Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000407 phagophore assembly site	IBA GO_REF:0000033	ACCEPT	Summary: ATG2A acts at the phagophore assembly site during autophagosome biogenesis. Reason: Accept as a core location/context. Human ATG2A localizes to ER-phagophore/autophagophore contact sites and functions in lipid transfer during phagophore expansion; the IBA assignment is consistent with direct human evidence and the conserved ATG2/Atg18 autophagy module. Supporting Evidence: PMID:30952800 localization of human ATG2A to contact sites between the ER and the autophagophore file:human/ATG2A/ATG2A-uniprot.txt Localizes to endoplasmic reticulum-autophagosome contact sites.
GO:0000422 autophagy of mitochondrion	IBA GO_REF:0000033	MODIFY	Summary: Mitophagy is too cargo-specific for ATG2A based on the available human evidence. Reason: ATG2A is required for phagophore expansion and can be recruited to ER-mitochondria contact sites, but the cached human ATG2A evidence supports general autophagosome assembly rather than an ATG2A-specific mitophagy cargo-selection function. The safer PN interpretation is core autophagosome biogenesis, not cargo-specific mitochondrial autophagy. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:31412244 mammalian Atg2A/B functions at the membrane expansion step during autophagosome biogenesis PMID:31412244 Atg2A translocates to the autophagosome formation site at the ER-mitochondria contact site
GO:0061908 phagophore	IBA GO_REF:0000033	ACCEPT	Summary: ATG2A is active at the expanding phagophore. Reason: Accept as a core cellular context. ATG2A is placed at the phagophore/ER interface and promotes phagophore expansion by lipid transfer and tethering. Supporting Evidence: PMID:31271352 we place the ATG2-WIPI complex between the ER and the phagophore edge file:human/ATG2A/ATG2A-uniprot.txt Tethers the edge of the isolation membrane (IM) to the endoplasmic reticulum (ER)
GO:0000425 pexophagy	IBA GO_REF:0000033	MODIFY	Summary: Pexophagy over-specifies the supported ATG2A process role. Reason: ATG2A is core autophagosome-biogenesis machinery. The available human evidence does not establish an ATG2A-specific role in peroxisome cargo recognition or peroxisome-selective autophagy, so this cargo-specific IBA should be generalized. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:30952800 protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation PMID:31271352 ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion
GO:0043495 protein-membrane adaptor activity	IBA GO_REF:0000033	ACCEPT	Summary: ATG2A has a core membrane-adaptor/tethering role at ER-phagophore contact sites. Reason: Accept as a core molecular function. ATG2A couples WIPI/Atg18-family PI3P effectors, ATG9A-containing membranes, and ER/phagophore membranes in a lipid-transfer assembly. This term captures the adaptor/tether aspect of the function alongside the more direct lipid transfer activity term. Supporting Evidence: PMID:31271352 ATG2 stably tethers two membranes and transfers lipids between them PMID:39174844 ATG2A tethers lipid vesicles at different orientations
GO:0061723 glycophagy	IBA GO_REF:0000033	MODIFY	Summary: Glycophagy is too cargo-specific for the reviewed ATG2A evidence. Reason: The evidence supports ATG2A as general phagophore expansion machinery. No cached human evidence shows that ATG2A specifically recognizes glycogen cargo or has a glycophagy-selective role independent of its core autophagosome-assembly function. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:30952800 fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells PMID:31271352 ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion
GO:0032266 phosphatidylinositol-3-phosphate binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: PI3P-associated recruitment is supported, but direct ATG2A PI3P binding is not established. Reason: Human ATG2A is recruited to PI3P-rich phagophore membranes through WIPI/Atg18-family effectors. The accessible evidence supports WIPI-mediated association with PI3P-containing membranes rather than ATG2A itself independently enabling phosphatidylinositol-3-phosphate binding. Supporting Evidence: PMID:31271352 WIPI4 and WIPI1 associate ATG2A stably to PI3P-containing vesicles PMID:32483132 WIPI proteins tend to recognize phosphoinositides and the WIR-peptide simultaneously
GO:0034727 piecemeal microautophagy of the nucleus	IBA GO_REF:0000033	MODIFY	Summary: Nucleophagy/PMN over-specifies the conserved ATG2A autophagy role. Reason: The annotation projects a cargo- and pathway-specific yeast selective-autophagy process to human ATG2A. Human ATG2A evidence supports autophagosome biogenesis through lipid transfer, not a direct ATG2A-specific role in piecemeal nuclear microautophagy. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:30952800 lipid transfer across contact sites is a principal contributor to autophagosome formation PMID:31271352 transfer of ER lipids to the phagophore, driving phagophore expansion
GO:0061709 reticulophagy	IBA GO_REF:0000033	MODIFY	Summary: Reticulophagy is plausible pathway context but not an ATG2A-specific cargo claim. Reason: ATG2A functions at ER-phagophore contact sites, but that does not by itself establish a selective ER-autophagy role for ATG2A. The conservative replacement is the general autophagosome-assembly process supported by direct lipid-transfer and rescue data. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:30952800 operating at the ER-autophagosome interface PMID:31271352 ATG2-mediated transfer of lipids from the ER to the phagophore
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: ER membrane localization is supported and central to ATG2A function. Reason: Accept. UniProt subcellular-location mapping agrees with direct human evidence placing ATG2A at ER-autophagosome/phagophore contact sites, where it mediates lipid transfer from ER-associated donor membranes. Supporting Evidence: PMID:30952800 operating at the ER-autophagosome interface file:human/ATG2A/ATG2A-uniprot.txt Endoplasmic reticulum membrane
GO:0005811 lipid droplet	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Lipid-droplet association is supported but secondary to the core autophagosome-biogenesis role. Reason: Keep as non-core. ATG2A has a documented lipid-droplet association and affects lipid-droplet morphology, but the PN-relevant core function is ER/phagophore lipid transfer for autophagosome assembly. Supporting Evidence: file:human/ATG2A/ATG2A-uniprot.txt Also regulates lipid droplets morphology and distribution within the cell
GO:0006914 autophagy	IEA GO_REF:0000002	MODIFY	Summary: Autophagy is correct but too broad for the reviewed ATG2A process. Reason: ATG2A is not merely associated with generic autophagy; direct experiments support a more specific role in autophagosome assembly through phagophore expansion and lipid transfer. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:30952800 lipid transfer across contact sites is a principal contributor to autophagosome formation PMID:31271352 ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion
GO:0034045 phagophore assembly site membrane	IEA GO_REF:0000044	ACCEPT	Summary: ATG2A localizes to the phagophore assembly site membrane. Reason: Accept. This location is supported by UniProt subcellular mapping and direct imaging/biochemical evidence placing ATG2A at the ER-phagophore edge. Supporting Evidence: PMID:31271352 between the ER and the phagophore edge file:human/ATG2A/ATG2A-uniprot.txt Preautophagosomal structure membrane
GO:0120009 intermembrane lipid transfer	IEA GO_REF:0000108	ACCEPT	Summary: ATG2A mediates intermembrane lipid transfer during phagophore expansion. Reason: Accept as a core biological process. The logical inference from lipid transfer activity is directly consistent with in vitro lipid-transfer assays, structural work, and cellular rescue data. Supporting Evidence: PMID:30952800 ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro PMID:39174844 mediating lipid transfer and re-equilibration between membranes for autophagosome formation
GO:0005515 protein binding	IPI PMID:20562859 Network organization of the human autophagy system.	MARK AS OVER ANNOTATED	Summary: Large-scale interaction evidence is real but generic protein binding is not informative. Reason: The Behrends et al. autophagy interaction network places ATG2A among ATG8/WIPI-associated autophagy proteins, but GO:0005515 does not capture ATG2A's actual molecular function. The informative functions are lipid transfer, membrane tether/adaptor activity, and ATG2-WIPI/Atg18 complex membership. Supporting Evidence: PMID:20562859 a network of 751 interactions among 409 candidate interacting proteins PMID:31271352 ATG2 stably tethers two membranes and transfers lipids between them
GO:0005515 protein binding	IPI PMID:31412244 TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes f...	MARK AS OVER ANNOTATED	Summary: ATG2A interactions with TOM40, ATG9A, and WIPI4 are functional context, not generic MF. Reason: The interactions in this study are biologically meaningful for MAM recruitment and phagophore growth, but generic protein binding should not be retained as the functional statement. The better-curated assertions are organelle membrane contact site, autophagosome assembly, and lipid-transfer/adaptor roles. Supporting Evidence: PMID:31412244 Atg2A directly interacts with Atg9A at the MAM to promote phagophore growth PMID:31412244 TOM70-TOM40 complex recruits Atg2A to the MAM
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: High-throughput binary interactome protein binding is not informative for ATG2A function. Reason: The binary interactome row does not add a mechanistic ATG2A function beyond generic protein binding and is not central to the autophagy/lipid-transfer evidence. It should not be treated as a core MF. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005515 protein binding	IPI PMID:32483132 Multi-site-mediated entwining of the linear WIR-motif around...	MARK AS OVER ANNOTATED	Summary: WIPI3/WIPI4 binding is specific evidence for the ATG2-WIPI/Atg18 complex, not generic binding. Reason: This structural evidence supports a specific WIR-mediated association of ATG2A with WIPI beta-propellers, not generic protein binding as a useful molecular-function statement. Because GO:0062079 is a cellular-component term, the complex context is captured separately as a NEW annotation rather than as a replacement for this MF row. Supporting Evidence: PMID:32483132 WIPI4 forms a complex with ATG2A/B PMID:32483132 disrupt the interactions between WIPI3/4 and ATG2A and impair the ATG2A-mediated autophagic process
GO:0010508 positive regulation of autophagy	IMP PMID:32483132 Multi-site-mediated entwining of the linear WIR-motif around...	MODIFY	Summary: ATG2A-WIPI disruption impairs autophagy, but ATG2A is core assembly machinery rather than only a regulator. Reason: The evidence shows that disrupting ATG2A-WIPI interactions impairs the ATG2A-mediated autophagic process. For ATG2A itself, the more direct process term is autophagosome assembly. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:32483132 impair the ATG2A-mediated autophagic process PMID:31271352 Direct tethering of the ER and the phagophore edge by the ATG2-WIPI complex
GO:0120013 lipid transfer activity	IMP PMID:39174844 Structural basis for lipid transfer by the ATG2A-ATG9A compl...	ACCEPT	Summary: Structural data support ATG2A lipid transfer activity with ATG9A/WIPI4 complexes. Reason: Accept as core molecular function. Structural and mechanistic evidence supports ATG2A as a lipid-transfer protein whose cavity and ATG9A/WIPI4-associated assemblies mediate lipid transfer during autophagosome formation. Supporting Evidence: PMID:39174844 Structural basis for lipid transfer by the ATG2A-ATG9A complex PMID:39174844 human ATG2A in complex with WD-repeat protein interacting with phosphoinositides 4
GO:0005789 endoplasmic reticulum membrane	EXP PMID:30952800 ATG2 transports lipids to promote autophagosome biogenesis.	ACCEPT	Summary: Direct evidence places ATG2A at the ER/autophagosome interface. Reason: Accept. This experimentally supported location is central to ATG2A's lipid-transfer function during phagophore expansion. Supporting Evidence: PMID:30952800 operating at the ER-autophagosome interface file:human/ATG2A/ATG2A-uniprot.txt Endoplasmic reticulum membrane
GO:0005811 lipid droplet	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Lipid-droplet localization is supported by homology/UniProt but is non-core for this review. Reason: Keep as non-core. ATG2-family lipid-droplet association is compatible with UniProt, but the core human ATG2A role for this PN-focused review is lipid transfer at ER/phagophore contact sites. Supporting Evidence: file:human/ATG2A/ATG2A-uniprot.txt Lipid droplet
GO:0034045 phagophore assembly site membrane	EXP PMID:30952800 ATG2 transports lipids to promote autophagosome biogenesis.	ACCEPT	Summary: Direct experimental evidence supports ATG2A at the phagophore assembly site membrane. Reason: Accept as a core location. ATG2A is positioned at ER-phagophore contact sites where lipid transfer supports phagophore expansion. Supporting Evidence: PMID:30952800 contact sites between the ER and the autophagophore PMID:31271352 we place the ATG2-WIPI complex between the ER and the phagophore edge
GO:0044232 organelle membrane contact site	IDA PMID:30952800 ATG2 transports lipids to promote autophagosome biogenesis.	ACCEPT	Summary: ATG2A is active at organelle membrane contact sites during autophagosome formation. Reason: Accept. ATG2A is a contact-site lipid-transfer protein, with direct evidence for ER-autophagophore localization and functional lipid transfer across membranes. Supporting Evidence: PMID:30952800 protein-mediated lipid transfer across contact sites is a principal contributor PMID:31271352 ATG2 stably tethers two membranes and transfers lipids between them
GO:0120013 lipid transfer activity	IDA PMID:30952800 ATG2 transports lipids to promote autophagosome biogenesis.	ACCEPT	Summary: Direct biochemical evidence supports ATG2A lipid transfer activity. Reason: Accept as core molecular function. Purified human ATG2A binds multiple glycerophospholipids and transfers lipids between membranes in vitro, and lipid-transfer-competent ATG2A fragments rescue autophagosome biogenesis. Supporting Evidence: PMID:30952800 ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro PMID:30952800 fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells
GO:0120013 lipid transfer activity	IDA PMID:31271352 The autophagic membrane tether ATG2A transfers lipids betwee...	ACCEPT	Summary: ATG2A lipid transfer activity is directly demonstrated and WIPI-facilitated. Reason: Accept as core molecular function. This study directly demonstrates human ATG2A lipid transfer, membrane tethering, and WIPI-enhanced association with PI3P-containing membranes. Supporting Evidence: PMID:31271352 human ATG2A is a lipid transfer protein PMID:31271352 WIPI proteins can facilitate ATG2A-mediated lipid transfer
GO:2000786 positive regulation of autophagosome assembly	IDA PMID:30952800 ATG2 transports lipids to promote autophagosome biogenesis.	MODIFY	Summary: ATG2A directly participates in autophagosome assembly rather than only regulating it. Reason: ATG2A lipid transfer supplies membrane for phagophore expansion, making autophagosome assembly the more direct process term. The regulation term is directionally true but less precise for a core autophagy machinery component. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:30952800 protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation PMID:30952800 rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells
GO:2000786 positive regulation of autophagosome assembly	IDA PMID:31271352 The autophagic membrane tether ATG2A transfers lipids betwee...	MODIFY	Summary: WIPI-facilitated ATG2A lipid transfer supports autophagosome assembly. Reason: The direct functional role is phagophore expansion/autophagosome assembly via lipid transfer. Use autophagosome assembly rather than a regulation term for this core machinery activity. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:31271352 transfer of ER lipids to the phagophore, driving phagophore expansion PMID:31271352 WIPI proteins can facilitate ATG2A-mediated lipid transfer
GO:0000045 autophagosome assembly	IMP PMID:28561066 WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-...	ACCEPT	Summary: ATG2A is a core autophagosome-assembly factor. Reason: Accept as core process. WIPI4-ATG2 translocates to nascent autophagosomes and later studies show ATG2A lipid transfer and tethering drive phagophore expansion. Supporting Evidence: PMID:28561066 WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes PMID:30952800 protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation
GO:0005515 protein binding	IPI PMID:28561066 WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-...	MARK AS OVER ANNOTATED	Summary: WIPI4 interaction should be represented as ATG2-WIPI/Atg18 complex context, not generic binding. Reason: The biologically meaningful claim is ATG2A association with WIPI4/WDR45 in the autophagy machinery. Generic protein binding is over-annotated for this evidence, and the GO:0062079 cellular-component complex context is captured separately as a NEW annotation rather than as a replacement for this MF row. Supporting Evidence: PMID:28561066 WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex PMID:31271352 we place the ATG2-WIPI complex between the ER and the phagophore edge
GO:0062079 ATG2-ATG18 complex	IDA PMID:31271352 The autophagic membrane tether ATG2A transfers lipids betwee...	NEW	Summary: The PN-projected ATG2-ATG18 complex term is a conservative, supported component annotation. Reason: The Proteostasis PN projection proposes GO:0062079 for the ATG2-WIPI complex component bucket. This is more precise than the existing phagophore assembly site locations and is supported by human ATG2A evidence showing ATG2-WIPI complexes at the ER-phagophore edge. The GO term uses the yeast Atg18 name, but mammalian WIPI proteins are Atg18-family PROPPINs, so this is a reasonable component-level propagation; it should not be expanded into cargo-specific selective-autophagy process annotations. Supporting Evidence: PMID:31271352 we place the ATG2-WIPI complex between the ER and the phagophore edge PMID:32483132 WIPI4 forms a complex with ATG2A/B file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml The GO ATG2-ATG18 complex term is the closest component-level target.

