Affinage

ATG2A

Autophagy-related protein 2 homolog A · UniProt Q2TAZ0

Length
1938 aa
Mass
212.9 kDa
Annotated
2026-06-09
23 papers in source corpus 17 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2014 Medium

    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

    PMID:24776541

    Open questions at the time
    • Did not define a molecular activity for ATG2A
    • Mechanism linking LD and autophagosome localization unresolved
  2. 2017 Medium

    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

    PMID:28800131

    Open questions at the time
    • Did not establish the biochemical function underlying completion failure
    • iDISC relevance beyond starvation untested
  3. 2018 High

    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

    PMID:30185561

    Open questions at the time
    • Tethering shown but lipid transfer activity not yet demonstrated
    • Identity of all donor membranes not defined
  4. 2019 High

    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

    PMID:31271352 PMID:31441376

    Open questions at the time
    • Did not show how transferred lipids re-equilibrate across the bilayer
    • Cellular lipid source not pinned down
  5. 2021 Medium

    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

    PMID:33619246

    Open questions at the time
    • Regulatory link is indirect to ATG2A protein function
    • Generality beyond hepatocellular carcinoma untested
  6. 2022 High

    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

    PMID:36347259

    Open questions at the time
    • Stoichiometry and full architecture not yet resolved
    • Vectoriality of transfer not directly demonstrated
  7. 2024 High

    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

    PMID:39174844

    Open questions at the time
    • Dynamics of lipid loading at the donor tip inferred from MD, not observed directly
  8. 2024 Medium

    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

    PMID:38622126

    Open questions at the time
    • Relative contribution of endosomal vs ER lipid sources unquantified
    • Structural basis of ANKFY1–ATG2A binding unknown
  9. 2025 Medium

    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

    PMID:40083067

    Open questions at the time
    • Whether SNARE tethering uses the lipid-transfer cavity or a separate interface is unknown
    • Cell-type specificity of this function unresolved
  10. 2025 Medium

    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

    PMID:41249819

    Open questions at the time
    • Mechanism distinguishing LD vs autophagic targeting not defined
    • DGAT2 recruitment mechanism beyond DAG binding unclear
  11. 2025 Low

    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

    PMID:40631414

    Open questions at the time
    • Single patient, no in vitro reconstitution of the mutant
    • Disease causality not confirmed in an independent cohort

