{"gene":"ATG2A","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2018,"finding":"ATG2A is a rod-shaped protein that tethers neighboring membranes through interactions at each of its tips; WIPI4 binds to one tip, enabling the ATG2A-WIPI4 complex to specifically tether PI3P-containing vesicles to PI3P-free vesicles, mediating ER-phagophore association.","method":"Single-particle electron microscopy, chemical cross-linking coupled with mass spectrometry, and biochemical vesicle-tethering assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal structural and biochemical methods (EM, XL-MS, in vitro tethering assays) in a single rigorous study","pmids":["30185561"],"is_preprint":false},{"year":2019,"finding":"Human ATG2A is a lipid transfer protein that can extract lipids from membrane vesicles and unload them to other vesicles; lipid transfer is more efficient between tethered vesicles; WIPI4 and WIPI1 associate ATG2A stably to PI3P-containing vesicles, facilitating ATG2A-mediated tethering and lipid transfer between PI3P-containing and PI3P-free vesicles.","method":"In vitro lipid transfer assay with membrane vesicles, fluorescence-based lipid mixing assays, reconstitution with purified proteins","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of lipid transfer activity with purified proteins, multiple assay conditions, independently confirmed in companion commentary (PMID:31441376)","pmids":["31271352","31441376"],"is_preprint":false},{"year":2022,"finding":"ATG9A and ATG2A form a heteromeric complex in which ATG2A facilitates lipid flow between tethered membranes and directly transfers lipids into the lipid-binding perpendicular branch of the ATG9A scramblase; multiple interfaces mediating this interaction were identified and mutational disruption of these interfaces impairs autophagy.","method":"Peptide arrays, crosslinking mass spectrometry, hydrogen-deuterium exchange mass spectrometry, cryo-electron microscopy, integrative structural modeling, mutational analyses with functional autophagy assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with XL-MS, HDX-MS, mutagenesis, and functional assays in one study","pmids":["36347259"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of human ATG2A-WIPI4 at 3.2 Å and ATG2A-WIPI4-ATG9A at 7 Å revealed a 3:1 stoichiometry of ATG9A-ATG2A complex with the ATG9A lateral pore directly aligned with the ATG2A lipid transfer cavity; ATG9A trimer interacts with both N-terminal and C-terminal tips of rod-shaped ATG2A; cryo-electron tomography showed ATG2A tethers lipid vesicles at different orientations; molecular dynamics simulations proposed a mechanism of lipid extraction from donor membranes.","method":"Cryo-electron microscopy (3.2 Å and 7 Å), cryo-electron tomography, molecular dynamics simulations","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures combined with cryo-ET and MD simulations providing mechanistic insight","pmids":["39174844"],"is_preprint":false},{"year":2017,"finding":"Deletion of ATG2A/B blocks autophagosome completion, leading to accumulation of immature autophagosomal membranes that promote non-canonical caspase-8 activation via an intracellular death-inducing signaling complex (iDISC) upon nutrient starvation; iDISC-induced caspase-8 dimerization and activation on these membranes requires the LC3 conjugation machinery and is independent of the extrinsic apoptosis pathway.","method":"ATG2A/B deletion (genetic KO), caspase-8 activation assays, immunofluorescence, co-immunoprecipitation, epistasis with LC3 conjugation mutants","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined phenotype and mechanistic pathway placement; single lab, multiple methods","pmids":["28800131"],"is_preprint":false},{"year":2014,"finding":"ATG2A localizes to cytoplasmic ADRP-positive lipid droplets that migrate bidirectionally along microtubules; this LD localization is independent of autophagic status; upon nutrient starvation and dependent on PI3P generation, ATG2A is additionally targeted to ER-associated early autophagosomal membranes marked by DFCP1 and WIPI-1; ATG2A is functionally involved in controlling lipid droplet number and size.","method":"Fluorescence microscopy (live imaging and colocalization), siRNA knockdown with lipid droplet phenotype quantification, PI3P dependency assay","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-imaging localization tied to functional consequence (LD number/size), single lab, two orthogonal methods","pmids":["24776541"],"is_preprint":false},{"year":2018,"finding":"ATG2A is enriched in lipid droplets of quiescent/reverted hepatic stellate cells; ATG2A deficiency in LX-2 cells leads to reduced α-SMA expression, increased perilipin-3, enlarged lipid droplets, and suppression of autophagic flux, indicating a role in linking lipid droplet homeostasis to autophagy and stellate cell activation state.","method":"Quantitative proteomics, immunoblotting, siRNA knockdown with lipid droplet and autophagic flux readouts","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with multiple readouts but no reconstitution or mechanistic dissection","pmids":["29915313"],"is_preprint":false},{"year":2024,"finding":"ANKFY1, an endosome-localized FYVE-domain protein, is a novel ATG2A-binding partner; ANKFY1 depletion impairs autophagosome growth and autophagic flux, phenocopying ATG2A/B depletion; ANKFY1 co-localizes with ATG2A between endosomes and phagophores; purified recombinant ANKFY1 binds PI3P and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes in vitro, implicating endosomes as a lipid source for ATG2A-mediated phagophore expansion.","method":"Co-immunoprecipitation, siRNA knockdown, fluorescence colocalization, in vitro lipid transfer assay with purified recombinant proteins and PI3P liposomes","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding demonstrated plus in vitro reconstitution of enhanced lipid transfer, single lab","pmids":["38622126"],"is_preprint":false},{"year":2021,"finding":"YTHDF1, induced by HIF-1α under hypoxia, promotes translation of ATG2A (and ATG14) by binding to m6A-modified ATG2A mRNA; this mechanism facilitates autophagy in hepatocellular carcinoma cells.","method":"Methylated RNA immunoprecipitation sequencing (MeRIP-seq), polysome profiling, proteomics, YTHDF1 KO/KD/OE in HCC cells and organoids","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus