Atg38 is an essential subunit of the autophagy-specific phosphatidylinositol 3-kinase (PtdIns3K) complex I in fission yeast. The protein contains an N-terminal MIT domain that mediates interaction with other complex I subunits and a C-terminal coiled-coil homodimerization domain. In S. pombe, Atg38 uniquely contains an Atg8-family-interacting motif (AIM) that establishes a positive feedback loop by binding lipidated Atg8 at the phagophore assembly site, enhancing PtdIns3K complex I recruitment and autophagosome formation efficiency. The protein is required for nitrogen starvation-induced autophagy. The alternative name mug167 (meiotically up-regulated gene 167) reflects transcriptomic identification but does not indicate a meiosis-specific function; rather, atg38 is a core autophagy component.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Atg38 localizes to both the cytosol and the phagophore assembly site (PAS). The UniProt record states subcellular location as "Cytoplasm, cytosol" in addition to the preautophagosomal structure membrane. This is supported by experimental evidence showing that Atg38 exists in a soluble cytoplasmic fraction when the C-terminal domain is disrupted. Reason: The cytosol localization is correct as a baseline localization for Atg38. The deep research indicates that "under nutrient-rich conditions without autophagy induction, Atg38-GFP signals are detected on the vacuolar membrane in addition to the cytoplasm" and UniProt confirms cytosol as one of the subcellular locations. Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md under nutrient-rich conditions without autophagy induction, Atg38-GFP signals are detected on the vacuolar membrane in addition to the cytoplasm file:SCHPO/atg38/atg38-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:31941401} |
| GO:0006914 autophagy | IEA GO_REF:0000043 | MODIFY | Summary: Atg38 is an essential component of the autophagy machinery. The deep research and primary literature clearly establish that atg38 deletion mutants show severely compromised viability during nitrogen starvation and complete absence of starvation-induced autophagy. Reason: While Atg38 is clearly involved in autophagy, the term GO:0006914 (autophagy) is quite broad. More specific experimental evidence demonstrates involvement in macroautophagy specifically. The more specific term GO:0016236 (macroautophagy) is already annotated with experimental evidence (IMP), so this broader IEA annotation is acceptable as a correct but less specific annotation. Proposed replacements: macroautophagy Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md In wild-type S. pombe cells, Pho8delta60 activity increases substantially in response to nitrogen starvation (a potent autophagy inducer), whereas in atg38 deletion mutants, this starvation-induced increase in Pho8delta60 activity is completely absent, demonstrating that Atg38 is absolutely required for autophagy under starvation stress file:SCHPO/atg38/atg38-deep-research-falcon.md atg38Ξ** blocked starvation-induced **CFP-Atg8** processing and abolished starvation-induced increase in **Pho8Ξ60** activity |
| GO:0034045 phagophore assembly site membrane | IEA GO_REF:0000044 | MODIFY | Summary: Atg38 localizes to the phagophore assembly site (PAS) membrane, which is the site of autophagosome nucleation. This is experimentally demonstrated and the IEA annotation correctly reflects the UniProt subcellular location annotation. Reason: The deep research clearly states that "Atg38 localizes to the PAS in an Atg14-dependent manner" and UniProt indicates "Preautophagosomal structure membrane" as a subcellular location. This IEA annotation is consistent with the experimental evidence from PMID:31941401. [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 Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md Atg38 localizes to the PAS in an Atg14-dependent manner, meaning that deletion of the atg14 gene completely abolishes PAS accumulation of Atg38 file:SCHPO/atg38/atg38-uniprot.txt Preautophagosomal structure membrane {ECO:0000269|PubMed:31941401} file:SCHPO/atg38/atg38-deep-research-falcon.md Atg38 forms starvation-induced puncta that colocalize with Atg8 at the PAS, and Atg14 is required for Atg38 puncta formation, consistent with complex I-dependent targeting |
