional level by several miRNAs, including miR-130a and miR-143, whose targeting of the ATG2B 3'-UTR suppresses autophagy and thereby modulates downstream outcomes such as NF-κB-driven inflammation [PMID:29562274], chemosensitivity [PMID:33077697], and cell proliferation [PMID:33611856]. Beyond bulk autophagy, ATG2B has a distinct role in hematopoiesis: it cooperates with GSKIP, and germline overexpression of the pair increases hematopoietic progenitor sensitivity to thrombopoietin and predisposes to myeloproliferative neoplasms [PMID:26280900], whereas combined loss of Atg2b and Gskip depletes the hematopoietic stem cell pool through an oxidative-phosphorylation-linked, autophagy-independent mechanism [PMID:34748402].","teleology":[{"year":2009,"claim":"Established the first link between ATG2B and human cancer by asking whether ATG2B is genetically altered in tumors with genomic instability.","evidence":"SSCP analysis of a mononucleotide repeat in MSI-H gastric and colorectal tumor samples","pmids":["19197948"],"confidence":"Low","gaps":["No functional validation that the frameshift mutations abolish ATG2B activity","Does not establish a causal role in tumorigenesis","Mechanism of any resulting autophagy deregulation untested"]},{"year":2012,"claim":"Defined ATG2B as a functional autophagy effector by showing its depletion reduces autophagosome formation, and identified miR-130a as a direct upstream repressor.","evidence":"miR-130a overexpression, ATG2B RNAi, and autophagosome assays in CLL cell lines and primary cells","pmids":["22350415"],"confidence":"Medium","gaps":["Molecular step of autophagosome formation served by ATG2B not defined","No direct 3'-UTR binding shown in this study","Partners in the autophagy machinery not identified"]},{"year":2015,"claim":"Revealed a non-canonical hematopoietic function by showing germline ATG2B/GSKIP overexpression primes progenitors toward myeloid malignancy.","evidence":"iPSC and primary-cell models from families with a 700-kb germline duplication, with TPO-stimulated differentiation assays","pmids":["26280900"],"confidence":"Medium","gaps":["Whether the effect requires ATG2B autophagic activity unresolved","Molecular basis of cooperation with GSKIP unknown","Mechanism of enhanced TPO sensitivity not defined"]},{"year":2016,"claim":"Extended miRNA control of ATG2B to innate immunity by showing miR-1303 restrains mycobacteria-induced autophagy via the ATG2B 3'-UTR.","evidence":"Luciferase 3'-UTR reporter and autophagy readout in BCG-infected macrophages with PI3K/NF-κB inhibitors","pmids":["26771516"],"confidence":"Low","gaps":["Single-method autophagy readout limits confidence","ATG2B protein-level effects of miR-1303 only indirectly shown","Physiological relevance to infection control untested"]},{"year":2018,"claim":"Placed ATG2B-driven autophagy upstream of inflammatory signaling by linking miR-143 repression of ATG2B to reduced IκBα and NF-κB activation.","evidence":"Dual-luciferase 3'-UTR reporter, LC3/IκBα immunoblot, and TEM in intestinal epithelial cells","pmids":["29562274"],"confidence":"Medium","gaps":["Mechanism connecting ATG2B autophagy to IκBα stability not detailed","In vivo relevance to Crohn's disease not directly tested","Whether NF-κB effect is autophagy-dependent unconfirmed"]},{"year":2020,"claim":"Demonstrated ATG2B is rate-limiting for autophagy-mediated chemoresistance by rescuing miR-143 phenotypes through ATG2B/ATG7 co-expression.","evidence":"miR-143 gain/loss, ATG2B+ATG7 rescue, viability and caspase apoptosis assays in AML lines and primary cells","pmids":["33077697"],"confidence":"Medium","gaps":["Relative contribution of ATG2B vs ATG7 not separated","Mechanistic link between autophagy and caspase suppression not defined","No structural or interaction data for ATG2B"]},{"year":2021,"claim":"Showed ATG2B/GSKIP loss depletes the HSC pool through an autophagy-independent, oxidative-phosphorylation-linked mechanism, dissociating ATG2B's hematopoietic role from bulk autophagy.","evidence":"Double-knockout mice with fetal-liver HSC flow cytometry, gene expression analysis, and autophagy flux assays","pmids":["34748402"],"confidence":"Medium","gaps":["Molecular mechanism of the OXPHOS gene increase unknown","How ATG2B and GSKIP act synergistically not defined","Whether a residual autophagy function contributes not excluded"]},{"year":2021,"claim":"Generalized ATG2B as a pro-autophagic, pro-proliferative effector in vascular cells downstream of miR-130a.","evidence":"miR-130a overexpression with ATG2B knockdown/rescue, proliferation and LC3 assays, and a rat arteriosclerosis model","pmids":["33611856"],"confidence":"Medium","gaps":["Link between autophagy and proliferation control mechanistically