polysome profiling demonstrates translational regulation; multiple HCC models; single lab","pmids":["33619246"],"is_preprint":false},{"year":2025,"finding":"ATG2A interacts with SNARE proteins STX17, SNAP29, and VAMP8 and facilitates their assembly; in Neuro-2a cells, ATG2A knockdown reduces colocalization of autophagosomes with Rab7-positive late endosomes/lysosomes, indicating that ATG2A acts as a tether to promote autophagosome-lysosome fusion in neural cells; ATG2A overexpression partially rescues autophagosome-lysosome fusion defects in Wdr45/Wdr45b-deficient cells; ATG2 and EPG5 function partially redundantly in this fusion step.","method":"Knockdown in Neuro-2a cells, co-immunoprecipitation for SNARE interactions, fluorescence colocalization (LC3 with RFP-RAB7), genetic rescue experiments","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of SNARE complex plus genetic KD with colocalization readout and epistasis with EPG5; single lab","pmids":["40083067"],"is_preprint":false},{"year":2025,"finding":"ATG2A promotes lipid droplet expansion by transferring DAG, TAG, and phosphatidic acid from the ER to LDs; ATG2A-mediated DAG transfer recruits DGAT2 to LD surfaces, enabling local TAG synthesis and LD expansion; in ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and new LDs nucleate instead; DGAT2 synergizes with ATG2A for LD expansion.","method":"ATG2A knockout cells with lipid droplet phenotype analysis, in vitro DAG-dependent DGAT2 recruitment assay, lipid tracking","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype and in vitro reconstitution of DGAT2 recruitment; single lab, two orthogonal methods","pmids":["41249819"],"is_preprint":false},{"year":2023,"finding":"ATG2A preferentially binds phospholipid monolayers (such as those surrounding lipid droplets) over bilayers; ATG2A drives phospholipid transport from artificial LDs with rates correlating with binding affinities; a transport-dead ATG2A mutant (TD-ATG2A), with mutations in the bridge interior, specifically blocks bridge-like lipid transport but not shuttle-like transport in vitro, and fails to rescue LD accumulation in ATG2 knockout cells, establishing that bridge-like lipid transport is required for LD homeostasis.","method":"In vitro lipid transfer assays with artificial LDs, membrane-binding assays, site-directed mutagenesis, ATG2 KO rescue experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus mutagenesis plus KO rescue; preprint, single lab","pmids":["37645754"],"is_preprint":true},{"year":2025,"finding":"ATG2A localizes to extra-Golgi ARFGAP1 puncta during autophagosome biogenesis; ATG2A co-immunoprecipitates with RAB1A (albeit indirectly); siRNA depletion of RAB1A/B blocks autophagy downstream of LC3B lipidation, similar to ATG2A depletion; when autophagosome formation or the early secretory pathway is perturbed, ARFGAP1 and RAB1A accumulate at ectopic autophagic machinery sites.","method":"Proximity labeling, fluorescence microscopy, co-immunoprecipitation, siRNA knockdown, epistasis with LC3B lipidation","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP reported as indirect, proximity labeling, preprint, single lab","pmids":["40196537"],"is_preprint":true},{"year":2025,"finding":"Conformational rearrangements of N-terminal amphipathic helices are critical for ATG2A-mediated lipid transport; an ATG2A mutant designed based on MD simulations transfers lipids three times faster than wild type in vitro; in complex with ATG9A, ATG2A forms a bridge between two parallel membranes at ~12 nm separation; the N-terminus acts as a gate with blocking helices that, upon release, act as additional membrane tethers.","method":"Molecular dynamics simulations, structural predictions, in vitro lipid transfer assays, engineered gain-of-function mutant","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 1 method (in vitro assay + mutagenesis) / Weak — preprint, single lab, no independent replication","pmids":["bio_10.1101_2025.11.16.688672"],"is_preprint":true},{"year":2025,"finding":"ATG2A is recruited to ATG9A compartments that initially contain only traces of PI, and mediates lipid transfer including PI into these compartments; ATG8 proteins enhance ATG2A-mediated lipid transfer; ATG2A is essential for the appearance of PI3P on ATG9A compartments in cells, supporting a feedback loop model in which lipid transfer activates ATG9A compartments for phagophore expansion.","method":"In vitro lipid transfer assays, cell-based ATG2A depletion with PI3P localization readout, ATG8 stimulation of lipid transfer assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — in vitro reconstitution plus cell depletion; preprint, single lab, no independent replication","pmids":["bio_10.1101_2025.08.16.670665"],"is_preprint":true},{"year":2025,"finding":"A homozygous missense variant G433A in ATG2A causes mislocalization of ATG2A to the cytosol, loss of colocalization with LC3B, failure of autophagosome formation, and accumulation of protein aggregates in patient-derived fibroblasts, establishing that Gly433 is required for proper ATG2A localization and autophagosome biogenesis.","method":"Patient-derived fibroblast analysis, immunofluorescence colocalization with LC3B, autophagosome formation assay, Proteostat/SQSTM1 aggregate quantification, computational molecular dynamics","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient fibroblast study, no in vitro reconstitution; cellular localization and phenotype established but no independent replication","pmids":["40631414"],"is_preprint":false}],"current_model":"ATG2A is a rod-shaped bridge-like lipid transfer protein that tethers the phagophore to the ER (and other membranes including endosomes and early secretory membranes) via tip interactions, with WIPI4 anchoring one tip to PI3P-enriched donor membranes; it transfers bulk phospholipids through its hydrophobic channel to expand the phagophore, directly coupling to the ATG9A scramblase (3:1 stoichiometry) to achieve vectorial lipid transport and re-equilibration across the bilayer; beyond autophagy, ATG2A transfers DAG, TAG, and PA from the ER to lipid droplets, recruiting DGAT2 to promote LD expansion; ATG2A also functions at a late autophagy stage by interacting with SNARE proteins STX17/SNAP29/VAMP8 to tether autophagosomes to lysosomes for fusion, particularly in neural cells."