Core Functions

ATG2A is a high-capacity glycerophospholipid transfer protein that tethers donor and acceptor membranes at ER-phagophore contact sites and supplies lipids for phagophore expansion during autophagosome assembly.

Molecular Function:

lipid transfer activity

Directly Involved In:

intermembrane lipid transfer autophagosome assembly

Cellular Locations:

organelle membrane contact site phagophore assembly site membrane endoplasmic reticulum membrane

Supporting Evidence:

PMID:30952800
ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro
PMID:31271352
ATG2 stably tethers two membranes and transfers lipids between them

ATG2A forms an ATG2-WIPI/Atg18-family complex at PI3P-rich phagophore edges, linking WIPI phosphoinositide effectors and ATG2A lipid-transfer activity to membrane expansion.

Molecular Function:

protein-membrane adaptor activity

Directly Involved In:

autophagosome assembly

Cellular Locations:

phagophore assembly site

Supporting Evidence:

PMID:31271352
we place the ATG2-WIPI complex between the ER and the phagophore edge
PMID:32483132
WIPI4 forms a complex with ATG2A/B

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

PMID:20562859

Network organization of the human autophagy system.

Large-scale autophagy interaction network places ATG2A in autophagy-associated interaction context.

"a network of 751 interactions among 409 candidate interacting proteins"

PMID:28561066

WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy.

WIPI4-ATG2 translocates to nascent autophagosomes.

"WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes"

PMID:30952800

ATG2 transports lipids to promote autophagosome biogenesis.

ATG2A transfers glycerophospholipids and supports autophagosome biogenesis.

"ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro"
ATG2A acts at ER-autophagosome contact sites.

"operating at the ER-autophagosome interface"

PMID:31271352

The autophagic membrane tether ATG2A transfers lipids between membranes.

Human ATG2A is a lipid transfer protein.

"human ATG2A is a lipid transfer protein"
ATG2-WIPI complex acts between ER and phagophore edge.

"we place the ATG2-WIPI complex between the ER and the phagophore edge"

PMID:31412244

TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion.

ATG2A/B loss impairs phagophore expansion.

"mammalian Atg2A/B functions at the membrane expansion step during autophagosome biogenesis"
Atg2A interacts with ATG9A at mitochondria-associated ER membranes.

"Atg2A directly interacts with Atg9A at the MAM to promote phagophore growth"

PMID:32296183

A reference map of the human binary protein interactome.

Binary interactome evidence is generic interaction context.

"A reference map of the human binary protein interactome"

PMID:32483132

Multi-site-mediated entwining of the linear WIR-motif around WIPI beta-propellers for autophagy.

WIPI proteins bind the ATG2A WIR motif and support ATG2A-mediated autophagy.

"WIPI4 forms a complex with ATG2A/B"

PMID:39174844

Structural basis for lipid transfer by the ATG2A-ATG9A complex.

Structural data support ATG2A-ATG9A/WIPI4 lipid-transfer assemblies.

"Structural basis for lipid transfer by the ATG2A-ATG9A complex"

PMID:38622126

ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores.

ANKFY1 is an endosome-localized, FYVE-domain ATG2A-binding protein that binds PI3P and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes, supporting endosome-to-phagophore lipid donation; ANKFY1 depletion phenocopies ATG2A/B loss.

PMID:37938170

ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A.

ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A and can form a heteromeric complex with ATG2A, consistent with ATG2A lipid transfer being coupled to ATG9-family scramblase activity.

PMID:37796195

Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy.

Lysosome damage induces non-canonical autophagy (CASM) and promotes ATG2/ATG8 engagement via an ATG2 LIR-dependent mode; the robustly demonstrated interaction was ATG2B-LC3A, with a proposed role in lysosome repair (ATG2A-specific contribution inferred rather than directly established).

PMID:38294121

Exploring the ATG9A interactome uncovers interaction with VPS13A.

ATG9A acts as a lipid scramblase whose function is thought to require interaction with the lipid transfer protein ATG2A; ATG9A and ATG2A are proposed to function together to expand the growing autophagosome, and ATG9A forms a distinct complex with VPS13A separate from the ATG9A-ATG2A complex.

file:human/ATG2A/ATG2A-uniprot.txt

UniProtKB record for human ATG2A

UniProt summarizes ATG2A as a lipid transfer protein involved in autophagosome assembly.

"Lipid transfer protein involved in autophagosome assembly"

file:human/ATG2A/ATG2A-goa.tsv

GOA annotations fetched for human ATG2A

file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml

Proteostasis Network autophagy-lysosome pathway mappings

PN mapping treats the ATG2-WIPI bucket as the ATG2-ATG18 complex.

"The GO ATG2-ATG18 complex term is the closest component-level target."

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv

Proteostasis Network projected candidate GO additions

ATG2A was projected to GO:0062079 ATG2-ATG18 complex.

"ATG2A was projected to GO:0062079 ATG2-ATG18 complex in the PN candidate additions table."

Suggested Experiments

Experiment: Rescue ATG2A/ATG2B double-knockout human cells with ATG2A variants that selectively disrupt WIPI binding, TOM40/MAM targeting, or ATG9A association, then quantify mitophagy, pexophagy, ER-phagy, and glycophagy reporters alongside bulk autophagic flux.

Hypothesis: ATG2A is required for selective-autophagy reporter completion primarily through its general phagophore-expansion function, not through cargo-specific recognition.

Type: Selective-autophagy separation-of-function rescue

Experiment: Use starvation time courses with endogenous tagging or proximity labeling of ATG2A, WIPI1/2/3/4, and ATG9A, followed by quantitative proteomics and imaging at ER-phagophore contact sites.

Hypothesis: Human ATG2A participates in condition- and stage-specific ATG2-WIPI/Atg18 complexes whose component composition explains the PN-projected ATG2-ATG18 complex annotation.