unclear","ATG2B interactors in VSMCs not identified","Direct miR-130a–ATG2B binding in this context not shown"]},{"year":2024,"claim":"Identified the post-translational stability control of ATG2B by establishing RNF5 as the E3 ligase driving its degradation and circDHX8 as an RNF5-sequestering stabilizer.","evidence":"RNA pulldown/MS, RIP, reciprocal co-IP, ubiquitination immunoblot, and circDHX8 interference in gastric cancer in vitro and in vivo","pmids":["38866787"],"confidence":"Medium","gaps":["Ubiquitination site(s) on ATG2B not mapped","Whether RNF5 ubiquitinates ATG2B directly vs via cofactors unconfirmed","Quantitative impact on autophagosome formation not measured"]},{"year":2024,"claim":"Defined acetylation as a regulatory switch on ATG2B by showing SIRT1 deacetylation activates ATG2B-dependent autophagy and couples it to acetate/glycolytic metabolism.","evidence":"CUT&TAG, co-IP, ACSS2 knockdown, stable-isotope labeling, and Seahorse assays in ovarian cancer models in vitro and in vivo","pmids":["39362518"],"confidence":"Medium","gaps":["Acetylation sites on ATG2B not mapped","How deacetylation mechanistically activates autophagy unclear","Interplay between SIRT1 activation and RNF5-mediated degradation not reconciled"]},{"year":null,"claim":"The molecular function of ATG2B within the autophagosome-formation machinery and the structural basis of its regulation remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical/structural characterization of ATG2B's role in membrane dynamics in this corpus","Acetylation and ubiquitination sites unmapped","How autophagy-dependent and autophagy-independent (HSC/OXPHOS) functions are partitioned is unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3,4,5]}],"complexes":[],"partners":["GSKIP","RNF5","SIRT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BY7","full_name":"Autophagy-related protein 2 homolog B","aliases":[],"length_aa":2078,"mass_kda":232.8,"function":"Lipid transfer protein required for both autophagosome formation and regulation of lipid droplet morphology and dispersion (PubMed:22219374, PubMed:31721365). Tethers the edge of the isolation membrane (IM) to the endoplasmic reticulum (ER) and mediates direct lipid transfer from ER to IM for IM expansion (PubMed:22219374, PubMed:31721365). Binds to the ER exit site (ERES), which is the membrane source for autophagosome formation, and extracts phospholipids from the membrane source and transfers them to ATG9 (ATG9A or ATG9B) to the IM for membrane expansion (By similarity). Lipid transfer activity is enhanced by WDR45/WIPI4, which promotes ATG2B-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes (PubMed:31721365)","subcellular_location":"Preautophagosomal structure membrane; Lipid droplet; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96BY7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATG2B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000066739","cell_line_id":"CID001815","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"WDR45","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001815","total_profiled":1310},"omim":[{"mim_id":"616604","title":"CHROMOSOME 14q32 DUPLICATION SYNDROME, 700-KB","url":"https://www.omim.org/entry/616604"},{"mim_id":"616226","title":"AUTOPHAGY-RELATED 2B; ATG2B","url":"https://www.omim.org/entry/616226"},{"mim_id":"616225","title":"AUTOPHAGY-RELATED 2A; ATG2A","url":"https://www.omim.org/entry/616225"},{"mim_id":"612205","title":"AUTOPHAGY-RELATED 9B; ATG9B","url":"https://www.omim.org/entry/612205"},{"mim_id":"604261","title":"AUTOPHAGY-RELATED 5; ATG5","url":"https://www.omim.org/entry/604261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATG2B"},"hgnc":{"alias_symbol":["FLJ10242","BLTP4B"],"prev_symbol":["C14orf103"]},"alphafold":{"accession":"Q96BY7","domains":[{"cath_id":"1.10.287","chopping":"1893-1963","consensus_level":"medium","plddt":74.4825,"start":1893,"end":1963},{"cath_id":"1.20.58","chopping":"1984-2078","consensus_level":"medium","plddt":74.8172,"start":1984,"end":2078}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BY7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BY7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BY7-F1-predicted_aligned_error_v6.png","plddt_mean":65.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATG2B","jax_strain_url":"https://www.jax.org/strain/search?query=ATG2B"},"sequence":{"accession":"Q96BY7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BY7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BY7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BY7"}},"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":"22350415","id":"PMC_22350415","title":"miRNA-130a targets ATG2B and DICER1 to inhibit autophagy and trigger killing of chronic lymphocytic leukemia cells.