atg2

Summary: Atg2 is essential for autophagosome assembly, functioning as a lipid transfer protein that tethers the ER to the expanding phagophore and mediates phospholipid transfer for membrane expansion. This is phylogenetically conserved across ATG2 family members (PMID:30911189).

Reason: This is a core function of Atg2 confirmed by extensive experimental evidence. The IBA annotation is well-supported by the phylogenetic analysis and confirmed by direct experimental evidence in S. pombe showing Atg2 is required for autophagosome formation (PMID:23950735, PMID:37553386). Note on the falcon supporting_text below: in Sun et al. 2013 (PMID:23950735), atg2Δ lacks the biochemical free-CFP band in the CFP-Atg8 processing (immunoblot) assay, but in the CFP-Atg8 puncta imaging assay atg2Δ is classified as Group 3 - cells form abnormally numerous, brighter, and long-lived Atg8 puncta. Maturation of autophagic structures is therefore severely impaired rather than a complete absence of puncta formation; the truly complete block of puncta formation belongs to the Atg8-conjugation and PI3K (atg6Δ, atg14Δ) mutants, not atg2Δ.

Summary: Atg2 localizes to the phagophore assembly site (PAS) where it tethers the ER to the nascent phagophore. This localization is conserved across eukaryotes.

Reason: PAS localization is a core aspect of Atg2 function, supported by the phylogenetic inference and confirmed by direct IDA evidence in S. pombe (PMID:23950735, PMID:31941401).

Summary: Atg2 participates in mitophagy (autophagy of mitochondria) as part of the core autophagy machinery required for selective organelle degradation.

Reason: The IBA annotation reflects that Atg2 is required for the autophagy machinery that degrades mitochondria. While Atg2 is not a mitophagy-specific receptor, it is essential for the general autophagy process that includes mitophagy. The deep research confirms Atg2 is critical for selective organelle autophagy including mitochondria and ER.

Summary: Atg2 localizes to the phagophore where it mediates lipid transfer at the membrane edge during autophagosome expansion.

Reason: Phagophore localization is central to Atg2 function and conserved across ATG2 family. Confirmed by IDA in S. pombe (PMID:37553386).

Summary: Atg2 is involved in pexophagy (selective autophagy of peroxisomes) as part of the core autophagy machinery. UniProt notes Atg2 is required for peroxisome degradation.

Reason: The IBA annotation is appropriate as Atg2 is required for the autophagy machinery that mediates selective peroxisome degradation. This is phylogenetically conserved and noted in the UniProt entry as a known function.

Summary: Atg2 functions as a protein-membrane adaptor, bridging the ER membrane and the phagophore through its distinct N-terminal and C-terminal membrane-binding regions.

Reason: This molecular function describes Atg2's tethering activity connecting two membranes. Confirmed by EXP evidence in S. pombe (PMID:30911189) and is phylogenetically conserved.

Summary: Atg2 is involved in glycophagy as part of the core autophagy machinery, though this is inferred from phylogenetic analysis with Drosophila and other species.

Reason: While Atg2 is essential for autophagy and would be required for glycophagy, there is no direct evidence in S. pombe for glycophagy involvement. The IBA is based on inference from other species. Accept as a non-core function.

Summary: Atg2 binding to PI3P is indirect, mediated through its partner Atg18 which directly binds PI3P via its PROPPIN domain.

Reason: The deep research indicates that PI3P binding is mediated by Atg18/WIPI proteins, not Atg2 directly. Atg2 recruitment to PI3P-enriched membranes depends on Atg18. The annotation should be considered in context - if this is meant to indicate functional association with PI3P through the Atg2-Atg18 complex, it may be misleading as a direct molecular function of Atg2. The falcon deep research reinforces this: in S. pombe the Atg18-family member Atg18a (not Atg2 itself) promotes PAS targeting of Atg2, consistent with PI3P recognition being delegated to the Atg18 partner. The more informative core molecular function of Atg2 is lipid transfer activity (GO:0120013).

Proposed replacements: lipid transfer activity

Summary: Atg2 is involved in piecemeal microautophagy of the nucleus (PMN) as part of the core autophagy machinery based on phylogenetic inference from S. cerevisiae.