Type: Endogenous ATG2-WIPI complex composition assay

Deep Research

Falcon

(ATG2A-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 23 citations 2 artifacts 2026-06-07T04:52:00.059842

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000015 Figure 7c (page 13) provides a schematic model for the lipid transfer assay that represents how ANKFY1 (together with WIPI4) facili (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human ATG2A (UniProt Q2TAZ0) functional annotation (2023–2024 focus)

0) Gene/protein identity verification (required)

The target is human ATG2A (autophagy-related protein 2 homolog A; UniProt Q2TAZ0; synonym KIAA0404), a large rod-like ATG2/RBG-family bridge lipid-transfer protein implicated in autophagosome membrane expansion and other lipid-transfer contexts. This identity is consistent across recent reviews and primary literature describing ATG2A as a long, groove-containing bulk lipid transporter/tether that works with WIPI proteins and ATG9 scramblases. (duarte2023theorganizationand pages 4-5, chiduza2024atg9bisa pages 1-2, vliet2024exploringtheatg9a pages 1-3)

1) Key concepts and definitions (current understanding)

1.1 Macroautophagy and the phagophore expansion problem

Macroautophagy (often “autophagy”) requires de novo growth of a cup-shaped precursor membrane, the phagophore, into a closed autophagosome. A major conceptual advance is that phagophore growth is driven not only by vesicle fusion but also by non-vesicular bulk lipid transfer at ER–phagophore membrane contact sites (MCSs). ATG2 proteins (ATG2A/B in mammals) are central to this model. (duarte2023theorganizationand pages 9-10, duarte2023theorganizationand pages 13-14)

1.2 Bridge-like (bulk) lipid transfer vs. shuttle lipid transfer

ATG2A is generally described as a bridge-like/bulk lipid transfer protein: a rod-like protein with a long hydrophobic groove/cavity that can accommodate lipid acyl chains and allow lipids to flow between membranes when the protein tethers them. This is contrasted with “shuttle” lipid transfer proteins that bind and carry single lipids. (duarte2023theorganizationand pages 13-14, duarte2023theorganizationand pages 4-5)

1.3 Lipid transfer must be coupled to lipid scrambling

Because bridge transfer is expected to deliver lipids predominantly into the cytosolic leaflet of a target membrane, efficient phagophore growth also requires lipid scrambling to equilibrate lipids between leaflets. The core model therefore couples ATG2A-mediated transfer with ATG9A/B scramblase activity, and ER scramblases VMP1/TMEM41B on the donor side. (chiduza2024atg9bisa pages 1-2, vliet2024exploringtheatg9a pages 1-3)

2) Molecular function of ATG2A

2.1 Core molecular function: tethering and bulk lipid transfer for phagophore growth

ATG2A is a tether and lipid transfer protein concentrated at phagophore extremities/rims where ER–phagophore contacts form. Purified ATG2-family proteins can tether membranes and transfer lipids between tethered membranes in vitro, and a principal lipid-transfer module has been mapped to the N-terminus (reported in recent synthesis as ATG2A aa 1–345). (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 9-10)

Structural synthesis describes ATG2A as a large rod (reported ~20 nm length) with a groove compatible with bulk phospholipid transport, fitting a “molecular highway/bridge” model for moving lipids from donor membranes (classically ER) to expanding phagophores. (duarte2023theorganizationand pages 13-14, duarte2023theorganizationand pages 4-5)

2.2 ATG2A as a bulk lipid transfer factor outside canonical phagophore growth: lipid droplets

A 2023 mechanistic study extended ATG2A’s biology to lipid droplets (LDs), showing ATG2A can catalyze bridge-like phospholipid transport from phospholipid monolayers (LD surfaces) and that bridge-like transport activity is required to prevent LD accumulation in cells. This work argues ATG2A is naturally recruited to monolayers and can transfer phospholipids more efficiently when one interacting surface is an LD-like monolayer. (korfhage2023atg2amediatedbridgelikelipid pages 1-2)

3) Key interaction partners and mechanistic roles

3.1 WIPI4/WDR45 (PI3P effector) – targeting and directionality

At ER–phagophore MCSs, WIPI4 (WDR45) is described as an ATG2A partner that binds PI3P and supports recruitment/directionality of ATG2A toward PI3P-positive autophagic membranes; recent synthesis notes WIPI4 binds ATG2A more strongly than WIPI1/2. (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 9-10)

3.2 ATG9A and ATG9B – scramblases coupled to ATG2A transfer

Recent reviews and primary literature converge on ATG2A forming a functional complex with ATG9A.
* A 2024 interactome-focused primary study frames ATG9A as a lipid scramblase whose scramblase function is “thought to require” interaction with ATG2A; ATG9A forms a complex with ATG2A and disrupting this complex inhibits autophagy, supporting cooperation in expanding the growing autophagosome. (vliet2024exploringtheatg9a pages 1-3)
* A 2024 mechanistic review of ATG9 paralogs describes ATG2A collaborating with ATG9A to transfer lipids to the growing autophagosome. It further summarizes structural modeling in which ATG2A’s C-terminus interacts with ATG9A to form a complex that couples ATG2A lipid transfer with ATG9 scramblase activity (described as essential for autophagosome biogenesis). (chiduza2024atg9bisa pages 1-2)
* A 2023 synthesis of ER–phagophore contact sites identifies two ATG9A-interacting sequences in ATG2A and reports that deleting the S2 region (mapped to the CLR, ~aa 1760–1779) reduces ATG2A–ATG9A binding and impairs autophagy progression. (duarte2023theorganizationand pages 5-7)

Together, these sources support the current consensus: ATG2A (bridge transfer) + ATG9A/B (scrambling) form a core lipid-supply machine for phagophore expansion. (duarte2023theorganizationand pages 5-7, chiduza2024atg9bisa pages 1-2, vliet2024exploringtheatg9a pages 1-3)

3.3 VMP1 and TMEM41B – ER-side scramblases interacting with ATG2A

A 2024 review of ATG9B/ATG9A biology summarizes that ER-resident scramblases VMP1 and TMEM41B interact with the N-terminus of ATG2A, and along with ATG9A are proposed to form a core lipid transfer/scrambling complex at ER–phagophore contact sites, with local ER lipid synthesis providing directionality. (chiduza2024atg9bisa pages 1-2)

A complementary biochemical synthesis also describes ATG2 N-terminal targeting to the ER through interactions with VMP1 and TMEM41B, placing these interactions in a mechanistic model for driving net lipid flux at the contact. (nguyen2023biochemicalreconstitutionof pages 134-138)

3.4 GABARAP/ATG8 family – LIR-mediated interactions and late-stage biogenesis

ATG2A contains conserved LIR motifs and is described as interacting with GABARAP-family ATG8 proteins, which is functionally important for sustaining phagophore formation and/or autophagosome closure in starvation conditions (as summarized in a 2023 contact-site review and a 2023 high-authority autophagy-gene review). (duarte2023theorganizationand pages 4-5, yamamoto2023autophagygenesin pages 16-17)

In addition, in a 2023 primary study of lysosome damage responses (CASM; see Section 5), ATG2–ATG8 engagement upon lysosomal damage depended on the ATG2A LIR region (rather than the WIPI4-binding region) in ATG2A/B DKO reconstitution assays, supporting an ATG8-dependent recruitment mode for ATG2 under non-canonical autophagy stimuli. (cross2023lysosomedamagetriggers pages 6-7)

3.5 ANKFY1 – 2024 discovery of an endosomal bridge for ATG2A lipid transfer

A key 2024 advance is identification of ANKFY1 as an ATG2A-binding factor that is endosome-localized and promotes ATG2A-mediated lipid transfer from endosomes to phagophores.

Mechanistically, Wei et al. (Cell Discovery; published April 2024; https://doi.org/10.1038/s41421-024-00659-y) report:
* ANKFY1 depletion impairs autophagosome growth and reduces autophagy flux, largely phenocopying ATG2A/B depletion.
* Purified ANKFY1 binds PI3P via its FYVE domain and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes.
* The authors propose ANKFY1 recruits ATG2A to PI3P-enriched endosomes, enabling endosome-to-phagophore lipid donation.
(wei2024ankfy1bridgesatg2amediated pages 1-2)

A schematic model of the ANKFY1/WIPI4/ATG2A liposome-transfer assay and the proposed endosome→phagophore lipid-transfer concept is shown in the retrieved figure panel. (wei2024ankfy1bridgesatg2amediated media 2bca71a4)

4) Subcellular localization and pathway context

4.1 ER–phagophore membrane contact sites (including omegasome-associated regions)

Current synthesis places ATG2A at phagophore extremities/rims, where it establishes/maintains close contacts with the ER (ER–phagophore MCSs) together with ATG9 and WIPI proteins. Recruitment is described as involving coincidence of ATG9 binding and PI3P-dependent WIPI binding, producing localization specificity to the right membrane subdomains. (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 9-10)

4.2 Endosome–phagophore interfaces (2024 extension)

The ANKFY1 discovery supports a model in which ATG2A can also function at endosome–phagophore interfaces, transferring PI3P and other lipids from PI3P-enriched endosomes to the phagophore during autophagy. (wei2024ankfy1bridgesatg2amediated pages 1-2, wei2024ankfy1bridgesatg2amediated media 2bca71a4)

4.3 Lipid droplets

ATG2A localizes to lipid droplets, and 2023 mechanistic work provides evidence that ATG2A’s bridge-like lipid transport regulates LD accumulation and that ATG2A has enhanced recruitment/activity on LD monolayers. (korfhage2023atg2amediatedbridgelikelipid pages 1-2)

5) Recent developments (prioritized 2023–2024)

5.1 2023 authoritative reviews consolidated the bridge-transfer paradigm

Two influential 2023 reviews synthesized emerging structural and biochemical data into a now widely used conceptual framework: autophagosomal membrane expansion is driven by coordinated action of bulk lipid transfer proteins (ATG2 family) and scramblases (ATG9, VMP1, TMEM41B) at ER–phagophore contacts. (duarte2023theorganizationand pages 13-14, yamamoto2023autophagygenesin pages 16-17)

5.2 2023–2024: Expansion beyond “ER-only” lipid donation

The 2024 ANKFY1 study provides direct evidence for a non-ER donor route, proposing endosomes as lipid sources for phagophore expansion via ATG2A when ANKFY1 recruits/activates the transfer on PI3P membranes. (wei2024ankfy1bridgesatg2amediated pages 1-2, wei2024ankfy1bridgesatg2amediated media 2bca71a4)

5.3 2023: ATG2 engagement in non-canonical autophagy during lysosome damage

Cross et al. (J Cell Biol; October 2023; https://doi.org/10.1083/jcb.202303078) report that lysosome damage triggers ATG8 conjugation (CASM) and promotes ATG2 engagement. In their system, a robust GFP-LC3A–ATG2B interaction was induced by lysosomotropic damage (LLOMe) and depended on LC3A lipidation and CASM-specific ATG16L1 function. ATG2–LC3 engagement required the ATG2 LIR rather than WIPI4-binding region, supporting a distinct recruitment logic under lysosomal stress. (cross2023lysosomedamagetriggers pages 6-7)

5.4 2024: Refining the “core lipid transfer complex” and paralog compensation

Chiduza et al. (Autophagy; online 2024; https://doi.org/10.1080/15548627.2023.2275905) describe ATG9B as a tissue-specific lipid scramblase that can compensate for ATG9A and reports that ATG9B can form a heteromeric complex with ATG2A, fitting the model of a coupled ATG2A–ATG9 scramblase module. (chiduza2024atg9bisa pages 1-2)

6) Relevant statistics and quantitative data (from recent studies)

Geometry/biophysics of ATG2A tethering/transfer: ATG2A is described as ~20 nm rod-like protein; ATG2A and ATG2B share 44.5% identity. (duarte2023theorganizationand pages 4-5)
Curvature preference: In the ANKFY1 study, ATG2A is described as binding/tethering ~30 nm small unilamellar vesicles better than ~100 nm large unilamellar vesicles, consistent with preference for high curvature/packing defects. (wei2024ankfy1bridgesatg2amediated pages 1-2)
Lipid droplet transfer assays (Korfhage et al., 2023 bioRxiv preprint; https://doi.org/10.1101/2023.08.14.553257): donor artificial LDs had median diameter ~165 nm (IQR 129–211 nm), and inclusion of a monolayer donor accelerated lipid mixing by ≥4-fold compared with ~100 nm liposomes of identical composition; a bridge-transport-dead ATG2A mutant failed to rescue LD accumulation in ATG2 KO cells. (korfhage2023atg2amediatedbridgelikelipid pages 1-2)

7) Current applications and real-world implementations

7.1 Practical implementations in cell biology and drug discovery pipelines (research use)

ATG2A is routinely used as a mechanistic handle for autophagosome biogenesis and membrane contact site biology via:
* ATG2A/B double knockout (DKO) systems plus rescue with WT or mutant ATG2A (e.g., LIR-deficient) to test requirements for autophagosome maturation/closure and stress-induced recruitment modes. (cross2023lysosomedamagetriggers pages 6-7)
* Coupled assays with ATG9A/B to dissect lipid transfer/scrambling coupling and to model membrane expansion defects relevant to proteostasis, neurobiology, and metabolic homeostasis. (chiduza2024atg9bisa pages 1-2, vliet2024exploringtheatg9a pages 1-3)

These are “real-world” implementations in the sense of widely applied experimental platforms; however, this evidence set does not establish any ATG2A-targeting therapeutic currently used clinically.

