Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000045 autophagosome assembly	IBA GO_REF:0000033	ACCEPT	Summary: ATG5 is essential for autophagosome assembly as a core component of the ATG12-ATG5-ATG16L1 complex. The complex functions as an E3-like enzyme for LC3 lipidation, which is required for autophagosome formation. Structural and biochemical studies confirm ATG5's central role in this process (PMID:23202584). Reason: Core function of ATG5. Phylogenetically conserved from yeast to human. IBA annotation is well-supported by extensive experimental evidence across species. Supporting Evidence: PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. PMID:9852036 Mutagenic analyses suggested that this conjugation was formed via an isopeptide bond between the C-terminal glycine of hApg12 and Lys-130 of hApg5. file:human/ATG5/ATG5-deep-research-falcon.md ATG5 is a core human autophagy protein in the ATG5 family, bearing ubiquitin-like folds that enable conjugation with ATG12 and assembly of the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like ligase for LC3/ATG8 lipidation during autophagosome biogenesis
GO:0034045 phagophore assembly site membrane	IBA GO_REF:0000033	ACCEPT	Summary: ATG5, as part of the ATG12-ATG5-ATG16L1 complex, localizes to the phagophore assembly site membrane. Recent studies show the complex preferentially associates with the convex surface of growing phagophores and participates in membrane remodeling. Reason: Well-supported cellular component annotation. The deep research confirms the complex preferentially associates with the convex surface of the growing isolation membrane (phagophore) and detaches/recycles once autophagosome closure is achieved. Supporting Evidence: PMID:32960676 RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein.
GO:0000423 mitophagy	IBA GO_REF:0000033	ACCEPT	Summary: ATG5 participates in mitophagy as part of the general autophagy machinery. The ATG12-ATG5-ATG16L1 complex is required for LC3 lipidation, which is essential for selective autophagy pathways including mitophagy. Reason: Valid annotation. Mitophagy requires the core autophagy machinery including ATG5. UniProt notes ATG5 is involved in mitochondrial quality control after oxidative damage.
GO:0035973 aggrephagy	IBA GO_REF:0000033	ACCEPT	Summary: ATG5 is involved in aggrephagy (selective autophagy of protein aggregates). The ATG12-ATG5 conjugate interacts with ALFY/WDFY3, which targets protein aggregates for autophagic degradation. Reason: Valid annotation supported by IBA and experimental evidence (IMP PMID:22982048). ATG5 interacts with WDFY3/ALFY which targets aggregates for degradation. Supporting Evidence: PMID:20417604 Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L, and LC3.
GO:0005776 autophagosome	IBA GO_REF:0000033	ACCEPT	Summary: ATG5 localizes to autophagosomes as part of the ATG12-ATG5-ATG16L1 complex during autophagosome formation. Direct experimental evidence from imaging studies (IDA PMID:15292400). Reason: Well-supported localization. Also supported by IDA evidence (PMID:15292400). Supporting Evidence: PMID:15292400 When HeLa cells are starved or treated with a proteasome inhibitor, Alfy relocalizes to characteristic filamentous cytoplasmic structures located close to autophagic membranes and ubiquitin-containing protein aggregates.
GO:0034727 piecemeal microautophagy of the nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: This annotation is based on phylogenetic inference. Piecemeal microautophagy of the nucleus (PMN) is primarily characterized in yeast. While the autophagy machinery is conserved, evidence for this specific process in human cells is limited. Reason: IBA annotation based on yeast ortholog function. PMN is well-characterized in yeast but less established in human cells. Keep as non-core function since ATG5's primary role is macroautophagy.
GO:0061908 phagophore	IBA GO_REF:0000033	ACCEPT	Summary: ATG5 localizes to the phagophore (isolation membrane) as part of the ATG12-ATG5-ATG16L1 complex. This is well-supported by structural and cell biology studies. Reason: Core localization site for ATG5 function. The complex acts at the phagophore to catalyze LC3 lipidation. Supporting Evidence: PMID:32960676 RAB33B plays a key role in recruiting the ATG16L1 complex to phagophores during starvation-induced autophagy.
GO:0034274 Atg12-Atg5-Atg16 complex	IBA GO_REF:0000033	ACCEPT	Summary: ATG5 is a core component of the Atg12-Atg5-Atg16 complex. This is the defining complex for ATG5 function, extensively supported by structural studies (PMID:23202584, PMID:24191030). Reason: Definitive complex membership. ATG5 is covalently conjugated to ATG12 and associates with ATG16L1 to form this E3-like complex. Supporting Evidence: PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12.