},"narrative":{"mechanistic_narrative":"ATG2A is a rod-shaped, bridge-like lipid transfer protein that expands the phagophore during autophagosome biogenesis by tethering donor membranes to the growing autophagic membrane and channeling bulk phospholipids through its elongated hydrophobic cavity [PMID:30185561, PMID:31271352, PMID:31441376]. WIPI4 (and WIPI1) bind one tip of ATG2A to anchor the protein stably to PI3P-containing donor membranes, coupling membrane tethering to vectorial lipid transfer between PI3P-rich and PI3P-free vesicles [PMID:30185561, PMID:31271352, PMID:31441376]. ATG2A works in direct partnership with the ATG9A scramblase, assembling a heteromeric complex in which the ATG9A lateral pore aligns with the ATG2A lipid-transfer cavity at a 3:1 ATG9A:ATG2A stoichiometry, so that lipids delivered through ATG2A are re-equilibrated across the bilayer to permit membrane growth [PMID:36347259, PMID:39174844]. Loss of ATG2A blocks autophagosome completion, causing accumulation of immature autophagosomal membranes that drive non-canonical, LC3-conjugation-dependent caspase-8 activation under starvation [PMID:28800131]. Beyond canonical phagophore expansion, ATG2A draws lipids from multiple donor membranes — endosomes via the PI3P-binding partner ANKFY1, which enhances ATG2A lipid transfer in vitro [PMID:38622126] — and acts at lipid droplets, where it transfers DAG, TAG, and phosphatidic acid from the ER and recruits DGAT2 to promote local TAG synthesis and LD expansion [PMID:41249819]. ATG2A additionally functions at a late autophagy step, interacting with the SNAREs STX17/SNAP29/VAMP8 to promote autophagosome–lysosome fusion in neural cells, partially redundantly with EPG5 [PMID:40083067]. A homozygous G433A variant that mislocalizes ATG2A to the cytosol and abolishes autophagosome formation links the protein to a human disease phenotype [PMID:40631414].","teleology":[{"year":2014,"claim":"Before its biochemical activity was known, ATG2A's dual localization established that it operates at both lipid droplets and ER-associated early autophagosomal membranes, hinting at a shared lipid-handling role.","evidence":"Live-imaging colocalization and siRNA knockdown with lipid droplet phenotype quantification in mammalian cells","pmids":["24776541"],"confidence":"Medium","gaps":["Did not define a molecular activity for ATG2A","Mechanism linking LD and autophagosome localization unresolved"]},{"year":2017,"claim":"Genetic deletion showed ATG2A is required for autophagosome completion, placing it at the membrane-maturation step and revealing that its loss diverts immature membranes into a caspase-8 activation platform.","evidence":"ATG2A/B knockout with caspase-8 activation assays and epistasis with LC3 conjugation mutants","pmids":["28800131"],"confidence":"Medium","gaps":["Did not establish the biochemical function underlying completion failure","iDISC relevance beyond starvation untested"]},{"year":2018,"claim":"Structural and tethering work answered how ATG2A bridges membranes, defining it as a rod with membrane-binding tips and WIPI4 as the PI3P-targeting adaptor for ER–phagophore association.","evidence":"Single-particle EM, crosslinking MS, and in vitro vesicle-tethering assays","pmids":["30185561"],"confidence":"High","gaps":["Tethering shown but lipid transfer activity not yet demonstrated","Identity of all donor membranes not defined"]},{"year":2019,"claim":"Reconstitution with purified proteins established ATG2A as a bona fide lipid transfer protein whose transfer is enhanced between tethered vesicles and by WIPI-mediated PI3P anchoring.","evidence":"In vitro lipid transfer and fluorescence lipid-mixing assays with purified proteins","pmids":["31271352","31441376"],"confidence":"High","gaps":["Did not show how transferred lipids re-equilibrate across the bilayer","Cellular lipid source not pinned down"]},{"year":2021,"claim":"A translational-control mechanism showed that ATG2A expression is upregulated via m6A-dependent YTHDF1 binding under hypoxia, coupling autophagy capacity to the tumor microenvironment.","evidence":"MeRIP-seq, polysome profiling, and YTHDF1 perturbation in HCC models","pmids":["33619246"],"confidence":"Medium","gaps":["Regulatory link is indirect to ATG2A protein function","Generality beyond hepatocellular carcinoma untested"]},{"year":2022,"claim":"Identifying the ATG2A–ATG9A heteromeric complex answered how transferred lipids cross the bilayer, showing ATG2A feeds lipids directly into the ATG9A scramblase branch to enable membrane growth.","evidence":"Peptide arrays, XL-MS, HDX-MS, cryo-EM, integrative modeling, and functional autophagy assays","pmids":["36347259"],"confidence":"High","gaps":["Stoichiometry and full architecture not yet resolved","Vectoriality of transfer not directly demonstrated"]},{"year":2024,"claim":"High-resolution structures defined the 3:1 ATG9A:ATG2A architecture with the ATG9A pore aligned to the ATG2A cavity and proposed the lipid-extraction mechanism, completing the structural model of the transfer machine.","evidence":"Cryo-EM (3.2 and 7 Å), cryo-ET, and molecular dynamics simulations","pmids":["39174844"],"confidence":"High","gaps":["Dynamics of lipid loading at the donor tip inferred from MD, not observed directly"]},{"year":2024,"claim":"Discovery of ANKFY1 as an endosomal ATG2A partner identified endosomes as a lipid donor for phagophore expansion and a new PI3P-binding cofactor that enhances transfer.","evidence":"Co-IP, knockdown, colocalization, and in vitro lipid transfer with purified ANKFY1 and PI3P liposomes","pmids":["38622126"],"confidence":"Medium","gaps":["Relative contribution of endosomal vs ER lipid sources unquantified","Structural basis of ANKFY1–ATG2A binding unknown"]},{"year":2025,"claim":"A new late-stage role showed ATG2A tethers autophagosomes to lysosomes via SNARE assembly, extending its function beyond phagophore growth into fusion, particularly in neural cells.","evidence":"Knockdown in Neuro-2a cells, co-IP of STX17/SNAP29/VAMP8, RAB7 colocalization, and EPG5 epistasis","pmids":["40083067"],"confidence":"Medium","gaps":["Whether SNARE tethering uses the lipid-transfer cavity or a separate interface is unknown","Cell-type specificity of this function unresolved"]},{"year":2025,"claim":"Lipid-droplet work showed ATG2A transfers neutral and signaling lipids from ER to LDs and recruits DGAT2 for local TAG synthesis, defining a