7.2 Translational relevance (current state)

High-authority reviews highlight that mutations in autophagy genes broadly contribute to human disease and emphasize lipid transfer at membrane contact sites as a key mechanism with disease relevance; ATG2-family function is central to this mechanistic theme. (duarte2023theorganizationand pages 13-14, yamamoto2023autophagygenesin pages 16-17)

Within the retrieved evidence, direct clinical applications (e.g., approved drugs targeting ATG2A) are not described; thus, translational relevance is primarily mechanism-driven (guiding target prioritization and pathway interpretation) rather than direct ATG2A intervention.

8) Expert opinions and analysis (authoritative synthesis)

ATG2A as the central bridge lipid-transfer factor for autophagosome expansion: 2023 reviews consolidate ATG2A as a core tether/transfer component at ER–phagophore contacts, analogous to VPS13-family bridge transfer proteins, establishing a prevailing “bulk lipid transfer + scramblase coupling” model for membrane growth. (duarte2023theorganizationand pages 13-14, yamamoto2023autophagygenesin pages 16-17)
Mechanistic coupling is essential: Synthesis of ATG2A–ATG9 interactions (including mapped binding sites such as the ATG2A CLR-associated S2) supports a view that physical coupling between transfer (ATG2A) and scrambling (ATG9) is required for productive bilayer expansion and autophagy progression. (duarte2023theorganizationand pages 5-7, chiduza2024atg9bisa pages 1-2)
Multiple donor routes likely exist: The ANKFY1 discovery provides evidence that ATG2A can be recruited to PI3P-positive endosomes and that endosomes may contribute lipids to phagophores. This suggests lipid sourcing is more flexible than an “ER-only” model and may be tuned by PI3P effectors and tethering factors. (wei2024ankfy1bridgesatg2amediated pages 1-2, wei2024ankfy1bridgesatg2amediated media 2bca71a4)

9) Visual evidence

The following retrieved figure shows the ANKFY1/WIPI4-assisted ATG2A lipid transfer model used in Wei et al. (2024), supporting the endosome-to-phagophore lipid donation concept.

(wei2024ankfy1bridgesatg2amediated media 2bca71a4)

10) Summary table (evidence map)

The table below provides a compact mapping of ATG2A identity, functions, partners, localization, quantitative findings, and 2023–2024 developments.

Aspect	Key points
Identity/domains	- Verified target: human ATG2A (UniProt Q2TAZ0), autophagy-related protein 2 homolog A; member of the ATG2/RBG bridge-like lipid transfer family with a rod-like architecture (duarte2023theorganizationand pages 4-5, chiduza2024atg9bisa pages 1-2, vliet2024exploringtheatg9a pages 1-3) - Contains an N-terminal chorein/N_chorein lipid-transfer module and a long hydrophobic groove/cavity consistent with bulk phospholipid transport (duarte2023theorganizationand pages 4-5, wei2024ankfy1bridgesatg2amediated pages 1-2) - Has a C-terminal CLR with amphipathic helices for membrane association, plus conserved LIR motifs and ATG9-binding regions including an S2 site around aa 1760–1779 (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 4-5)
Core molecular function	- Primary function is bulk/bridge-like lipid transfer to support phagophore expansion during autophagosome biogenesis (duarte2023theorganizationand pages 9-10, yamamoto2023autophagygenesin pages 16-17, vliet2024exploringtheatg9a pages 1-3) - Also acts as a membrane tether at ER–phagophore contact sites; purified ATG2 proteins tether highly curved membranes and transfer lipids between tethered membranes in vitro (duarte2023theorganizationand pages 5-7, wei2024ankfy1bridgesatg2amediated pages 1-2) - Outside canonical autophagosome growth, ATG2A can mediate bridge-like phospholipid transport on lipid droplet monolayers, affecting lipid droplet homeostasis (korfhage2023atg2amediatedbridgelikelipid pages 1-2)
Key interaction partners	- WIPI4/WDR45 is a strong ATG2A partner that helps target ATG2A toward PI3P-rich autophagic membranes and enhances tethering/lipid transfer directionality (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 9-10) - ATG9A/ATG9B interact functionally and physically with ATG2A; the complex couples ATG2A lipid transfer to ATG9 scramblase activity and is essential for phagophore expansion (duarte2023theorganizationand pages 5-7, chiduza2024atg9bisa pages 1-2, vliet2024exploringtheatg9a pages 1-3) - VMP1 and TMEM41B interact with the ATG2A N terminus at the ER side of the contact, while ANKFY1 was identified in 2024 as an endosomal ATG2A-binding factor that promotes PI3P-dependent lipid transfer from endosomes to phagophores (nguyen2023biochemicalreconstitutionof pages 134-138, wei2024ankfy1bridgesatg2amediated pages 1-2, chiduza2024atg9bisa pages 1-2)
Subcellular localization	- Enriched at phagophore extremities/rims and ER–phagophore membrane contact sites, including omegasome-associated regions during autophagosome formation (duarte2023theorganizationand pages 9-10, duarte2023theorganizationand pages 15-15) - Localizes with ATG9 and WIPI4 on early autophagic membranes, with coincidence binding to PI3P and ATG9 helping recruitment/specificity (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 9-10) - Additional pools localize to lipid droplets and, in 2024 work, to interfaces between PI3P-positive endosomes and phagophores via ANKFY1 (duarte2023theorganizationand pages 15-15, wei2024ankfy1bridgesatg2amediated pages 1-2, korfhage2023atg2amediatedbridgelikelipid pages 1-2)
Mechanistic model	- Current model: ATG2A forms a lipid bridge/highway between donor and acceptor membranes, transferring lipids from the ER to the expanding phagophore while scramblases equilibrate lipids across bilayer leaflets (duarte2023theorganizationand pages 13-14, chiduza2024atg9bisa pages 1-2) - Directionality/specificity is thought to arise from the combination of ATG2A with WIPI4, ATG9A, VMP1, and TMEM41B, with local ER lipid synthesis proposed to help drive net lipid flow (nguyen2023biochemicalreconstitutionof pages 134-138, chiduza2024atg9bisa pages 1-2) - A 2024 extension of this model proposes that endosomes can also donate PI3P and other lipids to phagophores through ANKFY1-assisted ATG2A transfer (wei2024ankfy1bridgesatg2amediated pages 1-2, wei2024ankfy1bridgesatg2amediated media 2bca71a4)
Quantitative/experimental data	- ATG2A is described as a rod-like protein of about ~20 nm length; ATG2A and ATG2B share 44.5% identity (duarte2023theorganizationand pages 4-5) - Purified ATG2A binds/tethers ~30 nm small unilamellar vesicles better than ~100 nm large unilamellar vesicles, consistent with preference for highly curved/packing-defective membranes (wei2024ankfy1bridgesatg2amediated pages 1-2) - In lipid-droplet assays, donor artificial LDs had median diameter ~165 nm (IQR 129–211 nm) and monolayer-containing donors accelerated lipid mixing by at least 4-fold relative to comparable ~100 nm bilayer liposomes; transport-dead ATG2A failed to rescue LD accumulation in knockout cells (korfhage2023atg2amediatedbridgelikelipid pages 1-2)
Recent 2023-2024 developments	- 2023 reviews consolidated ATG2A as a central RBG-family bulk lipid transporter/tether in autophagosome biogenesis, integrating structural and biochemical findings into a more unified bridge-transfer model (duarte2023theorganizationand pages 9-10, yamamoto2023autophagygenesin pages 16-17) - 2023 preprint work linked ATG2A bridge-like transport directly to lipid droplet accumulation/homeostasis, expanding its biology beyond phagophore growth (korfhage2023atg2amediatedbridgelikelipid pages 1-2) - 2024 studies added new partners and contexts: ANKFY1 as an endosomal recruiter/promoter of ATG2A-mediated transfer, and ATG9B as a tissue-specific scramblase that can also complex with ATG2A (wei2024ankfy1bridgesatg2amediated pages 1-2, chiduza2024atg9bisa pages 1-2)
Disease/physiology links	- ATG2A supports fundamental cellular lipid homeostasis through autophagosome biogenesis and lipid-droplet regulation, so perturbation is expected to impact stress adaptation and metabolism (korfhage2023atg2amediatedbridgelikelipid pages 1-2, yamamoto2023autophagygenesin pages 16-17) - Reviews of ER membrane-contact-site biology and autophagy genes place ATG2-family bridge lipid transport within broader mechanisms relevant to neurodegeneration and human disease, although ATG2A-specific Mendelian disease evidence remains less developed than for some partner proteins (duarte2023theorganizationand pages 13-14, yamamoto2023autophagygenesin pages 16-17) - Loss of ANKFY1 phenocopied ATG2A/B depletion for impaired autophagosome growth and reduced flux, underscoring the physiological importance of ATG2A-mediated membrane supply routes (wei2024ankfy1bridgesatg2amediated pages 1-2)
Non-canonical autophagy/lysosome damage	- In 2023, lysosome damage was shown to trigger CASM/non-canonical autophagy-dependent engagement of ATG2, linking ATG2A/B to lysosomal stress responses beyond canonical phagophore expansion (cross2023lysosomedamagetriggers pages 6-7) - In ATG2A/B double-knockout reconstitution experiments, ATG2–LC3 interaction during lysosome damage required the ATG2A LIR rather than the WIPI4-binding region, supporting a distinct ATG8-dependent recruitment mode (cross2023lysosomedamagetriggers pages 6-7) - ATG2A and ATG2B were recovered on damaged lysosomes, and the study proposed a role in lysosome repair alongside other damage-response pathways (cross2023lysosomedamagetriggers pages 6-7)

Table: This table summarizes the verified identity, molecular function, partners, localization, and recent mechanistic advances for human ATG2A (UniProt Q2TAZ0). It is useful as a compact evidence map linking ATG2A's lipid-transfer role to canonical autophagy, lipid droplet biology, and lysosomal damage responses.