GO:0006995 cellular response to nitrogen starvation	IBA GO_REF:0000033	ACCEPT	Summary: Autophagy is induced by nitrogen starvation, and ATG5 as a core autophagy component is involved in this response. This is a conserved response across eukaryotes. Reason: Valid annotation. Starvation-induced autophagy is a major trigger for ATG5 function.
GO:0098794 postsynapse	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Inferred from logical inference based on GO:0099170 (postsynaptic modulation). ATG5 has roles in synaptic autophagy, but this is a specialized context-dependent localization. Reason: IEA annotation based on logical inference. While autophagy occurs at synapses and ATG5 is involved, this is not a core localization for ATG5.
GO:0002376 immune system process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: Inferred from UniProt keyword Immunity. ATG5 has roles in innate immunity through its involvement in xenophagy and regulation of interferon responses. However, this is a very broad term. Reason: Too general. The ATG12-ATG5 conjugate negatively regulates type I IFN production (PMID:17709747), but this is secondary to its autophagy function. Supporting Evidence: PMID:17709747 The Atg5 Atg12 conjugate associates with innate antiviral immune responses.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: ATG5 localizes to the cytoplasm where it forms the ATG12-ATG5-ATG16L1 complex before recruitment to phagophores. Reason: Valid general localization. ATG5 is cytoplasmic before recruitment to membranes.
GO:0006914 autophagy	IEA GO_REF:0000120	ACCEPT	Summary: ATG5 is essential for autophagy. This is the core biological process annotation for ATG5. Reason: Core function. ATG5 is essential for autophagy as demonstrated across multiple species and supported by extensive experimental evidence. Supporting Evidence: PMID:26812546 Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.
GO:0006915 apoptotic process	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This annotation is based on the UniProt keyword Apoptosis and the alternative name Apoptosis-specific protein (ASP). However, this reflects early nomenclature before ATG5's core autophagy function was understood. The apoptotic role is primarily through calpain-cleavage of ATG5 generating a pro-apoptotic N-terminal fragment that translocates to mitochondria - this is NOT the full-length ATG5's evolved function. Reason: Over-annotation. ATG5's core evolved function is autophagosome biogenesis, not apoptosis. The UniProt alias Apoptosis-specific protein is historical nomenclature. While calpain- cleaved ATG5 can promote apoptosis, full-length ATG5 functions in autophagy. The deep research clearly states apoptosis crosstalk is secondary: calpain-mediated cleavage of ATG5 produces an N-terminal fragment that translocates to mitochondria and promotes apoptosis. This is a cleavage product, not the primary protein function.
GO:0034045 phagophore assembly site membrane	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation above. ATG5 localizes to phagophore assembly site membrane. Reason: Valid localization, duplicate of IBA annotation. Keep as IEA provides additional computational support.
GO:0043069 negative regulation of programmed cell death	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA machine learning prediction. This reflects autophagy's role as a survival mechanism that can prevent cell death under stress. However, this is an indirect effect of ATG5's autophagy function rather than a direct molecular function. Reason: Indirect effect. Autophagy generally promotes cell survival, so ATG5 indirectly affects programmed cell death. Not a core annotation.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	REMOVE	Summary: High-throughput mass spectrometry interaction data. Uninformative term - does not specify the binding partner or functional significance. Reason: Uninformative annotation. Protein binding alone provides no functional insight. The specific interactions (with ATG12, ATG16L1, ATG3, etc.) are more informative. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry.
GO:0005515 protein binding	IPI PMID:17709747 The Atg5 Atg12 conjugate associates with innate antiviral im...	REMOVE	Summary: Interaction with RIG-I (O95786-1) and MAVS (Q7Z434-1). This demonstrates ATG5's role in modulating innate immune signaling through direct protein interactions. Reason: Uninformative generic term. The specific interactions with RIG-I and MAVS are better captured by more specific MF or BP annotations. Generic protein binding should be replaced with more specific terms. Supporting Evidence: PMID:17709747 The Atg5 Atg12 conjugate associates with innate antiviral immune responses.
GO:0005515 protein binding	IPI PMID:20417604 The selective macroautophagic degradation of aggregated prot...	REMOVE	Summary: Interaction with WDFY3/ALFY (Q8IZQ1) for selective autophagy of aggregates. Reason: Generic protein binding is uninformative. The functional consequence (aggrephagy) is captured by the aggrephagy BP annotation. Supporting Evidence: PMID:20417604 The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.