non-autophagic role in LD expansion.","evidence":"ATG2A knockout LD phenotyping, in vitro DAG-dependent DGAT2 recruitment, and lipid tracking","pmids":["41249819"],"confidence":"Medium","gaps":["Mechanism distinguishing LD vs autophagic targeting not defined","DGAT2 recruitment mechanism beyond DAG binding unclear"]},{"year":2025,"claim":"A patient study tied ATG2A directly to human disease, showing a homozygous G433A variant mislocalizes the protein and abolishes autophagosome formation.","evidence":"Patient-derived fibroblast immunofluorescence, autophagosome and aggregate assays, and MD","pmids":["40631414"],"confidence":"Low","gaps":["Single patient, no in vitro reconstitution of the mutant","Disease causality not confirmed in an independent cohort"]},{"year":null,"claim":"How ATG2A's distinct functions — phagophore expansion, LD lipid transfer, and autophagosome–lysosome fusion — are selected and regulated at a given membrane, and whether they share the same lipid-transfer cavity, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanism for membrane-target selection","Regulation switching between LD and autophagy roles unknown","Whether SNARE-tethering activity requires lipid transfer untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,7,10,11]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5,0,10]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[5,10,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,10]}],"complexes":["ATG2A-WIPI4 complex","ATG2A-ATG9A complex","STX17/SNAP29/VAMP8 SNARE complex"],"partners":["WIPI4","WIPI1","ATG9A","ANKFY1","STX17","SNAP29","VAMP8","DGAT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2TAZ0","full_name":"Autophagy-related protein 2 homolog A","aliases":[],"length_aa":1938,"mass_kda":212.9,"function":"Lipid transfer protein involved in autophagosome assembly (PubMed:28561066, PubMed:30952800, PubMed:31271352). 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:30952800, PubMed:31271352). 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 (PubMed:30952800, PubMed:31271352). Lipid transfer activity is enhanced by WIPI1 and WDR45/WIPI4, which promote ATG2A-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes (PubMed:31271352). Also regulates lipid droplets morphology and distribution within the cell (PubMed:22219374, PubMed:28561066)","subcellular_location":"Preautophagosomal structure membrane; Lipid droplet; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q2TAZ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATG2A","classification":"Not Classified","n_dependent_lines":36,"n_total_lines":1208,"dependency_fraction":0.029801324503311258},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000110046","cell_line_id":"CID001814","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"HIST2H2AA3;HIST2H2AC","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001814","total_profiled":1310},"omim":[{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATG2A"},"hgnc":{"alias_symbol":["KIAA0404","BLTP4A"],"prev_symbol":[]},"alphafold":{"accession":"Q2TAZ0","domains":[{"cath_id":"-","chopping":"249-306_423-443_451-545_553-569_578-611","consensus_level":"medium","plddt":81.0057,"start":249,"end":611},{"cath_id":"-","chopping":"642-651_662-743_812-846","consensus_level":"medium","plddt":86.0264,"start":642,"end":846},{"cath_id":"-","chopping":"1765-1823_1843-1937","consensus_level":"medium","plddt":73.1627,"start":1765,"end":1937},{"cath_id":"3.10.450","chopping":"8-109_156-181","consensus_level":"medium","plddt":76.8462,"start":8,"end":181}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2TAZ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2TAZ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2TAZ0-F1-predicted_aligned_error_v6.png","plddt_mean":67.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATG2A","jax_strain_url":"https://www.jax.org/strain/search?query=ATG2A"},"sequence":{"accession":"Q2TAZ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2TAZ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2TAZ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2TAZ0"}},"corpus_meta":[{"pmid":"33619246","id":"PMC_33619246","title":"HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33619246","citation_count":336,"is_preprint":false},{"pmid":"31271352","id":"PMC_31271352","title":"The autophagic membrane tether ATG2A transfers lipids between membranes.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31271352","citation_count":279,"is_preprint":false},{"pmid":"30185561","id":"PMC_30185561","title":"Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30185561","citation_count":178,"is_preprint":false},{"pmid":"36347259","id":"PMC_36347259","title":"ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.","date":"2022","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/36347259","citation_count":117,"is_preprint":false},{"pmid":"28800131","id":"PMC_28800131","title":"Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/28800131","citation_count":68,"is_preprint":false},{"pmid":"24776541","id":"PMC_24776541","title":"Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells.","date":"2014","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24776541","citation_count":53,"is_preprint":false},{"pmid":"29915313","id":"PMC_29915313","title":"In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29915313","citation_count":45,"is_preprint":false},{"pmid":"39174844","id":"PMC_39174844","title":"Structural basis for lipid transfer by the ATG2A-ATG9A complex.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39174844","citation_count":28,"is_preprint":false},{"pmid":"30766969","id":"PMC_30766969","title":"The rod-shaped ATG2A-WIPI4 complex tethers membranes in vitro.","date":"2018","source":"Contact (Thousand Oaks (Ventura County, Calif.))","url":"https://pubmed.ncbi.nlm.nih.gov/30766969","citation_count":19,"is_preprint":false},{"pmid":"31441376","id":"PMC_31441376","title":"ATG2A transfers lipids between membranes in vitro.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31441376","citation_count":18,"is_preprint":false},{"pmid":"37460467","id":"PMC_37460467","title":"MGCG regulates glioblastoma tumorigenicity via hnRNPK/ATG2A and promotes autophagy.