Key cited sources (URLs and publication dates)

Duarte & Reggiori, 2023-01. The Organization and Function of the Phagophore-ER Membrane Contact Sites (CONTACT). https://doi.org/10.1177/25152564231183898 (duarte2023theorganizationand pages 5-7, duarte2023theorganizationand pages 9-10, duarte2023theorganizationand pages 4-5)
Yamamoto et al., 2023-01. Autophagy genes in biology and disease (Nature Reviews Genetics). https://doi.org/10.1038/s41576-022-00562-w (yamamoto2023autophagygenesin pages 16-17)
Cross et al., 2023-10. Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy (J Cell Biol). https://doi.org/10.1083/jcb.202303078 (cross2023lysosomedamagetriggers pages 6-7)
van Vliet et al., 2024-02. Exploring the ATG9A interactome uncovers interaction with VPS13A (J Cell Sci). https://doi.org/10.1242/jcs.261081 (vliet2024exploringtheatg9a pages 1-3)
Wei et al., 2024-04. ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores (Cell Discovery). https://doi.org/10.1038/s41421-024-00659-y (wei2024ankfy1bridgesatg2amediated pages 1-2, wei2024ankfy1bridgesatg2amediated media 2bca71a4)
Chiduza et al., 2024 (online; issue lists 2024-11). ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A (Autophagy). https://doi.org/10.1080/15548627.2023.2275905 (chiduza2024atg9bisa pages 1-2)
Korfhage et al., 2023-08 (preprint). ATG2A-mediated bridge-like lipid transport regulates lipid droplet accumulation (bioRxiv). https://doi.org/10.1101/2023.08.14.553257 (korfhage2023atg2amediatedbridgelikelipid pages 1-2)

References

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Artifacts

Edison artifact artifact-00

Citations

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https://doi.org/10.1242/jcs.261081,
https://doi.org/10.1101/2023.08.14.553257,
https://doi.org/10.53846/goediss-9864,
https://doi.org/10.1038/s41576-022-00562-w,
https://doi.org/10.1083/jcb.202303078,
https://doi.org/10.1038/s41421-024-00659-y,

📚 Additional Documentation

Notes

(ATG2A-notes.md)

ATG2A notes

Fetched human ATG2A with just fetch-gene human ATG2A on 2026-06-03. The scaffold seeded 30 review entries from 36 GOA rows because repeated protein binding rows were collapsed by publication in the generated review file.
Falcon deep research was started with fallback using just deep-research-falcon human ATG2A --fallback perplexity-lite; PMID caching completed with all eight review PMIDs present locally. Falcon timed out after 600 seconds, then the perplexity-lite fallback failed with an API quota 401, so no provider deep-research file was produced in this run.
Core function: ATG2A is best represented as a lipid-transfer/tethering factor for autophagosome assembly. Valverde et al. show that "ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro" and that ATG2-mediated lipid transfer at contact sites contributes to autophagosome formation PMID:30952800.
Maeda et al. directly state that "human ATG2A is a lipid transfer protein" and place the "ATG2-WIPI complex between the ER and the phagophore edge" PMID:31271352.
The PN projection for ATG2A is GO:0062079 ATG2-ATG18 complex from the PN path Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Regulation of autophagophore membrane composition|ATG2-WIPI complex component; the mapping rationale says "The GO ATG2-ATG18 complex term is the closest component-level target" [file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml].
I accepted the PN-projected complex conservatively as a new cellular-component annotation, supported by ATG2A-WIPI evidence, but did not use the PN projection to broaden cargo-specific process annotations. The IBA cargo-specific rows for mitophagy, pexophagy, glycophagy, reticulophagy, and piecemeal microautophagy of the nucleus were modified toward general autophagosome assembly unless direct ATG2A cargo-specific evidence was available.
Generic GO:0005515 protein binding rows were marked over-annotated, including WIPI-binding rows whose specific complex context is instead captured by the separate NEW GO:0062079 ATG2-ATG18 complex annotation. This follows the project guideline to avoid retaining protein binding when a more informative function or component term is available.

Falcon deep research findings (2026-06-07)

Synthesis of the Falcon (Edison Scientific) report against the existing COMPLETE review. PMIDs resolved from DOIs via PubMed ID-conversion. Only Wei 2024 (ANKFY1) is cached locally in publications/; the others are full_text_unavailable.

CONFIRMS (no annotation change needed): Core paradigm is unchanged — ATG2A is a rod-like (~20 nm) RBG/bridge-like bulk lipid-transfer protein with an N-terminal chorein lipid-transfer module and a long hydrophobic groove; it tethers ER and phagophore and transfers glycerophospholipids for phagophore expansion, coupled to ATG9A scramblase activity, and is recruited via WIPI4/WDR45 PI3P binding [doi:10.1177/25152564231183898 Duarte & Reggiori 2023 review "bulk lipid transfer + scramblase coupling"; consistent with PMID:30952800, PMID:31271352, PMID:39174844 already in review]. ATG2A/ATG2B share ~44.5% identity (paralog redundancy already noted).
NEW partner/donor route — ANKFY1 (endosome-to-phagophore lipid donation): Wei et al. 2024 identify ANKFY1 as a new ATG2A-binding, endosome-localized FYVE-domain protein that binds PI3P and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes; depletion phenocopies ATG2A/B loss (impaired autophagosome growth, reduced flux). Proposes endosomes (not only ER) as a lipid source for phagophore expansion via ATG2A [PMID:38622126 "ANKFY1 recruits ATG2A to PI3P-enriched endosomes and promotes ATG2A-mediated lipid transfer from endosomes to phagophores"; cached]. Strong, peer-reviewed (Cell Discovery) — added to references. Does not alter existing localization annotations (still ER/phagophore contact-site core) but broadens donor membrane context.
NEW context — ER-side scramblases VMP1 and TMEM41B interact with the ATG2A N-terminus, forming a proposed core lipid-transfer/scrambling complex at ER–phagophore contacts; local ER lipid synthesis proposed to provide directionality [Chiduza et al. 2024 PMID:37938170; Falcon also cites a thesis nguyen2023 which I do NOT use]. PROVISIONAL as ATG2A-specific binding-site detail; consistent with existing tether/adaptor annotations, no annotation change.
NEW context — ATG9B paralog: Chiduza et al. 2024 show ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A and can form a heteromeric complex with ATG2A PMID:37938170. Relevant to ATG2A–ATG9 coupling generally; ATG2A-shared, not ATG2A-unique. Added to references.
NEW context — non-canonical autophagy / lysosome damage (CASM): Cross et al. 2023 report lysosome damage triggers CASM and promotes ATG2/ATG8 engagement; the ATG2–LC3 interaction required the ATG2 LIR rather than the WIPI4-binding region. Note the robustly demonstrated interaction was GFP-LC3A–ATG2B (paralog), with ATG2A inferred — so this is an ATG2-family/ATG2B-leaning finding, not firmly ATG2A-specific PMID:37796195. Suggests a possible LIR/ATG8-dependent recruitment mode and lysosome-repair role; PROVISIONAL for ATG2A. Captured as a suggested question rather than an annotation change.
PROVISIONAL (preprint, do NOT use for annotations) — lipid droplets: Korfhage et al. 2023 (bioRxiv, NOT peer-reviewed) report ATG2A bridge-like phospholipid transport from LD monolayers regulates LD accumulation, with a transport-dead ATG2A mutant failing to rescue LD accumulation; LD-like monolayer donors accelerated lipid mixing ≥4-fold vs ~100 nm liposomes [doi:10.1101/2023.08.14.553257 preprint]. Supports the existing KEEP_AS_NON_CORE lipid-droplet annotations; preprint status means it is NOT used to change annotations or as supporting_text.
van Vliet et al. 2024 (ATG9A interactome, PMID:38294121, DOI:10.1242/jcs.261081, PubMed-verified title "Exploring the ATG9A interactome uncovers interaction with VPS13A.") reaffirms ATG9A–ATG2A complex (scramblase function "thought to require" ATG2A interaction) and reports a distinct ATG9A–VPS13A complex; ATG2A role here is confirmatory of existing ATG9A coupling. Added to references (statement-only, full_text_unavailable) on 2026-06-07.
PMID verification (2026-06-07, PubMed ID-converter): DOI 10.1038/s41421-024-00659-y -> PMID:38622126 (ANKFY1/Wei 2024); DOI 10.1080/15548627.2023.2275905 -> PMID:37938170 (ATG9B/Chiduza 2024); DOI 10.1083/jcb.202303078 -> PMID:37796195 (CASM/Cross 2023); DOI 10.1242/jcs.261081 -> PMID:38294121 (van Vliet 2024). All four already-or-now present in references are confirmed correct; no guessed PMIDs.
Disease/physiology: no ATG2A-specific Mendelian disease established in the retrieved evidence; relevance is mechanistic (autophagy/lipid homeostasis, neurodegeneration context) [doi:10.1038/s41576-022-00562-w Yamamoto et al. 2023 Nat Rev Genet review, general]. No new disease annotation warranted.

Pn Notes

(ATG2A-pn-notes.md)

ATG2A PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q2TAZ0
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1375)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATG2A/ATG2A-ai-review.yaml
AIGR review HTML: present - genes/human/ATG2A/ATG2A-ai-review.html
Gene notes: present - genes/human/ATG2A/ATG2A-notes.md
GOA TSV: present - genes/human/ATG2A/ATG2A-goa.tsv
UniProt record: present - genes/human/ATG2A/ATG2A-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATG2A.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATG2A.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATG2A/ATG2A-deep-research-falcon.md

AIGR Review Snapshot

Description: ATG2A is a large autophagy-related lipid transfer protein that acts at ER-phagophore contact sites during autophagosome biogenesis. It forms functional assemblies with WIPI/Atg18-family PI3P effectors and ATG9A-containing membranes, tethers membrane compartments, and transfers glycerophospholipids to support phagophore expansion. ATG2A also associates with lipid droplets and ER-mitochondria contact sites, but its principal characterized role is membrane supply for autophagosome formation.
Existing/core annotation action counts: ACCEPT: 13; KEEP_AS_NON_CORE: 2; MARK_AS_OVER_ANNOTATED: 6; MODIFY: 9; NEW: 1

PN Consistency Summary

Consistency: Fully consistent. Deep research, notes, review YAML agree ATG2A is a rod-like bulk lipid-transfer/tethering protein bridging ER and phagophore, partnered with WIPI4/ATG18 and coupled to ATG9A scramblase. PN component placement (ATG2-WIPI complex) matches exactly. Review core = GO:0120013 lipid transfer + GO:0043495 protein-membrane adaptor → GO:0000045 autophagosome assembly.
PN story / NEW pressure: PN projects GO:0062079 (ATG2-ATG18 complex), absent from GOA (more_specific_than_existing_goa). The review accepted it as NEW (IDA) — well-supported by ATG2A-WIPI4 evidence (PMID:31271352). Term verified real. Conclude: ADD, already done in-review. This is the well-behaved case: PN projects a MORE specific component term than existing GOA, and the review adopted it. No over-reach.
Evidence alignment: PN reference titles (ATG2A-WIPI4 complex structure, ATG2 essential for autophagosome formation, lipid-droplet/early-autophagosome targeting) overlap the review's lipid-transfer core (PMID:30952800, PMID:31271352) and lipid-droplet non-core. PN refs are titles-only (not all PMIDs in review) but biologically concordant; no conflicts.
Verdict: Consistent and well-supported; PN GO:0062079 correctly added as NEW. Exemplary specific-component projection. No edits warranted.