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22350415","citation_count":168,"is_preprint":false},{"pmid":"26280900","id":"PMC_26280900","title":"Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26280900","citation_count":104,"is_preprint":false},{"pmid":"33824300","id":"PMC_33824300","title":"LncRNA-HOTAIR activates autophagy and promotes the imatinib resistance of gastrointestinal stromal tumor cells through a mechanism involving the miR-130a/ATG2B pathway.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33824300","citation_count":54,"is_preprint":false},{"pmid":"29562274","id":"PMC_29562274","title":"MicroRNA-143 Targets ATG2B to Inhibit Autophagy and Increase Inflammatory Responses in Crohn's Disease.","date":"2018","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29562274","citation_count":52,"is_preprint":false},{"pmid":"32335541","id":"PMC_32335541","title":"MicroRNA-375 exacerbates knee osteoarthritis through repressing chondrocyte autophagy by targeting ATG2B.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32335541","citation_count":45,"is_preprint":false},{"pmid":"35029026","id":"PMC_35029026","title":"Autophagy inhibits cancer stemness in triple-negative breast cancer via miR-181a-mediated regulation of ATG5 and/or ATG2B.","date":"2022","source":"Molecular 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/33130456","citation_count":10,"is_preprint":false},{"pmid":"34748402","id":"PMC_34748402","title":"Loss of Atg2b and Gskip Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size.","date":"2021","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34748402","citation_count":5,"is_preprint":false},{"pmid":"37658706","id":"PMC_37658706","title":"Ame-miR-980-3p participates in autophagy-mediated midgut remodelling in Apis mellifera via targeting Atg2B.","date":"2023","source":"Insect molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37658706","citation_count":5,"is_preprint":false},{"pmid":"37226314","id":"PMC_37226314","title":"Effect of melatonin on ATG2B-mediated autophagy regulation in sheep granulosa cells with different FecB genotypes.","date":"2023","source":"Journal of pineal 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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":"33250346","id":"PMC_33250346","title":"Polymorphism in autophagy gene ATG2B is not associated with bladder cancer recurrence after intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in Asian patients.","date":"2020","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33250346","citation_count":0,"is_preprint":false},{"pmid":"40773487","id":"PMC_40773487","title":"Ghrelin improves small intestinal barrier damage in sepsis by promoting miR-143/ATG2B-mediated autophagy.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40773487","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16877,"output_tokens":2831,"usd":0.046548,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10106,"output_tokens":3366,"usd":0.06734,"stage2_stop_reason":"end_turn"},"total_usd":0.113888,"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\": 2015,\n      \"finding\": \"Germline overexpression of ATG2B (together with GSKIP) enhances hematopoietic progenitor differentiation, including megakaryocyte differentiation, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during myeloproliferative neoplasm development.\",\n      \"method\": \"Induced pluripotent stem cell models and primary cells from families carrying a 700-kb germline duplication; functional differentiation assays with TPO stimulation\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC and primary cell models with functional differentiation readout, single lab, two orthogonal cellular systems\",\n      \"pmids\": [\"26280900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of both Atg2b and Gskip (but not either alone) in mice causes decreased hematopoietic stem cell (HSC) pool size, increased HSC death, and lethality in utero with anemia; mechanistically, double knockout increased expression of oxidative phosphorylation genes without affecting bulk autophagy, indicating a synergistic non-autophagy role for Atg2b and Gskip in HSC maintenance.\",\n      \"method\": \"Double-knockout mouse model; flow cytometry of HSC populations in fetal liver; gene expression analysis; autophagy flux assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean double-KO mouse with defined cellular phenotype and pathway analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34748402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATG2B is a direct target of miR-130a; miR-130a-mediated downregulation of ATG2B reduces autophagosome formation and inhibits autophagic flux in CLL cells.