| GO:0051321 meiotic cell cycle | IEA GO_REF:0000043 | REMOVE | Summary: This annotation is based on the UniProt keyword "Meiosis" which was assigned because of the alternative gene name mug167 (meiotically up-regulated gene 167). However, this naming reflects transcriptomic identification context, not functional involvement in meiosis. Reason: The deep research explicitly states: "the primary function of Atg38 is not meiosis-specific; rather, it represents a housekeeping component of the autophagy machinery that is essential for both vegetative autophagy and the nitrogen starvation response that precedes sexual differentiation. The dual naming convention reflects the different experimental contexts in which the gene was discovered." The connection to meiosis is purely circumstantial - the gene was named mug167 because it was found to be upregulated during meiosis in a transcriptomic screen, but this does not indicate a meiosis-specific function. The primary and well-characterized function of Atg38 is in autophagy. This represents a classic over-annotation based on naming rather than functional evidence. Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md the primary function of Atg38 is not meiosis-specific; rather, it represents a housekeeping component of the autophagy machinery that is essential for both vegetative autophagy and the nitrogen starvation response that precedes sexual differentiation file:SCHPO/atg38/atg38-deep-research-perplexity.md The alternative designation of Atg38 as the meiotically up-regulated gene 167 (MUG167) protein reflects its identification in transcriptomic studies examining gene expression changes during the transition from vegetative growth to meiosis file:SCHPO/atg38/atg38-deep-research-falcon.md supporting a relatively specific defect in autophagy initiation/efficiency |
| GO:0016236 macroautophagy | NAS PMID:31941401 Atg38-Atg8 interaction in fission yeast establishes a positi... | ACCEPT | Summary: Atg38 is essential for macroautophagy as demonstrated by multiple experimental approaches in PMID:31941401 including Pho8delta60 assays, CFP-Atg8 processing assays, and electron microscopy of autophagosome formation. Reason: The NAS (Non-traceable Author Statement) evidence is well-supported by the extensive experimental data in PMID:31941401 and the deep research review. The primary literature demonstrates that Atg38 is absolutely required for nitrogen starvation-induced autophagy. Multiple assays confirm this: Pho8delta60 activity (autophagy flux), CFP-Atg8 processing, and Tdh1-YFP processing all show complete loss of autophagy in atg38 deletion mutants. Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md Macroautophagy (autophagy) is driven by the coordinated actions of core autophagy-related (Atg) proteins file:SCHPO/atg38/atg38-deep-research-perplexity.md Wild-type cells show robust nitrogen starvation-induced Tdh1-YFP processing, while atg38 mutants show severely reduced or absent processing file:SCHPO/atg38/atg38-deep-research-falcon.md primary biological role is in **autophagosome formation efficiency**, by promoting PI3K complex I recruitment/accumulation at the PAS and supporting downstream assembly steps, including Atg8 lipidation and autophagosome growth |
| GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I | EXP PMID:34499173 Visual detection of binary, ternary and quaternary protein i... | ACCEPT | Summary: PMID:34499173 used a Pil1 co-tethering assay to systematically characterize protein-protein interactions in autophagy complexes, finding that Atg38 is incorporated into the PtdIns3K complex I via an Atg38-Vps34 interaction. Reason: The complex membership is well-established. PMID:34499173 provides direct experimental evidence for Atg38 incorporation into PtdIns3K complex I. This is consistent with the extensive characterization in PMID:31941401 and the UniProt annotation describing Atg38 as a "Component of the autophagy-specific vps34 PI3-kinase complex I composed of vps15, atg6, pik3/vps34, atg14 and atg38." Supporting Evidence: PMID:34499173 Atg38 is incorporated into the PtdIns3K complex I via an Atg38-Vps34 interaction file:SCHPO/atg38/atg38-uniprot.txt Component of the autophagy-specific vps34 PI3-kinase complex I composed of vps15, atg6, pik3/vps34, atg14 and atg38 file:SCHPO/atg38/atg38-deep-research-falcon.md Biochemical co-purification shows *S. pombe* Atg38 associates with complex I components file:SCHPO/atg38/atg38-deep-research-falcon.md but not with the complex II-specific subunit **Vps38**, supporting complex I-specific incorporation |
| GO:0005515 protein binding | IPI PMID:31941401 Atg38-Atg8 interaction in fission yeast establishes a positi... | MODIFY | Summary: PMID:31941401 demonstrated direct interaction between Atg38 and Atg8 via the AIM motif in Atg38. However, the term "protein binding" (GO:0005515) is uninformative. Reason: The annotation captures a real interaction (Atg38-Atg8 binding via AIM motif) but GO:0005515 is overly generic and provides no meaningful functional information. GO does not have a specific "Atg8 binding" term. The falcon deep research establishes that this AIM-mediated Atg8 binding bridges a downstream autophagosome protein (Atg8) to the upstream PI3K initiation complex, creating a positive-feedback loop that amplifies PAS accumulation of PI3K complex I and downstream factors. This bridging/coupling activity is best captured by the molecular function GO:0060090 (molecular adaptor activity), which describes binding that brings together two or more molecules so they function in a coordinated way. This is more informative