Full Consistency Review

UniProt: Q2TAZ0 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE (Falcon DR present)
PN placement: Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Regulation of autophagophore membrane composition|ATG2-WIPI complex component ; PN-node mapping: type(ATG2-WIPI component)=mapped/ok GO:0062079 (ATG2-ATG18 complex, more_specific_than_existing_goa); group/branch=no_mapping; class=context_only GO:0016236 (macroautophagy). PN Notes: lipid transporter carrying phospholipids to phagophore, recruits ATG9. 5 reference titles (Atg2A-WIPI4 structure, lipid-droplet targeting, autophagosome biogenesis reviews).
Consistency: Fully consistent. Deep research, notes, review YAML agree ATG2A is a rod-like bulk lipid-transfer/tethering protein bridging ER and phagophore, partnered with WIPI4/ATG18 and coupled to ATG9A scramblase. PN component placement (ATG2-WIPI complex) matches exactly. Review core = GO:0120013 lipid transfer + GO:0043495 protein-membrane adaptor → GO:0000045 autophagosome assembly.
PN story / NEW pressure: PN projects GO:0062079 (ATG2-ATG18 complex), absent from GOA (more_specific_than_existing_goa). The review accepted it as NEW (IDA) — well-supported by ATG2A-WIPI4 evidence (PMID:31271352). Term verified real. Conclude: ADD, already done in-review. This is the well-behaved case: PN projects a MORE specific component term than existing GOA, and the review adopted it. No over-reach.
Mapping strategy: ATG2A is a clean driver for the ATG2-WIPI component node; the type→GO:0062079 mapping is appropriately specific (more specific than existing GOA, opposite of the TOMM20/RAB7A "too broad" rejections). The notes correctly resisted broadening cargo-specific process terms (mitophagy/pexophagy/glycophagy IBA rows MODIFY'd toward general autophagosome assembly) and kept class-level macroautophagy as context_only. Sound strategy.
Evidence alignment: PN reference titles (ATG2A-WIPI4 complex structure, ATG2 essential for autophagosome formation, lipid-droplet/early-autophagosome targeting) overlap the review's lipid-transfer core (PMID:30952800, PMID:31271352) and lipid-droplet non-core. PN refs are titles-only (not all PMIDs in review) but biologically concordant; no conflicts.
Verdict: Consistent and well-supported; PN GO:0062079 correctly added as NEW. Exemplary specific-component projection. No edits warranted.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATG2A/ATG2A-ai-review.yaml
PN workbook rows: 1

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Regulation of autophagophore membrane composition | ATG2-WIPI complex component