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37460467","citation_count":14,"is_preprint":false},{"pmid":"38622126","id":"PMC_38622126","title":"ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores.","date":"2024","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38622126","citation_count":10,"is_preprint":false},{"pmid":"39697182","id":"PMC_39697182","title":"Highly Efficient Delivery of Novel MiR-13896 by Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Inhibits Gastric Cancer Progression by Targeting ATG2A-Mediated Autophagy.","date":"2024","source":"Biomaterials research","url":"https://pubmed.ncbi.nlm.nih.gov/39697182","citation_count":10,"is_preprint":false},{"pmid":"41249819","id":"PMC_41249819","title":"ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth.","date":"2025","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41249819","citation_count":6,"is_preprint":false},{"pmid":"37645754","id":"PMC_37645754","title":"ATG2A-mediated bridge-like lipid transport regulates lipid droplet accumulation.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37645754","citation_count":6,"is_preprint":false},{"pmid":"40116844","id":"PMC_40116844","title":"ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/40116844","citation_count":4,"is_preprint":false},{"pmid":"40083067","id":"PMC_40083067","title":"ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/40083067","citation_count":3,"is_preprint":false},{"pmid":"40074142","id":"PMC_40074142","title":"Polymyxin B induces pigmentation by upregulating ATG2A-ERK/CREB-MITF-PMEL17 signaling axis.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40074142","citation_count":2,"is_preprint":false},{"pmid":"30258221","id":"PMC_30258221","title":"Author Correction: In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30258221","citation_count":2,"is_preprint":false},{"pmid":"40196537","id":"PMC_40196537","title":"ATG2A engages Rab1a and ARFGAP1 positive membranes during autophagosome biogenesis.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40196537","citation_count":1,"is_preprint":false},{"pmid":"40631414","id":"PMC_40631414","title":"An Unstable ATG2A Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40631414","citation_count":1,"is_preprint":false},{"pmid":"41848282","id":"PMC_41848282","title":"ATG2A connects lipid droplets and the ER to regulate lipid storage.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41848282","citation_count":0,"is_preprint":false},{"pmid":"39633821","id":"PMC_39633821","title":"Crohn's disease after multiple doses of rituximab treatment in a child with refractory nephrotic syndrome and an ATG2A mutation: a case report.","date":"2024","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/39633821","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.16.688672","title":"Pathway and gates for ATG2A-mediated lipid transport in autophagy","date":"2025-11-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.16.688672","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.24.645001","title":"<i>In situ</i>  cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.645001","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.16.670665","title":"A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation","date":"2025-08-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.16.670665","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.24.645038","title":"ATG2A interacts with RAB1A and ARFGAP1 positive membranes during autophagosome biogenesis","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.645038","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14241,"output_tokens":4446,"usd":0.054706,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12426,"output_tokens":3884,"usd":0.079615,"stage2_stop_reason":"end_turn"},"total_usd":0.134321,"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\": 2018,\n      \"finding\": \"ATG2A is a rod-shaped protein that tethers neighboring membranes through interactions at each of its tips; WIPI4 binds to one tip, enabling the ATG2A-WIPI4 complex to specifically tether PI3P-containing vesicles to PI3P-free vesicles, mediating ER-phagophore association.\",\n      \"method\": \"Single-particle electron microscopy, chemical cross-linking coupled with mass spectrometry, and biochemical vesicle-tethering assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal structural and biochemical methods (EM, XL-MS, in vitro tethering assays) in a single rigorous study\",\n      \"pmids\": [\"30185561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human ATG2A is a lipid transfer protein that can extract lipids from membrane vesicles and unload them to other vesicles; lipid transfer is more efficient between tethered vesicles; WIPI4 and WIPI1 associate ATG2A stably to PI3P-containing vesicles, facilitating ATG2A-mediated tethering and lipid transfer between PI3P-containing and PI3P-free vesicles.\",\n      \"method\": \"In vitro lipid transfer assay with membrane vesicles, fluorescence-based lipid mixing assays, reconstitution with purified proteins\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of lipid transfer activity with purified proteins, multiple assay conditions, independently confirmed in companion commentary (PMID:31441376)\",\n      \"pmids\": [\"31271352\", \"31441376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATG9A and ATG2A form a heteromeric complex in which ATG2A facilitates lipid flow between tethered membranes and directly transfers lipids into the lipid-binding perpendicular branch of the ATG9A scramblase; multiple interfaces mediating this interaction were identified and mutational disruption of these interfaces impairs autophagy.\",\n      \"method\": \"Peptide arrays, crosslinking mass spectrometry, hydrogen-deuterium exchange mass spectrometry, cryo-electron microscopy, integrative structural modeling, mutational analyses with functional autophagy assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with XL-MS, HDX-MS, mutagenesis, and functional assays in one study\",\n      \"pmids\": [\"36347259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of human ATG2A-WIPI4 at 3.2 Å and ATG2A-WIPI4-ATG9A at 7 Å revealed a 3:1 stoichiometry of ATG9A-ATG2A complex with the ATG9A lateral pore directly aligned with the ATG2A lipid transfer cavity; ATG9A trimer interacts with both N-terminal and C-terminal tips of rod-shaped ATG2A; cryo-electron tomography showed ATG2A tethers lipid vesicles at different orientations; molecular dynamics simulations proposed a mechanism of lipid extraction from donor membranes.