than the generic protein binding term and, unlike a complex membership (CC) term, is a true molecular function. Proposed replacements: molecular adaptor activity Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md Atg38 contains a conserved Atg8-family-interacting motif (AIM) that directly engages with lipidated Atg8 on autophagosomal membranes PMID:31941401 Atg38 directly interacts with Atg8 via the AIM file:SCHPO/atg38/atg38-deep-research-falcon.md Atg38 directly binds **Atg8** via a defined **AIM** and that this binding recruits Atg38 to Atg8-positive autophagy initiation structures file:SCHPO/atg38/atg38-deep-research-falcon.md supporting a model in which Atg38βAtg8 binding amplifies PI3K complex I presence and downstream assembly at the PAS |
| GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I | IDA PMID:31941401 Atg38-Atg8 interaction in fission yeast establishes a positi... | ACCEPT | Summary: PMID:31941401 identified Atg38 as a subunit of the PtdIns3K complex I through biochemical characterization and functional assays. This is a core finding of the paper establishing Atg38 as the fifth subunit of this autophagy-specific complex. Reason: The IDA evidence is directly supported by the experimental work in PMID:31941401. The publication states that "Atg38 functions as a physical linkage mechanism connecting the Vps15-Vps34 catalytic arm and the Atg14-Vps30 regulatory arm of complex I." This is the defining functional role of Atg38 and the complex membership annotation is appropriate with IDA evidence. Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md ATG38, a 26 kilodalton protein encoded by the atg38 gene... serves as an essential fifth subunit of the autophagy-specific phosphatidylinositol 3-kinase (PI3K) complex I file:SCHPO/atg38/atg38-deep-research-perplexity.md Atg38 functions as a physical linkage mechanism connecting the Vps15-Vps34 catalytic arm and the Atg14-Vps30 regulatory arm of complex I file:SCHPO/atg38/atg38-deep-research-falcon.md Atg38/NRBF2 is widely accepted as a **fifth subunit** of the autophagy-initiating Vps34/PI3K complex I file:SCHPO/atg38/atg38-deep-research-falcon.md A fission-yeast-specific feature highlighted in a review is that Atg38 in *S. pombe* binds **directly to Vps34** |
| GO:0000407 phagophore assembly site | IDA PMID:31941401 Atg38-Atg8 interaction in fission yeast establishes a positi... | ACCEPT | Summary: PMID:31941401 demonstrated Atg38 localization to the phagophore assembly site (PAS) through fluorescence microscopy. The study showed that Atg38 accumulates at the PAS in an Atg14-dependent manner and that the Atg38-Atg8 interaction promotes PAS accumulation. Reason: The IDA annotation is well-supported by the experimental data. The publication explicitly demonstrates Atg38 localization to the PAS and characterizes the mechanism through which this localization is achieved (via interaction with Atg8 through the AIM motif and dependence on Atg14). Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md Atg38 localizes to the PAS in an Atg14-dependent manner, meaning that deletion of the atg14 gene completely abolishes PAS accumulation of Atg38 file:SCHPO/atg38/atg38-deep-research-perplexity.md The Atg38-Atg8 interaction promotes PAS accumulation of Atg38 file:SCHPO/atg38/atg38-deep-research-falcon.md Experimental microscopy shows Atg38 localizes to starvation-induced puncta colocalizing with Atg8, i.e., the PAS/phagophore assembly site |
| GO:0016236 macroautophagy | IMP PMID:31941401 Atg38-Atg8 interaction in fission yeast establishes a positi... | ACCEPT | Summary: PMID:31941401 demonstrated through mutant phenotype analysis that Atg38 is essential for macroautophagy. The atg38 deletion mutant shows complete absence of autophagy as measured by multiple assays (Pho8delta60, CFP-Atg8 processing, Tdh1-YFP processing). Reason: The IMP (Inferred from Mutant Phenotype) evidence is the gold standard for demonstrating functional involvement in a biological process. The publication clearly shows that atg38 deletion completely abolishes nitrogen starvation-induced autophagy. Additionally, disruption of the Atg38-Atg8 interaction leads to reduced autophagosome size and autophagic flux, further confirming the essential role. Supporting Evidence: file:SCHPO/atg38/atg38-deep-research-perplexity.md In wild-type S. pombe cells, Pho8delta60 activity increases substantially in response to nitrogen starvation (a potent autophagy inducer), whereas in atg38 deletion mutants, this starvation-induced increase in Pho8delta60 activity is completely absent, demonstrating that Atg38 is absolutely required for autophagy under starvation stress file:SCHPO/atg38/atg38-uniprot.txt Defective in nitrogen starvation-induced autophagy file:SCHPO/atg38/atg38-deep-research-falcon.md mean autophagosome diameter was **451 nm** (WT Atg38 condition) versus **271 nm** in cells expressing **Atg38[AIM mut]** |
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