UniProt: Q2TAZ0
In branches: ALP
Notes: Component of ATG2-WIPI complex, which recruits ATG9 to the autophagosome. ATG2A and ATG2B are lipid transporters, carry phospholipids to the phagophore
PN references (titles):
- Mammalian Autophagy: How Does It Work? | Annual Review of Biochemistry (annualreviews.org)
- Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex | PNAS
- Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets | Molecular Biology of the Cell (molbiolcell.org)
- Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells[S] - Journal of Lipid Research (jlr.org)
- Autophagosome biogenesis comes out of the black box | Nature Cell Biology
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Regulation of autophagophore membrane composition|ATG2-WIPI complex component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0062079 ATG2-ATG18 complex]
  rationale: This PN component bucket corresponds to the ATG2-WIPI/ATG18 lipid-transfer complex used during autophagophore membrane expansion. The GO ATG2-ATG18 complex term is the closest component-level target.
- [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Regulation of autophagophore membrane composition
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0062079 ATG2-ATG18 complex | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Regulation of autophagophore membrane composition|ATG2-WIPI complex component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q2TAZ0
gene_symbol: ATG2A
product_type: PROTEIN
status: COMPLETE
tags:
- proteostasis
- pn
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATG2A is a large autophagy-related lipid transfer protein that acts at ER-phagophore
  contact sites during autophagosome biogenesis. It forms functional assemblies with WIPI/Atg18-family
  PI3P effectors and ATG9A-containing membranes, tethers membrane compartments, and transfers
  glycerophospholipids to support phagophore expansion. ATG2A also associates with lipid droplets and
  ER-mitochondria contact sites, but its principal characterized role is membrane supply for
  autophagosome formation.
alternative_products:
- name: '1'
  id: Q2TAZ0-1
- name: '2'
  id: Q2TAZ0-3
  sequence_note: VSP_030515
- name: '3'
  id: Q2TAZ0-4
  sequence_note: VSP_030510, VSP_030516
- name: '4'
  id: Q2TAZ0-5
  sequence_note: VSP_030511, VSP_030512
existing_annotations:
- term:
    id: GO:0000407
    label: phagophore assembly site
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ATG2A acts at the phagophore assembly site during autophagosome biogenesis.
    action: ACCEPT
    reason: >-
      Accept as a core location/context. Human ATG2A localizes to ER-phagophore/autophagophore
      contact sites and functions in lipid transfer during phagophore expansion; the IBA assignment is
      consistent with direct human evidence and the conserved ATG2/Atg18 autophagy module.
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: localization of human ATG2A to contact sites between the ER and the autophagophore
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Localizes to endoplasmic reticulum-autophagosome contact sites.
- term:
    id: GO:0000422
    label: autophagy of mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Mitophagy is too cargo-specific for ATG2A based on the available human evidence.
    action: MODIFY
    reason: >-
      ATG2A is required for phagophore expansion and can be recruited to ER-mitochondria contact sites,
      but the cached human ATG2A evidence supports general autophagosome assembly rather than an
      ATG2A-specific mitophagy cargo-selection function. The safer PN interpretation is core
      autophagosome biogenesis, not cargo-specific mitochondrial autophagy.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    - PMID:31412244
    supported_by:
    - reference_id: PMID:31412244
      supporting_text: mammalian Atg2A/B functions at the membrane expansion step during autophagosome biogenesis
    - reference_id: PMID:31412244
      supporting_text: Atg2A translocates to the autophagosome formation site at the ER-mitochondria contact site
- term:
    id: GO:0061908
    label: phagophore
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ATG2A is active at the expanding phagophore.
    action: ACCEPT
    reason: >-
      Accept as a core cellular context. ATG2A is placed at the phagophore/ER interface and promotes
      phagophore expansion by lipid transfer and tethering.
    additional_reference_ids:
    - PMID:31271352
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Tethers the edge of the isolation membrane (IM) to the endoplasmic reticulum (ER)
- term:
    id: GO:0000425
    label: pexophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Pexophagy over-specifies the supported ATG2A process role.
    action: MODIFY
    reason: >-
      ATG2A is core autophagosome-biogenesis machinery. The available human evidence does not establish
      an ATG2A-specific role in peroxisome cargo recognition or peroxisome-selective autophagy, so this
      cargo-specific IBA should be generalized.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation
    - reference_id: PMID:31271352
      supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion
- term:
    id: GO:0043495
    label: protein-membrane adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: ATG2A has a core membrane-adaptor/tethering role at ER-phagophore contact sites.
    action: ACCEPT
    reason: >-
      Accept as a core molecular function. ATG2A couples WIPI/Atg18-family PI3P effectors, ATG9A-containing
      membranes, and ER/phagophore membranes in a lipid-transfer assembly. This term captures the adaptor/tether
      aspect of the function alongside the more direct lipid transfer activity term.
    additional_reference_ids:
    - PMID:31271352
    - PMID:31412244
    - PMID:39174844
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: ATG2 stably tethers two membranes and transfers lipids between them
    - reference_id: PMID:39174844
      supporting_text: ATG2A tethers lipid vesicles at different orientations
- term:
    id: GO:0061723
    label: glycophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Glycophagy is too cargo-specific for the reviewed ATG2A evidence.
    action: MODIFY
    reason: >-
      The evidence supports ATG2A as general phagophore expansion machinery. No cached human evidence shows
      that ATG2A specifically recognizes glycogen cargo or has a glycophagy-selective role independent of
      its core autophagosome-assembly function.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells
    - reference_id: PMID:31271352
      supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion
- term:
    id: GO:0032266
    label: phosphatidylinositol-3-phosphate binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: PI3P-associated recruitment is supported, but direct ATG2A PI3P binding is not established.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Human ATG2A is recruited to PI3P-rich phagophore membranes through WIPI/Atg18-family effectors.
      The accessible evidence supports WIPI-mediated association with PI3P-containing membranes rather than
      ATG2A itself independently enabling phosphatidylinositol-3-phosphate binding.
    additional_reference_ids:
    - PMID:31271352
    - PMID:32483132
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: WIPI4 and WIPI1 associate ATG2A stably to PI3P-containing vesicles
    - reference_id: PMID:32483132
      supporting_text: WIPI proteins tend to recognize phosphoinositides and the WIR-peptide simultaneously
- term:
    id: GO:0034727
    label: piecemeal microautophagy of the nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Nucleophagy/PMN over-specifies the conserved ATG2A autophagy role.
    action: MODIFY
    reason: >-
      The annotation projects a cargo- and pathway-specific yeast selective-autophagy process to human
      ATG2A. Human ATG2A evidence supports autophagosome biogenesis through lipid transfer, not a direct
      ATG2A-specific role in piecemeal nuclear microautophagy.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: lipid transfer across contact sites is a principal contributor to autophagosome formation
    - reference_id: PMID:31271352
      supporting_text: transfer of ER lipids to the phagophore, driving phagophore expansion
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Reticulophagy is plausible pathway context but not an ATG2A-specific cargo claim.
    action: MODIFY
    reason: >-
      ATG2A functions at ER-phagophore contact sites, but that does not by itself establish a selective
      ER-autophagy role for ATG2A. The conservative replacement is the general autophagosome-assembly
      process supported by direct lipid-transfer and rescue data.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: operating at the ER-autophagosome interface
    - reference_id: PMID:31271352
      supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization is supported and central to ATG2A function.
    action: ACCEPT
    reason: >-
      Accept. UniProt subcellular-location mapping agrees with direct human evidence placing ATG2A at
      ER-autophagosome/phagophore contact sites, where it mediates lipid transfer from ER-associated donor
      membranes.
    additional_reference_ids:
    - PMID:30952800
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: operating at the ER-autophagosome interface
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lipid-droplet association is supported but secondary to the core autophagosome-biogenesis role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep as non-core. ATG2A has a documented lipid-droplet association and affects lipid-droplet morphology,
      but the PN-relevant core function is ER/phagophore lipid transfer for autophagosome assembly.
    additional_reference_ids:
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Also regulates lipid droplets morphology and distribution within the cell
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Autophagy is correct but too broad for the reviewed ATG2A process.
    action: MODIFY
    reason: >-
      ATG2A is not merely associated with generic autophagy; direct experiments support a more specific role
      in autophagosome assembly through phagophore expansion and lipid transfer.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: lipid transfer across contact sites is a principal contributor to autophagosome formation
    - reference_id: PMID:31271352
      supporting_text: ATG2-mediated transfer of lipids from the ER to the phagophore enables phagophore expansion
- term:
    id: GO:0034045
    label: phagophore assembly site membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ATG2A localizes to the phagophore assembly site membrane.
    action: ACCEPT
    reason: >-
      Accept. This location is supported by UniProt subcellular mapping and direct imaging/biochemical
      evidence placing ATG2A at the ER-phagophore edge.
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: between the ER and the phagophore edge
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Preautophagosomal structure membrane
- term:
    id: GO:0120009
    label: intermembrane lipid transfer
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: ATG2A mediates intermembrane lipid transfer during phagophore expansion.
    action: ACCEPT
    reason: >-
      Accept as a core biological process. The logical inference from lipid transfer activity is directly
      consistent with in vitro lipid-transfer assays, structural work, and cellular rescue data.
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    - PMID:39174844
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro
    - reference_id: PMID:39174844
      supporting_text: mediating lipid transfer and re-equilibration between membranes for autophagosome formation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: Large-scale interaction evidence is real but generic protein binding is not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The Behrends et al. autophagy interaction network places ATG2A among ATG8/WIPI-associated autophagy
      proteins, but GO:0005515 does not capture ATG2A's actual molecular function. The informative functions
      are lipid transfer, membrane tether/adaptor activity, and ATG2-WIPI/Atg18 complex membership.
    additional_reference_ids:
    - PMID:20562859
    - PMID:31271352
    supported_by:
    - reference_id: PMID:20562859
      supporting_text: a network of 751 interactions among 409 candidate interacting proteins
    - reference_id: PMID:31271352
      supporting_text: ATG2 stably tethers two membranes and transfers lipids between them
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31412244
  qualifier: enables
  review:
    summary: ATG2A interactions with TOM40, ATG9A, and WIPI4 are functional context, not generic MF.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interactions in this study are biologically meaningful for MAM recruitment and phagophore growth,
      but generic protein binding should not be retained as the functional statement. The better-curated
      assertions are organelle membrane contact site, autophagosome assembly, and lipid-transfer/adaptor roles.
    additional_reference_ids:
    - PMID:31412244
    supported_by:
    - reference_id: PMID:31412244
      supporting_text: Atg2A directly interacts with Atg9A at the MAM to promote phagophore growth
    - reference_id: PMID:31412244
      supporting_text: TOM70-TOM40 complex recruits Atg2A to the MAM
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome protein binding is not informative for ATG2A function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The binary interactome row does not add a mechanistic ATG2A function beyond generic protein binding
      and is not central to the autophagy/lipid-transfer evidence. It should not be treated as a core MF.
    additional_reference_ids:
    - PMID:32296183
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32483132
  qualifier: enables
  review:
    summary: WIPI3/WIPI4 binding is specific evidence for the ATG2-WIPI/Atg18 complex, not generic binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This structural evidence supports a specific WIR-mediated association of ATG2A with WIPI
      beta-propellers, not generic protein binding as a useful molecular-function statement. Because
      GO:0062079 is a cellular-component term, the complex context is captured separately as a NEW
      annotation rather than as a replacement for this MF row.
    additional_reference_ids:
    - PMID:32483132
    - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
    supported_by:
    - reference_id: PMID:32483132
      supporting_text: WIPI4 forms a complex with ATG2A/B
    - reference_id: PMID:32483132
      supporting_text: disrupt the interactions between WIPI3/4 and ATG2A and impair the ATG2A-mediated autophagic process
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IMP
  original_reference_id: PMID:32483132
  qualifier: involved_in
  review:
    summary: ATG2A-WIPI disruption impairs autophagy, but ATG2A is core assembly machinery rather than only a regulator.
    action: MODIFY
    reason: >-
      The evidence shows that disrupting ATG2A-WIPI interactions impairs the ATG2A-mediated autophagic process.
      For ATG2A itself, the more direct process term is autophagosome assembly.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:32483132
    - PMID:31271352
    supported_by:
    - reference_id: PMID:32483132
      supporting_text: impair the ATG2A-mediated autophagic process
    - reference_id: PMID:31271352
      supporting_text: Direct tethering of the ER and the phagophore edge by the ATG2-WIPI complex
- term:
    id: GO:0120013
    label: lipid transfer activity
  evidence_type: IMP
  original_reference_id: PMID:39174844
  qualifier: enables
  review:
    summary: Structural data support ATG2A lipid transfer activity with ATG9A/WIPI4 complexes.
    action: ACCEPT
    reason: >-
      Accept as core molecular function. Structural and mechanistic evidence supports ATG2A as a lipid-transfer
      protein whose cavity and ATG9A/WIPI4-associated assemblies mediate lipid transfer during autophagosome
      formation.
    additional_reference_ids:
    - PMID:39174844
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:39174844
      supporting_text: Structural basis for lipid transfer by the ATG2A-ATG9A complex
    - reference_id: PMID:39174844
      supporting_text: human ATG2A in complex with WD-repeat protein interacting with phosphoinositides 4
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:30952800
  qualifier: located_in
  review:
    summary: Direct evidence places ATG2A at the ER/autophagosome interface.
    action: ACCEPT
    reason: >-
      Accept. This experimentally supported location is central to ATG2A's lipid-transfer function during
      phagophore expansion.
    additional_reference_ids:
    - PMID:30952800
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: operating at the ER-autophagosome interface
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Lipid-droplet localization is supported by homology/UniProt but is non-core for this review.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep as non-core. ATG2-family lipid-droplet association is compatible with UniProt, but the core
      human ATG2A role for this PN-focused review is lipid transfer at ER/phagophore contact sites.
    additional_reference_ids:
    - file:human/ATG2A/ATG2A-uniprot.txt
    supported_by:
    - reference_id: file:human/ATG2A/ATG2A-uniprot.txt
      supporting_text: Lipid droplet
- term:
    id: GO:0034045
    label: phagophore assembly site membrane
  evidence_type: EXP
  original_reference_id: PMID:30952800
  qualifier: located_in
  review:
    summary: Direct experimental evidence supports ATG2A at the phagophore assembly site membrane.
    action: ACCEPT
    reason: >-
      Accept as a core location. ATG2A is positioned at ER-phagophore contact sites where lipid transfer
      supports phagophore expansion.
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: contact sites between the ER and the autophagophore
    - reference_id: PMID:31271352
      supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge
- term:
    id: GO:0044232
    label: organelle membrane contact site
  evidence_type: IDA
  original_reference_id: PMID:30952800
  qualifier: is_active_in
  review:
    summary: ATG2A is active at organelle membrane contact sites during autophagosome formation.
    action: ACCEPT
    reason: >-
      Accept. ATG2A is a contact-site lipid-transfer protein, with direct evidence for ER-autophagophore
      localization and functional lipid transfer across membranes.
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor
    - reference_id: PMID:31271352
      supporting_text: ATG2 stably tethers two membranes and transfers lipids between them
- term:
    id: GO:0120013
    label: lipid transfer activity
  evidence_type: IDA
  original_reference_id: PMID:30952800
  qualifier: enables
  review:
    summary: Direct biochemical evidence supports ATG2A lipid transfer activity.
    action: ACCEPT
    reason: >-
      Accept as core molecular function. Purified human ATG2A binds multiple glycerophospholipids and
      transfers lipids between membranes in vitro, and lipid-transfer-competent ATG2A fragments rescue
      autophagosome biogenesis.
    additional_reference_ids:
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro
    - reference_id: PMID:30952800
      supporting_text: fully sufficient to rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells
- term:
    id: GO:0120013
    label: lipid transfer activity
  evidence_type: IDA
  original_reference_id: PMID:31271352
  qualifier: enables
  review:
    summary: ATG2A lipid transfer activity is directly demonstrated and WIPI-facilitated.
    action: ACCEPT
    reason: >-
      Accept as core molecular function. This study directly demonstrates human ATG2A lipid transfer,
      membrane tethering, and WIPI-enhanced association with PI3P-containing membranes.
    additional_reference_ids:
    - PMID:31271352
    - PMID:30952800
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: human ATG2A is a lipid transfer protein
    - reference_id: PMID:31271352
      supporting_text: WIPI proteins can facilitate ATG2A-mediated lipid transfer
- term:
    id: GO:2000786
    label: positive regulation of autophagosome assembly
  evidence_type: IDA
  original_reference_id: PMID:30952800
  qualifier: involved_in
  review:
    summary: ATG2A directly participates in autophagosome assembly rather than only regulating it.
    action: MODIFY
    reason: >-
      ATG2A lipid transfer supplies membrane for phagophore expansion, making autophagosome assembly the
      more direct process term. The regulation term is directionally true but less precise for a core
      autophagy machinery component.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:30952800
    supported_by:
    - reference_id: PMID:30952800
      supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation
    - reference_id: PMID:30952800
      supporting_text: rescue blocked autophagosome biogenesis in ATG2A/ATG2B KO cells
- term:
    id: GO:2000786
    label: positive regulation of autophagosome assembly
  evidence_type: IDA
  original_reference_id: PMID:31271352
  qualifier: involved_in
  review:
    summary: WIPI-facilitated ATG2A lipid transfer supports autophagosome assembly.
    action: MODIFY
    reason: >-
      The direct functional role is phagophore expansion/autophagosome assembly via lipid transfer. Use
      autophagosome assembly rather than a regulation term for this core machinery activity.
    proposed_replacement_terms:
    - id: GO:0000045
      label: autophagosome assembly
    additional_reference_ids:
    - PMID:31271352
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: transfer of ER lipids to the phagophore, driving phagophore expansion
    - reference_id: PMID:31271352
      supporting_text: WIPI proteins can facilitate ATG2A-mediated lipid transfer
- term:
    id: GO:0000045
    label: autophagosome assembly
  evidence_type: IMP
  original_reference_id: PMID:28561066
  qualifier: involved_in
  review:
    summary: ATG2A is a core autophagosome-assembly factor.
    action: ACCEPT
    reason: >-
      Accept as core process. WIPI4-ATG2 translocates to nascent autophagosomes and later studies show
      ATG2A lipid transfer and tethering drive phagophore expansion.
    additional_reference_ids:
    - PMID:28561066
    - PMID:30952800
    - PMID:31271352
    supported_by:
    - reference_id: PMID:28561066
      supporting_text: WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes
    - reference_id: PMID:30952800
      supporting_text: protein-mediated lipid transfer across contact sites is a principal contributor to autophagosome formation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28561066
  qualifier: enables
  review:
    summary: WIPI4 interaction should be represented as ATG2-WIPI/Atg18 complex context, not generic binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The biologically meaningful claim is ATG2A association with WIPI4/WDR45 in the autophagy machinery.
      Generic protein binding is over-annotated for this evidence, and the GO:0062079 cellular-component
      complex context is captured separately as a NEW annotation rather than as a replacement for this MF row.
    additional_reference_ids:
    - PMID:28561066
    - PMID:31271352
    - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
    supported_by:
    - reference_id: PMID:28561066
      supporting_text: WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex
    - reference_id: PMID:31271352
      supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge
- term:
    id: GO:0062079
    label: ATG2-ATG18 complex
  evidence_type: IDA
  original_reference_id: PMID:31271352
  qualifier: part_of
  review:
    summary: The PN-projected ATG2-ATG18 complex term is a conservative, supported component annotation.
    action: NEW
    reason: >-
      The Proteostasis PN projection proposes GO:0062079 for the ATG2-WIPI complex component bucket. This
      is more precise than the existing phagophore assembly site locations and is supported by human ATG2A
      evidence showing ATG2-WIPI complexes at the ER-phagophore edge. The GO term uses the yeast Atg18 name,
      but mammalian WIPI proteins are Atg18-family PROPPINs, so this is a reasonable component-level
      propagation; it should not be expanded into cargo-specific selective-autophagy process annotations.
    additional_reference_ids:
    - PMID:31271352
    - PMID:32483132
    - PMID:39174844
    - file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - reference_id: PMID:31271352
      supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge
    - reference_id: PMID:32483132
      supporting_text: WIPI4 forms a complex with ATG2A/B
    - reference_id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
      supporting_text: The GO ATG2-ATG18 complex term is the closest component-level target.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: PMID:20562859
  title: Network organization of the human autophagy system.
  findings:
  - statement: Large-scale autophagy interaction network places ATG2A in autophagy-associated interaction context.
    supporting_text: a network of 751 interactions among 409 candidate interacting proteins
- id: PMID:28561066
  title: WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits
    in the control of autophagy.
  findings:
  - statement: WIPI4-ATG2 translocates to nascent autophagosomes.
    supporting_text: WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes
- id: PMID:30952800
  title: ATG2 transports lipids to promote autophagosome biogenesis.
  findings:
  - statement: ATG2A transfers glycerophospholipids and supports autophagosome biogenesis.
    supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro
  - statement: ATG2A acts at ER-autophagosome contact sites.
    supporting_text: operating at the ER-autophagosome interface
- id: PMID:31271352
  title: The autophagic membrane tether ATG2A transfers lipids between membranes.
  findings:
  - statement: Human ATG2A is a lipid transfer protein.
    supporting_text: human ATG2A is a lipid transfer protein
  - statement: ATG2-WIPI complex acts between ER and phagophore edge.
    supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge
- id: PMID:31412244
  title: TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore
    Expansion.
  findings:
  - statement: ATG2A/B loss impairs phagophore expansion.
    supporting_text: mammalian Atg2A/B functions at the membrane expansion step during autophagosome biogenesis
  - statement: Atg2A interacts with ATG9A at mitochondria-associated ER membranes.
    supporting_text: Atg2A directly interacts with Atg9A at the MAM to promote phagophore growth
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: Binary interactome evidence is generic interaction context.
    supporting_text: A reference map of the human binary protein interactome
- id: PMID:32483132
  title: Multi-site-mediated entwining of the linear WIR-motif around WIPI beta-propellers
    for autophagy.
  findings:
  - statement: WIPI proteins bind the ATG2A WIR motif and support ATG2A-mediated autophagy.
    supporting_text: WIPI4 forms a complex with ATG2A/B
- id: PMID:39174844
  title: Structural basis for lipid transfer by the ATG2A-ATG9A complex.
  findings:
  - statement: Structural data support ATG2A-ATG9A/WIPI4 lipid-transfer assemblies.
    supporting_text: Structural basis for lipid transfer by the ATG2A-ATG9A complex
- id: PMID:38622126
  title: ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores.
  findings:
  - statement: >-
      ANKFY1 is an endosome-localized, FYVE-domain ATG2A-binding protein that binds PI3P and enhances
      ATG2A-mediated lipid transfer between PI3P-containing liposomes, supporting endosome-to-phagophore
      lipid donation; ANKFY1 depletion phenocopies ATG2A/B loss.
- id: PMID:37938170
  title: ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A.
  full_text_unavailable: true
  findings:
  - statement: >-
      ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A and can form
      a heteromeric complex with ATG2A, consistent with ATG2A lipid transfer being coupled to ATG9-family
      scramblase activity.
- id: PMID:37796195
  title: Lysosome damage triggers direct ATG8 conjugation and ATG2 engagement via non-canonical autophagy.
  full_text_unavailable: true
  findings:
  - statement: >-
      Lysosome damage induces non-canonical autophagy (CASM) and promotes ATG2/ATG8 engagement via an
      ATG2 LIR-dependent mode; the robustly demonstrated interaction was ATG2B-LC3A, with a proposed
      role in lysosome repair (ATG2A-specific contribution inferred rather than directly established).
- id: PMID:38294121
  title: Exploring the ATG9A interactome uncovers interaction with VPS13A.
  full_text_unavailable: true
  findings:
  - statement: >-
      ATG9A acts as a lipid scramblase whose function is thought to require interaction with the lipid
      transfer protein ATG2A; ATG9A and ATG2A are proposed to function together to expand the growing
      autophagosome, and ATG9A forms a distinct complex with VPS13A separate from the ATG9A-ATG2A complex.
- id: file:human/ATG2A/ATG2A-uniprot.txt
  title: UniProtKB record for human ATG2A
  findings:
  - statement: UniProt summarizes ATG2A as a lipid transfer protein involved in autophagosome assembly.
    supporting_text: Lipid transfer protein involved in autophagosome assembly
- id: file:human/ATG2A/ATG2A-goa.tsv
  title: GOA annotations fetched for human ATG2A
  findings: []
- id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml
  title: Proteostasis Network autophagy-lysosome pathway mappings
  findings:
  - statement: PN mapping treats the ATG2-WIPI bucket as the ATG2-ATG18 complex.
    supporting_text: The GO ATG2-ATG18 complex term is the closest component-level target.
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
  title: Proteostasis Network projected candidate GO additions
  findings:
  - statement: ATG2A was projected to GO:0062079 ATG2-ATG18 complex.
    supporting_text: ATG2A was projected to GO:0062079 ATG2-ATG18 complex in the PN candidate additions table.
core_functions:
- description: >-
    ATG2A is a high-capacity glycerophospholipid transfer protein that tethers donor and acceptor
    membranes at ER-phagophore contact sites and supplies lipids for phagophore expansion during
    autophagosome assembly.
  molecular_function:
    id: GO:0120013
    label: lipid transfer activity
  directly_involved_in:
  - id: GO:0120009
    label: intermembrane lipid transfer
  - id: GO:0000045
    label: autophagosome assembly
  locations:
  - id: GO:0044232
    label: organelle membrane contact site
  - id: GO:0034045
    label: phagophore assembly site membrane
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:30952800
    supporting_text: ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro
  - reference_id: PMID:31271352
    supporting_text: ATG2 stably tethers two membranes and transfers lipids between them
- description: >-
    ATG2A forms an ATG2-WIPI/Atg18-family complex at PI3P-rich phagophore edges, linking WIPI
    phosphoinositide effectors and ATG2A lipid-transfer activity to membrane expansion.
  molecular_function:
    id: GO:0043495
    label: protein-membrane adaptor activity
  directly_involved_in:
  - id: GO:0000045
    label: autophagosome assembly
  locations:
  - id: GO:0000407
    label: phagophore assembly site
  supported_by:
  - reference_id: PMID:31271352
    supporting_text: we place the ATG2-WIPI complex between the ER and the phagophore edge
  - reference_id: PMID:32483132
    supporting_text: WIPI4 forms a complex with ATG2A/B
proposed_new_terms: []
suggested_questions:
- question: >-
    Should human ATG2A be annotated to phosphatidylinositol-3-phosphate binding only as part of
    a WIPI/Atg18-containing complex, rather than as an independent ATG2A molecular function?
  experts:
  - GO autophagy editors
  - autophagy lipid-transfer experts
- question: >-
    Which selective autophagy cargo pathways have ATG2A-specific evidence beyond the general requirement
    for ATG2A-mediated phagophore expansion?
  experts:
  - GO autophagy editors
  - Proteostasis Consortium ALP curators
- question: >-
    Should GO:0062079 be updated to explicitly mention mammalian ATG2-WIPI complexes, since the current
    definition names the Saccharomyces cerevisiae ATG2-ATG18 composition?
  experts:
  - GO cellular-component editors
  - ComplexPortal curators
- question: >-
    Given the ANKFY1 finding that ATG2A can accept lipids from PI3P-positive endosomes, should ATG2A
    localization/process annotations extend beyond ER-phagophore contact sites to endosome-phagophore
    interfaces, or is this best captured by an ANKFY1-dependent recruitment annotation rather than a
    new ATG2A site?
  experts:
  - GO autophagy editors
  - autophagy membrane-contact-site experts
- question: >-
    Does human ATG2A (as opposed to ATG2B) have a direct, LIR/ATG8-dependent role in non-canonical
    autophagy (CASM) and lysosome repair upon lysosomal damage, distinct from its WIPI4-dependent
    canonical phagophore-expansion function?
  experts:
  - GO autophagy editors
  - lysosome biology experts
suggested_experiments:
- experiment_type: Selective-autophagy separation-of-function rescue
  description: >-
    Rescue ATG2A/ATG2B double-knockout human cells with ATG2A variants that selectively disrupt
    WIPI binding, TOM40/MAM targeting, or ATG9A association, then quantify mitophagy, pexophagy,
    ER-phagy, and glycophagy reporters alongside bulk autophagic flux.
  hypothesis: >-
    ATG2A is required for selective-autophagy reporter completion primarily through its general
    phagophore-expansion function, not through cargo-specific recognition.
- experiment_type: Endogenous ATG2-WIPI complex composition assay
  description: >-
    Use starvation time courses with endogenous tagging or proximity labeling of ATG2A, WIPI1/2/3/4,
    and ATG9A, followed by quantitative proteomics and imaging at ER-phagophore contact sites.
  hypothesis: >-
    Human ATG2A participates in condition- and stage-specific ATG2-WIPI/Atg18 complexes whose
    component composition explains the PN-projected ATG2-ATG18 complex annotation.