\",\n      \"method\": \"Cryo-electron microscopy (3.2 Å and 7 Å), cryo-electron tomography, molecular dynamics simulations\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures combined with cryo-ET and MD simulations providing mechanistic insight\",\n      \"pmids\": [\"39174844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of ATG2A/B blocks autophagosome completion, leading to accumulation of immature autophagosomal membranes that promote non-canonical caspase-8 activation via an intracellular death-inducing signaling complex (iDISC) upon nutrient starvation; iDISC-induced caspase-8 dimerization and activation on these membranes requires the LC3 conjugation machinery and is independent of the extrinsic apoptosis pathway.\",\n      \"method\": \"ATG2A/B deletion (genetic KO), caspase-8 activation assays, immunofluorescence, co-immunoprecipitation, epistasis with LC3 conjugation mutants\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined phenotype and mechanistic pathway placement; single lab, multiple methods\",\n      \"pmids\": [\"28800131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATG2A localizes to cytoplasmic ADRP-positive lipid droplets that migrate bidirectionally along microtubules; this LD localization is independent of autophagic status; upon nutrient starvation and dependent on PI3P generation, ATG2A is additionally targeted to ER-associated early autophagosomal membranes marked by DFCP1 and WIPI-1; ATG2A is functionally involved in controlling lipid droplet number and size.\",\n      \"method\": \"Fluorescence microscopy (live imaging and colocalization), siRNA knockdown with lipid droplet phenotype quantification, PI3P dependency assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-imaging localization tied to functional consequence (LD number/size), single lab, two orthogonal methods\",\n      \"pmids\": [\"24776541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATG2A is enriched in lipid droplets of quiescent/reverted hepatic stellate cells; ATG2A deficiency in LX-2 cells leads to reduced α-SMA expression, increased perilipin-3, enlarged lipid droplets, and suppression of autophagic flux, indicating a role in linking lipid droplet homeostasis to autophagy and stellate cell activation state.\",\n      \"method\": \"Quantitative proteomics, immunoblotting, siRNA knockdown with lipid droplet and autophagic flux readouts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with multiple readouts but no reconstitution or mechanistic dissection\",\n      \"pmids\": [\"29915313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANKFY1, an endosome-localized FYVE-domain protein, is a novel ATG2A-binding partner; ANKFY1 depletion impairs autophagosome growth and autophagic flux, phenocopying ATG2A/B depletion; ANKFY1 co-localizes with ATG2A between endosomes and phagophores; purified recombinant ANKFY1 binds PI3P and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes in vitro, implicating endosomes as a lipid source for ATG2A-mediated phagophore expansion.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, fluorescence colocalization, in vitro lipid transfer assay with purified recombinant proteins and PI3P liposomes\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding demonstrated plus in vitro reconstitution of enhanced lipid transfer, single lab\",\n      \"pmids\": [\"38622126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1, induced by HIF-1α under hypoxia, promotes translation of ATG2A (and ATG14) by binding to m6A-modified ATG2A mRNA; this mechanism facilitates autophagy in hepatocellular carcinoma cells.\",\n      \"method\": \"Methylated RNA immunoprecipitation sequencing (MeRIP-seq), polysome profiling, proteomics, YTHDF1 KO/KD/OE in HCC cells and organoids\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus polysome profiling demonstrates translational regulation; multiple HCC models; single lab\",\n      \"pmids\": [\"33619246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATG2A interacts with SNARE proteins STX17, SNAP29, and VAMP8 and facilitates their assembly; in Neuro-2a cells, ATG2A knockdown reduces colocalization of autophagosomes with Rab7-positive late endosomes/lysosomes, indicating that ATG2A acts as a tether to promote autophagosome-lysosome fusion in neural cells; ATG2A overexpression partially rescues autophagosome-lysosome fusion defects in Wdr45/Wdr45b-deficient cells; ATG2 and EPG5 function partially redundantly in this fusion step.\",\n      \"method\": \"Knockdown in Neuro-2a cells, co-immunoprecipitation for SNARE interactions, fluorescence colocalization (LC3 with RFP-RAB7), genetic rescue experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of SNARE complex plus genetic KD with colocalization readout and epistasis with EPG5; single lab\",\n      \"pmids\": [\"40083067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATG2A promotes lipid droplet expansion by transferring DAG, TAG, and phosphatidic acid from the ER to LDs; ATG2A-mediated DAG transfer recruits DGAT2 to LD surfaces, enabling local TAG synthesis and LD expansion; in ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and new LDs nucleate instead; DGAT2 synergizes with ATG2A for LD expansion.\",\n      \"method\": \"ATG2A knockout cells with lipid droplet phenotype analysis, in vitro DAG-dependent DGAT2 recruitment assay, lipid tracking\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype and in vitro reconstitution of DGAT2 recruitment; single lab, two orthogonal methods\",\n      \"pmids\": [\"41249819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATG2A preferentially binds phospholipid monolayers (such as those surrounding lipid droplets) over bilayers; ATG2A drives phospholipid transport from artificial LDs with rates correlating with binding affinities; a transport-dead ATG2A mutant (TD-ATG2A), with mutations in the bridge interior, specifically blocks bridge-like lipid transport but not shuttle-like transport in vitro, and fails to rescue LD accumulation in ATG2 knockout cells, establishing that bridge-like lipid transport is required for LD homeostasis.