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No mechanism for membrane-target selection
  • Regulation switching between LD and autophagy roles unknown
  • Whether SNARE-tethering activity requires lipid transfer untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0060090 molecular adaptor activity 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005811 lipid droplet 3 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1430728 Metabolism 2
Partners
ANKFY1ATG9ADGAT2SNAP29STX17VAMP8WIPI1WIPI4
Complex memberships
ATG2A-ATG9A complexATG2A-WIPI4 complexSTX17/SNAP29/VAMP8 SNARE complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. Single-particle electron microscopy, chemical cross-linking coupled with mass spectrometry, and biochemical vesicle-tethering assays Proceedings of the National Academy of Sciences of the United States of America High 30185561
2019 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. In vitro lipid transfer assay with membrane vesicles, fluorescence-based lipid mixing assays, reconstitution with purified proteins eLife High 31271352 31441376
2022 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. Peptide arrays, crosslinking mass spectrometry, hydrogen-deuterium exchange mass spectrometry, cryo-electron microscopy, integrative structural modeling, mutational analyses with functional autophagy assays Molecular cell High 36347259
2024 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. Cryo-electron microscopy (3.2 Å and 7 Å), cryo-electron tomography, molecular dynamics simulations Nature structural & molecular biology High 39174844
2017 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. ATG2A/B deletion (genetic KO), caspase-8 activation assays, immunofluorescence, co-immunoprecipitation, epistasis with LC3 conjugation mutants Cell death and differentiation Medium 28800131
2014 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. Fluorescence microscopy (live imaging and colocalization), siRNA knockdown with lipid droplet phenotype quantification, PI3P dependency assay Journal of lipid research Medium 24776541
2018 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. Quantitative proteomics, immunoblotting, siRNA knockdown with lipid droplet and autophagic flux readouts Scientific reports Low 29915313
2024 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. Co-immunoprecipitation, siRNA knockdown, fluorescence colocalization, in vitro lipid transfer assay with purified recombinant proteins and PI3P liposomes Cell discovery Medium 38622126
2021 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. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), polysome profiling, proteomics, YTHDF1 KO/KD/OE in HCC cells and organoids Signal transduction and targeted therapy Medium 33619246
2025 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. Knockdown in Neuro-2a cells, co-immunoprecipitation for SNARE interactions, fluorescence colocalization (LC3 with RFP-RAB7), genetic rescue experiments Autophagy Medium 40083067
2025 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. ATG2A knockout cells with lipid droplet phenotype analysis, in vitro DAG-dependent DGAT2 recruitment assay, lipid tracking Nature structural & molecular biology Medium 41249819
2023 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. In vitro lipid transfer assays with artificial LDs, membrane-binding assays, site-directed mutagenesis, ATG2 KO rescue experiments bioRxivpreprint Medium 37645754
2025 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. Proximity labeling, fluorescence microscopy, co-immunoprecipitation, siRNA knockdown, epistasis with LC3B lipidation bioRxivpreprint Low 40196537
2025 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. Molecular dynamics simulations, structural predictions, in vitro lipid transfer assays, engineered gain-of-function mutant bioRxivpreprint Low bio_10.1101_2025.11.16.688672
2025 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. In vitro lipid transfer assays, cell-based ATG2A depletion with PI3P localization readout, ATG8 stimulation of lipid transfer assay bioRxivpreprint Low bio_10.1101_2025.08.16.670665
2025 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. Patient-derived fibroblast analysis, immunofluorescence colocalization with LC3B, autophagosome formation assay, Proteostat/SQSTM1 aggregate quantification, computational molecular dynamics Clinical genetics Low 40631414

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Signal transduction and targeted therapy 336 33619246
2019 The autophagic membrane tether ATG2A transfers lipids between membranes. eLife 279 31271352
2018 Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex. Proceedings of the National Academy of Sciences of the United States of America 178 30185561
2022 ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation. Molecular cell 117 36347259
2017 Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis. Cell death and differentiation 68 28800131
2014 Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells. Journal of lipid research 53 24776541
2018 In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A. Scientific reports 45 29915313
2024 Structural basis for lipid transfer by the ATG2A-ATG9A complex. Nature structural & molecular biology 28 39174844
2018 The rod-shaped ATG2A-WIPI4 complex tethers membranes in vitro. Contact (Thousand Oaks (Ventura County, Calif.)) 19 30766969
2019 ATG2A transfers lipids between membranes in vitro. Autophagy 18 31441376
2023 MGCG regulates glioblastoma tumorigenicity via hnRNPK/ATG2A and promotes autophagy. Cell death & disease 14 37460467
2024 ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores. Cell discovery 10 38622126
2024 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. Biomaterials research 10 39697182
2025 ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth. Nature structural & molecular biology 6 41249819
2023 ATG2A-mediated bridge-like lipid transport regulates lipid droplet accumulation. bioRxiv : the preprint server for biology 6 37645754
2025 ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation. Autophagy 4 40116844
2025 ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells. Autophagy 3 40083067
2025 Polymyxin B induces pigmentation by upregulating ATG2A-ERK/CREB-MITF-PMEL17 signaling axis. Life sciences 2 40074142
2018 Author Correction: In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A. Scientific reports 2 30258221
2025 ATG2A engages Rab1a and ARFGAP1 positive membranes during autophagosome biogenesis. bioRxiv : the preprint server for biology 1 40196537
2025 An Unstable ATG2A Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy. Clinical genetics 1 40631414
2026 ATG2A connects lipid droplets and the ER to regulate lipid storage. Autophagy 0 41848282
2024 Crohn's disease after multiple doses of rituximab treatment in a child with refractory nephrotic syndrome and an ATG2A mutation: a case report. Frontiers in pediatrics 0 39633821

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