ATG2A

Gene Description

Existing Annotations Review

Core Functions

ATG2A is a high-capacity glycerophospholipid transfer protein that tethers donor and acceptor membranes at ER-phagophore contact sites and supplies lipids for phagophore expansion during autophagosome assembly.

ATG2A forms an ATG2-WIPI/Atg18-family complex at PI3P-rich phagophore edges, linking WIPI phosphoinositide effectors and ATG2A lipid-transfer activity to membrane expansion.

References

Suggested Questions for Experts

Suggested Experiments

Tags

Deep Research

Falcon

Research report: Human ATG2A (UniProt Q2TAZ0) functional annotation (2023–2024 focus)

0) Gene/protein identity verification (required)

1) Key concepts and definitions (current understanding)

1.1 Macroautophagy and the phagophore expansion problem

1.2 Bridge-like (bulk) lipid transfer vs. shuttle lipid transfer

1.3 Lipid transfer must be coupled to lipid scrambling

2) Molecular function of ATG2A

2.1 Core molecular function: tethering and bulk lipid transfer for phagophore growth

2.2 ATG2A as a bulk lipid transfer factor outside canonical phagophore growth: lipid droplets

3) Key interaction partners and mechanistic roles

3.1 WIPI4/WDR45 (PI3P effector) – targeting and directionality

3.2 ATG9A and ATG9B – scramblases coupled to ATG2A transfer

3.3 VMP1 and TMEM41B – ER-side scramblases interacting with ATG2A

3.4 GABARAP/ATG8 family – LIR-mediated interactions and late-stage biogenesis

3.5 ANKFY1 – 2024 discovery of an endosomal bridge for ATG2A lipid transfer

4) Subcellular localization and pathway context

4.1 ER–phagophore membrane contact sites (including omegasome-associated regions)

4.2 Endosome–phagophore interfaces (2024 extension)

4.3 Lipid droplets

5) Recent developments (prioritized 2023–2024)

5.1 2023 authoritative reviews consolidated the bridge-transfer paradigm

5.2 2023–2024: Expansion beyond “ER-only” lipid donation

5.3 2023: ATG2 engagement in non-canonical autophagy during lysosome damage

5.4 2024: Refining the “core lipid transfer complex” and paralog compensation

6) Relevant statistics and quantitative data (from recent studies)

7) Current applications and real-world implementations

7.1 Practical implementations in cell biology and drug discovery pipelines (research use)

7.2 Translational relevance (current state)

8) Expert opinions and analysis (authoritative synthesis)

9) Visual evidence

10) Summary table (evidence map)

Key cited sources (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

ATG2A notes

Falcon deep research findings (2026-06-07)

Pn Notes

ATG2A PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Regulation of autophagophore membrane composition | ATG2-WIPI complex component

Projected GO annotations (1)

Note

📄 View Raw YAML