\",\n      \"method\": \"In vitro lipid transfer assays with artificial LDs, membrane-binding assays, site-directed mutagenesis, ATG2 KO rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus mutagenesis plus KO rescue; preprint, single lab\",\n      \"pmids\": [\"37645754\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATG2A localizes to extra-Golgi ARFGAP1 puncta during autophagosome biogenesis; ATG2A co-immunoprecipitates with RAB1A (albeit indirectly); siRNA depletion of RAB1A/B blocks autophagy downstream of LC3B lipidation, similar to ATG2A depletion; when autophagosome formation or the early secretory pathway is perturbed, ARFGAP1 and RAB1A accumulate at ectopic autophagic machinery sites.\",\n      \"method\": \"Proximity labeling, fluorescence microscopy, co-immunoprecipitation, siRNA knockdown, epistasis with LC3B lipidation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP reported as indirect, proximity labeling, preprint, single lab\",\n      \"pmids\": [\"40196537\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conformational rearrangements of N-terminal amphipathic helices are critical for ATG2A-mediated lipid transport; an ATG2A mutant designed based on MD simulations transfers lipids three times faster than wild type in vitro; in complex with ATG9A, ATG2A forms a bridge between two parallel membranes at ~12 nm separation; the N-terminus acts as a gate with blocking helices that, upon release, act as additional membrane tethers.\",\n      \"method\": \"Molecular dynamics simulations, structural predictions, in vitro lipid transfer assays, engineered gain-of-function mutant\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 method (in vitro assay + mutagenesis) / Weak — preprint, single lab, no independent replication\",\n      \"pmids\": [\"bio_10.1101_2025.11.16.688672\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATG2A is recruited to ATG9A compartments that initially contain only traces of PI, and mediates lipid transfer including PI into these compartments; ATG8 proteins enhance ATG2A-mediated lipid transfer; ATG2A is essential for the appearance of PI3P on ATG9A compartments in cells, supporting a feedback loop model in which lipid transfer activates ATG9A compartments for phagophore expansion.\",\n      \"method\": \"In vitro lipid transfer assays, cell-based ATG2A depletion with PI3P localization readout, ATG8 stimulation of lipid transfer assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro reconstitution plus cell depletion; preprint, single lab, no independent replication\",\n      \"pmids\": [\"bio_10.1101_2025.08.16.670665\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A homozygous missense variant G433A in ATG2A causes mislocalization of ATG2A to the cytosol, loss of colocalization with LC3B, failure of autophagosome formation, and accumulation of protein aggregates in patient-derived fibroblasts, establishing that Gly433 is required for proper ATG2A localization and autophagosome biogenesis.\",\n      \"method\": \"Patient-derived fibroblast analysis, immunofluorescence colocalization with LC3B, autophagosome formation assay, Proteostat/SQSTM1 aggregate quantification, computational molecular dynamics\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient fibroblast study, no in vitro reconstitution; cellular localization and phenotype established but no independent replication\",\n      \"pmids\": [\"40631414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATG2A is a rod-shaped bridge-like lipid transfer protein that tethers the phagophore to the ER (and other membranes including endosomes and early secretory membranes) via tip interactions, with WIPI4 anchoring one tip to PI3P-enriched donor membranes; it transfers bulk phospholipids through its hydrophobic channel to expand the phagophore, directly coupling to the ATG9A scramblase (3:1 stoichiometry) to achieve vectorial lipid transport and re-equilibration across the bilayer; beyond autophagy, ATG2A transfers DAG, TAG, and PA from the ER to lipid droplets, recruiting DGAT2 to promote LD expansion; ATG2A also functions at a late autophagy stage by interacting with SNARE proteins STX17/SNAP29/VAMP8 to tether autophagosomes to lysosomes for fusion, particularly in neural cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATG2A is a rod-shaped, bridge-like lipid transfer protein that expands the phagophore during autophagosome biogenesis by tethering donor membranes to the growing autophagic membrane and channeling bulk phospholipids through its elongated hydrophobic cavity [#0, #1]. WIPI4 (and WIPI1) bind one tip of ATG2A to anchor the protein stably to PI3P-containing donor membranes, coupling membrane tethering to vectorial lipid transfer between PI3P-rich and PI3P-free vesicles [#0, #1]. ATG2A works in direct partnership with the ATG9A scramblase, assembling a heteromeric complex in which the ATG9A lateral pore aligns with the ATG2A lipid-transfer cavity at a 3:1 ATG9A:ATG2A stoichiometry, so that lipids delivered through ATG2A are re-equilibrated across the bilayer to permit membrane growth [#2, #3]. Loss of ATG2A blocks autophagosome completion, causing accumulation of immature autophagosomal membranes that drive non-canonical, LC3-conjugation-dependent caspase-8 activation under starvation [#4]. Beyond canonical phagophore expansion, ATG2A draws lipids from multiple donor membranes — endosomes via the PI3P-binding partner ANKFY1, which enhances ATG2A lipid transfer in vitro [#7] — and acts at lipid droplets, where it transfers DAG, TAG, and phosphatidic acid from the ER and recruits DGAT2 to promote local TAG synthesis and LD expansion [#10]. ATG2A additionally functions at a late autophagy step, interacting with the SNAREs STX17/SNAP29/VAMP8 to promote autophagosome–lysosome fusion in neural cells, partially redundantly with EPG5 [#9]. A homozygous G433A variant that mislocalizes ATG2A to the cytosol and abolishes autophagosome formation links the protein to a human disease phenotype [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before its biochemical activity was known, ATG2A's dual localization established that it operates at both lipid droplets and ER-associated early autophagosomal membranes, hinting at a shared lipid-handling role.\",\n      \"evidence\": \"Live-imaging colocalization and siRNA knockdown with lipid droplet phenotype quantification in mammalian cells\",\n      \"pmids\": [\"24776541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define a molecular activity for ATG2A\", \"Mechanism linking LD and autophagosome localization unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic deletion showed ATG2A is required for autophagosome completion, placing it at the membrane-maturation step and revealing that its loss diverts immature membranes into a caspase-8 activation platform.