\",\n      \"method\": \"miRNA overexpression, RNA interference knockdown of ATG2B, autophagosome formation assay in CLL cell lines and primary CLL cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined autophagy phenotype, validated in primary cells and cell lines, single lab\",\n      \"pmids\": [\"22350415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-143 directly targets ATG2B 3'-UTR; miR-143-mediated suppression of ATG2B inhibits autophagy, reduces IκBα levels, and increases inflammatory responses in intestinal epithelial cells, placing ATG2B upstream of NF-κB signaling in Crohn's disease-associated inflammation.\",\n      \"method\": \"3'-UTR dual-luciferase reporter assay; immunoblot for LC3 and IκBα; transmission electron microscopy for autophagy; constitutive miR-143 expression and ATG2B depletion in intestinal epithelial cells\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation plus multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"29562274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-143 directly targets ATG2B and ATG7; co-expression of ATG2B and ATG7 rescues miR-143-suppressed autophagy and attenuates miR-143-enhanced cytarabine cytotoxicity via suppression of caspase-dependent apoptosis in AML cells, establishing ATG2B as a critical component of the autophagic machinery regulating chemosensitivity.\",\n      \"method\": \"miR-143 overexpression and knockdown; ATG2B and ATG7 co-expression rescue experiments; cell viability assays; caspase apoptosis assays in AML cell lines and primary AML cells\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue co-expression experiment plus primary AML cells, single lab, multiple functional readouts\",\n      \"pmids\": [\"33077697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-130a suppresses VSMC proliferation by targeting ATG2B and inhibiting ATG2B-dependent autophagy; ATG2B overexpression reverses miR-130a-mediated autophagy inhibition and rescues proliferation, placing ATG2B as a pro-autophagic and pro-proliferative effector downstream of miR-130a in vascular smooth muscle cells.\",\n      \"method\": \"miR-130a overexpression; ATG2B knockdown and rescue plasmid co-transfection; CCK-8/cell cycle assays; LC3 Western blot; rat arteriosclerosis model with immunohistochemistry\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue co-transfection experiment confirmed in vivo in rat model, single lab\",\n      \"pmids\": [\"33611856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-1303 directly targets ATG2B mRNA, negatively regulating ATG2B protein production and thereby downregulating mycobacteria-induced autophagy in macrophages; miR-1303 production is upregulated during BCG infection and regulated by PI3K and NF-κB signaling.\",\n      \"method\": \"Luciferase reporter assay targeting ATG2B 3'-UTR; miR-1303 overexpression; autophagy measurement in BCG-infected cells; PI3K/NF-κB pathway inhibitors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter plus single-method autophagy readout, single lab\",\n      \"pmids\": [\"26771516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase RNF5 mediates ubiquitin-dependent degradation of ATG2B; the circular RNA circDHX8 directly binds RNF5 and inhibits RNF5-mediated degradation, thereby stabilizing ATG2B protein and promoting autophagy and gastric cancer malignancy. Additionally, ATG2B is an acetylated protein subjected to SIRT1-mediated deacetylation, which enhances its binding to RNF5.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RNA immunoprecipitation (RIP), co-immunoprecipitation; Western blotting for ubiquitination; circDHX8 interference in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus MS identification plus RIP, single lab, multiple orthogonal biochemical methods\",\n      \"pmids\": [\"38866787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT1 mediates deacetylation of ATG2B (and ATG5), and this deacetylation activates autophagy in ovarian cancer cells; the ACSS2/SIRT1/ATG2B axis links acetate metabolism and glycolysis to autophagy regulation.\",\n      \"method\": \"CUT&TAG; co-immunoprecipitation; ACSS2 knockdown; stable-isotope labeling; Seahorse metabolic assays; in vitro and in vivo tumor models\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&TAG and co-IP for deacetylation mechanism, confirmed in vivo, single lab\",\n      \"pmids\": [\"39362518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATG2B harbors a mononucleotide repeat susceptible to frameshift mutations in microsatellite instability-high (MSI-H) gastric and colorectal cancers; frameshift mutations were detected in 10 MSI-H cancers, suggesting ATG2B loss-of-function mutations may deregulate autophagy in these tumors.