Reason: While PMN is documented in S. cerevisiae and Atg2 would be required as part of the autophagy machinery, there is no direct evidence for this specific process in S. pombe. Keep as non-core function based on phylogenetic inference.

Summary: Atg2 is involved in reticulophagy (ER-phagy) as part of the core autophagy machinery. The deep research confirms Atg2 is critical for selective autophagy of ER.

Reason: The deep research states Atg2 is particularly important for selective autophagy of organelles including ER. This is consistent with Atg2's role at ER-phagophore contact sites. Accept as representing a core selective autophagy function.

Summary: Atg2 associates with the ER membrane through its N-terminal region, tethering the ER to the phagophore at membrane contact sites.

Reason: ER membrane association is a core aspect of Atg2 function, essential for lipid transfer from ER to phagophore. The IEA from UniProt subcellular location is accurate and supported by the deep research and UniProt entry.

Summary: Atg2 is a lipid transfer protein that transports phospholipids from ER to phagophore, and also transfers triglycerides.

Reason: Lipid transport is a core molecular function of Atg2. While GO:0120010 (intermembrane phospholipid transfer) or GO:0120013 (lipid transfer activity) are more specific, this broader IEA annotation from keyword mapping is not incorrect.

Summary: Atg2 is essential for autophagy, functioning in autophagosome biogenesis through lipid transfer and membrane tethering.

Reason: Autophagy is the core biological process for Atg2. This IEA annotation from InterPro/UniProt combined methods is accurate and supported by extensive experimental evidence including IMP annotations for macroautophagy.

Summary: Atg2 is required for normal sporulation in S. pombe, which depends on autophagy for nutrient recycling during nitrogen starvation. The gene was originally identified as mug36 (meiotically up-regulated gene 36).

Reason: While Atg2 is upregulated during meiosis/sporulation and autophagy-deficient mutants show partial sporulation defects, this is a consequence of the autophagy function rather than a direct role in sporulation machinery. The deep research notes that autophagy supplies nutrients for sporulation, so Atg2 involvement is indirect.

Summary: Atg2 localizes to the phagophore assembly site membrane where it functions in membrane tethering and lipid transfer.

Reason: This cellular component annotation accurately reflects Atg2 localization. Confirmed by IDA evidence at PAS (PMID:23950735, PMID:31941401), and the falcon deep research adds that Atg2 is required for retrograde recycling of Atg9/Ctl1 away from the PAS. [2026-08 re-review against GO issue #29437] The supporting evidence quoted here describes PAS puncta / PAS accumulation, not a membrane. GO:0034045 asserts, via bounding_layer_of, that a membrane bounds the phagophore assembly site; the PAS is a liquid-like protein condensate with no bounding bilayer (PMID:32025038), and the term additionally carries 'phagophore' and 'isolation membrane' as synonyms of the distinct term GO:0061908. This annotation derives solely from the UniProt SL-0221 subcellular location via GO_REF:0000044, which is the propagation source rather than independent evidence. Generalize to the structure the cited experiments actually show.

Proposed replacements: phagophore assembly site

Summary: This annotation derives from the UniProt Meiosis keyword assigned because atg2/mug36 was identified as meiotically up-regulated. However, Atg2 is autophagy machinery, not meiotic cell cycle machinery.

Reason: This is a clear over-annotation. Atg2 is autophagy machinery that becomes upregulated during meiosis/sporulation because autophagy provides nutrients needed for this process. Atg2 has no direct role in meiotic cell cycle regulation (chromosome segregation, cell division, etc.). The gene was named mug36 (meiotically up-regulated) based on expression pattern, not function. ATG genes are not meiotic regulators - they are upregulated during meiosis because autophagy is induced. This SPKW-derived annotation conflates correlation (upregulation during meiosis) with causation (involvement in meiosis).

Summary: Recent work demonstrates that ATG2 can transfer triglycerides in addition to phospholipids. This expands our understanding of ATG2 as a broad lipid transfer protein. However, the cited study (PMID:41296734) examines human ATG2A exclusively; there is no direct S. pombe atg2 triglyceride-transfer data, so the assertion for S. pombe rests on cross-species inference from the conserved bridge-like lipid transfer domain.