\",\n      \"evidence\": \"ATG2A/B knockout with caspase-8 activation assays and epistasis with LC3 conjugation mutants\",\n      \"pmids\": [\"28800131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish the biochemical function underlying completion failure\", \"iDISC relevance beyond starvation untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural and tethering work answered how ATG2A bridges membranes, defining it as a rod with membrane-binding tips and WIPI4 as the PI3P-targeting adaptor for ER–phagophore association.\",\n      \"evidence\": \"Single-particle EM, crosslinking MS, and in vitro vesicle-tethering assays\",\n      \"pmids\": [\"30185561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tethering shown but lipid transfer activity not yet demonstrated\", \"Identity of all donor membranes not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstitution with purified proteins established ATG2A as a bona fide lipid transfer protein whose transfer is enhanced between tethered vesicles and by WIPI-mediated PI3P anchoring.\",\n      \"evidence\": \"In vitro lipid transfer and fluorescence lipid-mixing assays with purified proteins\",\n      \"pmids\": [\"31271352\", \"31441376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show how transferred lipids re-equilibrate across the bilayer\", \"Cellular lipid source not pinned down\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A translational-control mechanism showed that ATG2A expression is upregulated via m6A-dependent YTHDF1 binding under hypoxia, coupling autophagy capacity to the tumor microenvironment.\",\n      \"evidence\": \"MeRIP-seq, polysome profiling, and YTHDF1 perturbation in HCC models\",\n      \"pmids\": [\"33619246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulatory link is indirect to ATG2A protein function\", \"Generality beyond hepatocellular carcinoma untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying the ATG2A–ATG9A heteromeric complex answered how transferred lipids cross the bilayer, showing ATG2A feeds lipids directly into the ATG9A scramblase branch to enable membrane growth.\",\n      \"evidence\": \"Peptide arrays, XL-MS, HDX-MS, cryo-EM, integrative modeling, and functional autophagy assays\",\n      \"pmids\": [\"36347259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and full architecture not yet resolved\", \"Vectoriality of transfer not directly demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"High-resolution structures defined the 3:1 ATG9A:ATG2A architecture with the ATG9A pore aligned to the ATG2A cavity and proposed the lipid-extraction mechanism, completing the structural model of the transfer machine.\",\n      \"evidence\": \"Cryo-EM (3.2 and 7 Å), cryo-ET, and molecular dynamics simulations\",\n      \"pmids\": [\"39174844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of lipid loading at the donor tip inferred from MD, not observed directly\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of ANKFY1 as an endosomal ATG2A partner identified endosomes as a lipid donor for phagophore expansion and a new PI3P-binding cofactor that enhances transfer.\",\n      \"evidence\": \"Co-IP, knockdown, colocalization, and in vitro lipid transfer with purified ANKFY1 and PI3P liposomes\",\n      \"pmids\": [\"38622126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of endosomal vs ER lipid sources unquantified\", \"Structural basis of ANKFY1–ATG2A binding unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A new late-stage role showed ATG2A tethers autophagosomes to lysosomes via SNARE assembly, extending its function beyond phagophore growth into fusion, particularly in neural cells.\",\n      \"evidence\": \"Knockdown in Neuro-2a cells, co-IP of STX17/SNAP29/VAMP8, RAB7 colocalization, and EPG5 epistasis\",\n      \"pmids\": [\"40083067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNARE tethering uses the lipid-transfer cavity or a separate interface is unknown\", \"Cell-type specificity of this function unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lipid-droplet work showed ATG2A transfers neutral and signaling lipids from ER to LDs and recruits DGAT2 for local TAG synthesis, defining a non-autophagic role in LD expansion.\",\n      \"evidence\": \"ATG2A knockout LD phenotyping, in vitro DAG-dependent DGAT2 recruitment, and lipid tracking\",\n      \"pmids\": [\"41249819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism distinguishing LD vs autophagic targeting not defined\", \"DGAT2 recruitment mechanism beyond DAG binding unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A patient study tied ATG2A directly to human disease, showing a homozygous G433A variant mislocalizes the protein and abolishes autophagosome formation.\",\n      \"evidence\": \"Patient-derived fibroblast immunofluorescence, autophagosome and aggregate assays, and MD\",\n      \"pmids\": [\"40631414\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single patient, no in vitro reconstitution of the mutant\", \"Disease causality not confirmed in an independent cohort\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATG2A's distinct functions — phagophore expansion, LD lipid transfer, and autophagosome–lysosome fusion — are selected and regulated at a given membrane, and whether they share the same lipid-transfer cavity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism for membrane-target selection\", \"Regulation switching between LD and autophagy roles unknown\", \"Whether SNARE-tethering activity requires lipid transfer untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 7, 10, 11]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5, 0, 10]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [5, 10, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [\n      \"ATG2A-WIPI4 complex\",\n      \"ATG2A-ATG9A complex\",\n      \"STX17/SNAP29/VAMP8 SNARE complex\"\n    ],\n    \"partners\": [\n      \"WIPI4\",\n      \"WIPI1\",\n      \"ATG9A\",\n      \"ANKFY1\",\n      \"STX17\",\n      \"SNAP29\",\n      \"VAMP8\",\n      \"DGAT2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}