\",\n      \"method\": \"Single-strand conformation polymorphism (SSCP) analysis of mononucleotide repeats in tumor samples\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mutation detection only, no functional validation of ATG2B-specific mechanism, single study\",\n      \"pmids\": [\"19197948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG2B upregulated in LPS-pretreated BMSC-derived exosomes (L-Exo) attenuates septic liver injury by enhancing mitophagy and inhibiting release of mitochondrial DNA into the cytosol, thereby suppressing macrophage STING signaling.\",\n      \"method\": \"In vivo cecal ligation and puncture sepsis model; in vitro macrophage experiments; exosome ultracentrifugation; mitophagy assays; mtDNA cytosolic release measurement; STING pathway analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ATG2B identified as major factor but mechanistic specificity relies on correlative exosome cargo analysis; single lab, limited direct ATG2B manipulation\",\n      \"pmids\": [\"36857936\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATG2B is an autophagy-related protein that promotes autophagosome formation and autophagic flux; it is post-translationally regulated by SIRT1-mediated deacetylation (which activates it) and RNF5-mediated ubiquitin-dependent degradation (which destabilizes it), and is transcriptionally/post-transcriptionally repressed by multiple miRNAs (miR-130a, miR-143, miR-375, miR-1303, miR-1278, miR-181a, miR-320a); in hematopoiesis, ATG2B cooperates with GSKIP to maintain HSC pool size and, when overexpressed, enhances progenitor sensitivity to TPO to predispose to myeloid malignancies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATG2B is a component of the core autophagic machinery that promotes autophagosome formation and sustains autophagic flux across multiple cell types [#2, #4]. Its function is gated by opposing post-translational controls: SIRT1-mediated deacetylation activates ATG2B-dependent autophagy and links acetate metabolism and glycolysis to autophagy through an ACSS2/SIRT1/ATG2B axis [#8], while the same deacetylation enhances ATG2B binding to the E3 ubiquitin ligase RNF5, which drives its ubiquitin-dependent degradation; the circular RNA circDHX8 antagonizes RNF5 to stabilize ATG2B and promote autophagy [#7]. ATG2B is additionally repressed at the post-transcriptional level by several miRNAs, including miR-130a and miR-143, whose targeting of the ATG2B 3'-UTR suppresses autophagy and thereby modulates downstream outcomes such as NF-\\u03baB-driven inflammation [#3], chemosensitivity [#4], and cell proliferation [#5]. Beyond bulk autophagy, ATG2B has a distinct role in hematopoiesis: it cooperates with GSKIP, and germline overexpression of the pair increases hematopoietic progenitor sensitivity to thrombopoietin and predisposes to myeloproliferative neoplasms [#0], whereas combined loss of Atg2b and Gskip depletes the hematopoietic stem cell pool through an oxidative-phosphorylation-linked, autophagy-independent mechanism [#1].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the first link between ATG2B and human cancer by asking whether ATG2B is genetically altered in tumors with genomic instability.\",\n      \"evidence\": \"SSCP analysis of a mononucleotide repeat in MSI-H gastric and colorectal tumor samples\",\n      \"pmids\": [\"19197948\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation that the frameshift mutations abolish ATG2B activity\", \"Does not establish a causal role in tumorigenesis\", \"Mechanism of any resulting autophagy deregulation untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined ATG2B as a functional autophagy effector by showing its depletion reduces autophagosome formation, and identified miR-130a as a direct upstream repressor.\",\n      \"evidence\": \"miR-130a overexpression, ATG2B RNAi, and autophagosome assays in CLL cell lines and primary cells\",\n      \"pmids\": [\"22350415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular step of autophagosome formation served by ATG2B not defined\", \"No direct 3'-UTR binding shown in this study\", \"Partners in the autophagy machinery not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-canonical hematopoietic function by showing germline ATG2B/GSKIP overexpression primes progenitors toward myeloid malignancy.\",\n      \"evidence\": \"iPSC and primary-cell models from families with a 700-kb germline duplication, with TPO-stimulated differentiation assays\",\n      \"pmids\": [\"26280900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect requires ATG2B autophagic activity unresolved\", \"Molecular basis of cooperation with GSKIP unknown\", \"Mechanism of enhanced TPO sensitivity not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended miRNA control of ATG2B to innate immunity by showing miR-1303 restrains mycobacteria-induced autophagy via the ATG2B 3'-UTR.