Reason: The biological assignment (triglyceride transfer activity for the ATG2 family) is plausible, but the TAS evidence code is not appropriate for the S. pombe atg2 annotation. PMID:41296734 (Korfhage et al., PNAS 2025, "ATG2 is a triglyceride transfer protein") studies HUMAN ATG2A exclusively - all biochemical work uses purified ATG2A on synthetic liposomes/lipid droplets, and the lipidomics is of purified ATG2A; the paper contains no S. pombe atg2 data. TAS (Traceable Author Statement) requires the cited paper to directly state the function for the annotated protein. An inference from mammalian ATG2A to S. pombe atg2 based on structural conservation is sequence/ortholog-based inference (ISS/ISO/IBA), not TAS. The term itself is retained because the function is likely conserved given the conserved hydrophobic-channel lipid-transfer domain, but the evidence code should be corrected to reflect cross-species inference rather than a direct traceable statement for S. pombe atg2. Until confirmed experimentally in S. pombe (see suggested experiments), this should not be treated as a directly established S. pombe atg2 function.

Proposed replacements: triglyceride transfer activity

Summary: Atg2 is involved in mitophagy as part of the core autophagy machinery required for selective mitochondrial degradation. This IC annotation is inferred from autophagosome assembly (GO:0000045) and autophagy of mitochondrion (GO:0000422).

Reason: The IC inference is sound - Atg2 is essential for autophagosome assembly which is required for mitophagy. Also supported by IBA for GO:0000422. Accept as core function.

Summary: Direct experimental evidence shows Atg2 is required for autophagosome formation in S. pombe. Atg2-tdT colocalizes with phagophores and is essential for autophagy.

Reason: Strong experimental evidence confirming Atg2's core role in autophagosome assembly. This is the primary function of the protein.

Summary: Direct assay shows Atg2 localizes to phagophores during autophagy in S. pombe.

Reason: IDA evidence confirms phagophore localization, consistent with Atg2's role in lipid transfer at phagophore-ER contact sites. The falcon deep research adds high-resolution APEX2 EM evidence placing Atg2 specifically at the phagophore rim/tips.

Summary: Experimental evidence from crystallography and functional studies shows Atg2 bridges membranes, acting as a protein-membrane adaptor that tethers ER to phagophore.

Reason: Core molecular function demonstrated by structural and functional studies. The Chorein_N domain crystal structure and lipid transfer assays confirm this activity.

Summary: Atg2 mediates intermembrane phospholipid transfer as a bridge-like lipid transfer protein, transferring phospholipids from ER to expanding phagophore.

Reason: Core biological process for Atg2, directly demonstrated biochemically (PMID:30911189) and reviewed in PMID:32213462 as part of the chorein-N motif protein family mechanism.

Summary: Direct assay shows Atg2 localizes to the phagophore assembly site in S. pombe, consistent with its role in autophagosome biogenesis.

Reason: IDA confirms PAS localization. The study on Atg38-Atg8 interaction shows PAS accumulation of Atg2 is reduced by disrupting the Atg38-Atg8 interaction, confirming Atg2's PAS localization.

Summary: Mutant phenotype analysis shows atg2 deletion impairs macroautophagy in S. pombe.

Reason: IMP evidence from mutant phenotype analysis confirms Atg2 is required for macroautophagy. This is the core biological process for the protein. The falcon supporting_text below refers to the biochemical CFP-Atg8 processing (free-CFP immunoblot) assay, which atg2Δ fails. In the complementary imaging assay (Sun et al. 2013, PMID:23950735) atg2Δ is a Group 3 mutant - Atg8 puncta are abnormally numerous and long-lived, i.e. autophagosome maturation is severely impaired rather than puncta being absent. Both readouts agree that productive macroautophagy flux is blocked.

Summary: Direct assay shows Atg2 localizes to PAS, and Atg2 is required for normal PAS dynamics.

Reason: IDA evidence confirming PAS localization. The study shows Atg8 puncta in atg2 delta cells are long-lasting structures, indicating Atg2's role in PAS organization.

Summary: Mutant phenotype analysis in the global screen for autophagy factors shows atg2 deletion causes macroautophagy defects.

Reason: Confirmed by IMP mutant phenotype - atg2 delta shows defective Atg8 processing and long-lasting Atg8 puncta, indicating impaired macroautophagy.