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter and autophagy readout in BCG-infected macrophages with PI3K/NF-\\u03baB inhibitors\",\n      \"pmids\": [\"26771516\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method autophagy readout limits confidence\", \"ATG2B protein-level effects of miR-1303 only indirectly shown\", \"Physiological relevance to infection control untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ATG2B-driven autophagy upstream of inflammatory signaling by linking miR-143 repression of ATG2B to reduced I\\u03baB\\u03b1 and NF-\\u03baB activation.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter, LC3/I\\u03baB\\u03b1 immunoblot, and TEM in intestinal epithelial cells\",\n      \"pmids\": [\"29562274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ATG2B autophagy to I\\u03baB\\u03b1 stability not detailed\", \"In vivo relevance to Crohn's disease not directly tested\", \"Whether NF-\\u03baB effect is autophagy-dependent unconfirmed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated ATG2B is rate-limiting for autophagy-mediated chemoresistance by rescuing miR-143 phenotypes through ATG2B/ATG7 co-expression.\",\n      \"evidence\": \"miR-143 gain/loss, ATG2B+ATG7 rescue, viability and caspase apoptosis assays in AML lines and primary cells\",\n      \"pmids\": [\"33077697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ATG2B vs ATG7 not separated\", \"Mechanistic link between autophagy and caspase suppression not defined\", \"No structural or interaction data for ATG2B\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ATG2B/GSKIP loss depletes the HSC pool through an autophagy-independent, oxidative-phosphorylation-linked mechanism, dissociating ATG2B's hematopoietic role from bulk autophagy.\",\n      \"evidence\": \"Double-knockout mice with fetal-liver HSC flow cytometry, gene expression analysis, and autophagy flux assays\",\n      \"pmids\": [\"34748402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the OXPHOS gene increase unknown\", \"How ATG2B and GSKIP act synergistically not defined\", \"Whether a residual autophagy function contributes not excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized ATG2B as a pro-autophagic, pro-proliferative effector in vascular cells downstream of miR-130a.\",\n      \"evidence\": \"miR-130a overexpression with ATG2B knockdown/rescue, proliferation and LC3 assays, and a rat arteriosclerosis model\",\n      \"pmids\": [\"33611856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between autophagy and proliferation control mechanistically unclear\", \"ATG2B interactors in VSMCs not identified\", \"Direct miR-130a–ATG2B binding in this context not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the post-translational stability control of ATG2B by establishing RNF5 as the E3 ligase driving its degradation and circDHX8 as an RNF5-sequestering stabilizer.\",\n      \"evidence\": \"RNA pulldown/MS, RIP, reciprocal co-IP, ubiquitination immunoblot, and circDHX8 interference in gastric cancer in vitro and in vivo\",\n      \"pmids\": [\"38866787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site(s) on ATG2B not mapped\", \"Whether RNF5 ubiquitinates ATG2B directly vs via cofactors unconfirmed\", \"Quantitative impact on autophagosome formation not measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined acetylation as a regulatory switch on ATG2B by showing SIRT1 deacetylation activates ATG2B-dependent autophagy and couples it to acetate/glycolytic metabolism.\",\n      \"evidence\": \"CUT&TAG, co-IP, ACSS2 knockdown, stable-isotope labeling, and Seahorse assays in ovarian cancer models in vitro and in vivo\",\n      \"pmids\": [\"39362518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylation sites on ATG2B not mapped\", \"How deacetylation mechanistically activates autophagy unclear\", \"Interplay between SIRT1 activation and RNF5-mediated degradation not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular function of ATG2B within the autophagosome-formation machinery and the structural basis of its regulation remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical/structural characterization of ATG2B's role in membrane dynamics in this corpus\", \"Acetylation and ubiquitination sites unmapped\", \"How autophagy-dependent and autophagy-independent (HSC/OXPHOS) functions are partitioned is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GSKIP\", \"RNF5\", \"SIRT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}