GO:0005515 protein binding	IPI PMID:20562859 Network organization of the human autophagy system.	REMOVE	Summary: Network mapping of autophagy system interactions. Reason: Generic protein binding from high-throughput study. Uninformative. Supporting Evidence: PMID:20562859 Network organization of the human autophagy system.
GO:0005515 protein binding	IPI PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3...	REMOVE	Summary: Structural study showing ATG5 interaction with ATG16L1 (Q676U5). Reason: Generic protein binding is uninformative. The ATG12-ATG5-ATG16 complex membership annotation is more informative. Supporting Evidence: PMID:23202584 Dec 2. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy.
GO:0005515 protein binding	IPI PMID:23262492 Interaction between FIP200 and ATG16L1 distinguishes ULK1 co...	REMOVE	Summary: Interaction between FIP200/RB1CC1 and ATG16L1 complex. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:23262492 Dec 23. Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy.
GO:0005515 protein binding	IPI PMID:23392225 FIP200 regulates targeting of Atg16L1 to the isolation membr...	REMOVE	Summary: FIP200 regulation of Atg16L1 targeting. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:23392225 FIP200 regulates targeting of Atg16L1 to the isolation membrane.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	REMOVE	Summary: High-throughput genetic variant effect on protein interactions. Reason: Generic protein binding from high-throughput study. Uninformative. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Reference map of human binary protein interactome. Reason: Generic protein binding from high-throughput interactome study. Uninformative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: Interactome mapping in neurodegeneration context. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Dual proteome-scale network study. Reason: Generic protein binding from high-throughput study. Uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: OpenCell endogenous tagging study. Reason: Generic protein binding from high-throughput study. Uninformative. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	REMOVE	Summary: Multimodal cell mapping study. Reason: Generic protein binding from high-throughput study. Uninformative. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0000045 autophagosome assembly	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation supporting autophagosome assembly role. Reason: Core function, duplicate of IBA annotation. Computational support for core function.
GO:0005776 autophagosome	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from mouse ortholog. Reason: Valid localization, consistent with IBA and IDA annotations.
GO:0005930 axoneme	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. ATG5 localizes to ciliary axoneme and is involved in ciliogenesis regulation. Reason: Specialized localization related to ATG5's role in cilium assembly regulation. Non-core function.
GO:0010040 response to iron(II) ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from rat ortholog. Iron can induce autophagy-related processes including ferroptosis. Reason: Context-specific response. Not a core function of ATG5.
GO:0010508 positive regulation of autophagy	IEA GO_REF:0000107	ACCEPT	Summary: Transfer from rat ortholog. ATG5 is essential for autophagy execution rather than regulation per se. Reason: While ATG5 is more of an essential component than a regulator, its presence does positively enable autophagy to occur.
GO:0030424 axon	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from rat ortholog. ATG5 is involved in axon maintenance through autophagy. Reason: Context-specific localization. UniProt notes ATG5 is involved in the maintenance of axon morphology and membrane structures. Non-core tissue-specific function.
GO:0032480 negative regulation of type I interferon production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The ATG12-ATG5 conjugate negatively regulates type I IFN production by associating with RIG-I and MAVS (PMID:17709747). Reason: This is a secondary function of ATG5, not its core autophagy role. The ATG12-ATG5 conjugate moonlights as an immune modulator. Supporting Evidence: PMID:17709747 the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1)
GO:0032991 protein-containing complex	IEA GO_REF:0000120	REMOVE	Summary: Generic annotation indicating ATG5 is part of a protein complex. Reason: Too generic. The specific ATG12-ATG5-ATG16 complex annotation is more informative.
GO:0035973 aggrephagy	IEA GO_REF:0000107	ACCEPT	Summary: Duplicate of IBA annotation. Transfer from mouse ortholog. Reason: Valid annotation, duplicate support for aggrephagy role.
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from rat ortholog. This reflects autophagy's survival-promoting effects. Reason: Indirect effect of autophagy function. Autophagy promotes survival, thereby indirectly inhibiting apoptosis. Not a direct function.
GO:0043687 post-translational protein modification	IEA GO_REF:0000107	ACCEPT	Summary: ATG5 is involved in the LC3 lipidation (post-translational modification) process. Reason: Valid annotation. LC3 lipidation to PE is a post-translational modification catalyzed by the ATG12-ATG5-ATG16L1 complex.
GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: MAM contact sites are reported as sites of autophagosome formation. ATG5 may localize here during autophagosome biogenesis. Reason: Specialized localization. MAM sites can serve as platforms for autophagosome formation but this is context-specific.
GO:0045202 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from rat ortholog. ATG5 functions in synaptic autophagy. Reason: Tissue-specific localization. Autophagy occurs at synapses but this is not a core localization for ATG5.
GO:0045824 negative regulation of innate immune response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Related to ATG5's role in suppressing type I IFN responses through RIG-I/MAVS interaction. Reason: Secondary function. Not core autophagy role. Supporting Evidence: PMID:17709747 The Atg5 Atg12 conjugate associates with innate antiviral immune responses.
GO:0050687 negative regulation of defense response to virus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. ATG5 suppresses antiviral responses. Reason: Secondary function related to immune modulation. Supporting Evidence: PMID:17709747 The Atg5 Atg12 conjugate associates with innate antiviral immune responses.
GO:0061684 chaperone-mediated autophagy	IEA GO_REF:0000107	UNDECIDED	Summary: Transfer from rat ortholog. CMA is a distinct autophagy pathway that does not classically require ATG5. Reason: CMA is mechanistically distinct from macroautophagy and typically does not require ATG5. This annotation may be questionable. Unable to verify specific role.
GO:0062029 positive regulation of stress granule assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from rat ortholog. Autophagy can affect stress granule dynamics. Reason: Indirect effect. Not a core ATG5 function.
GO:0071500 cellular response to nitrosative stress	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. Autophagy is induced by nitrosative stress. Reason: Stress response involving autophagy. Not a core ATG5 function.
GO:0098685 Schaffer collateral - CA1 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. Specific synapse type localization. Reason: Highly specific tissue/cell-type localization. Not core function.
GO:0098930 axonal transport	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. ATG5 may affect axonal transport through autophagy. Reason: Indirect effect through autophagy in neurons. Not a core function.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Combined annotation indicating localization at glutamatergic synapses. Reason: Tissue-specific localization. Not a core function.
GO:0099072 regulation of postsynaptic membrane neurotransmitter receptor levels	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. Autophagy can regulate receptor turnover. Reason: Specialized neuronal function. Not a core ATG5 function.
GO:0099170 postsynaptic modulation of chemical synaptic transmission	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from mouse ortholog. Related to synaptic autophagy. Reason: Specialized neuronal function. Not a core ATG5 function.
GO:1902017 regulation of cilium assembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: ATG5 promotes ciliogenesis through autophagic degradation of ciliogenesis regulators like OFD1 and IFT20. Reason: Documented function but secondary to core autophagy role.
GO:1902617 response to fluoride	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Transfer from rat ortholog. Fluoride can induce autophagy. Reason: Context-specific stress response. Not a core function.
GO:0016236 macroautophagy	IMP PMID:25484072 Insights into autophagosome maturation revealed by the struc...	ACCEPT	Summary: Experimental evidence from ComplexPortal showing ATG5 role in macroautophagy. Reason: Core function. Macroautophagy is the primary autophagy pathway that ATG5 participates in. Supporting Evidence: PMID:25484072 Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners.
GO:0050687 negative regulation of defense response to virus	IDA PMID:19666601 The autophagy machinery is required to initiate hepatitis C ...	KEEP AS NON CORE	Summary: Direct experimental evidence showing ATG5 is required for HCV replication initiation, thereby suppressing antiviral defense. Reason: Well-supported but secondary function. ATG5 acts as a proviral factor in HCV infection. Supporting Evidence: PMID:19666601 autophagy proteins (i.e., Beclin-1, Atg4B, Atg5, and Atg12) are proviral factors required for translation of incoming hepatitis C virus (HCV) RNA
GO:1901096 regulation of autophagosome maturation	IMP PMID:22342342 A mammalian autophagosome maturation mechanism mediated by T...	ACCEPT	Summary: ATG5 via the ATG12-ATG5 conjugate interacts with TECPR1 to regulate autophagosome- lysosome fusion. Reason: Important function related to autophagy completion. Supporting Evidence: PMID:22342342 TECPR1 binds to the Atg12-Atg5 conjugate and phosphatidylinositol 3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion.
GO:1904973 positive regulation of viral translation	IDA PMID:19666601 The autophagy machinery is required to initiate hepatitis C ...	KEEP AS NON CORE	Summary: ATG5 is required for translation of incoming HCV RNA, demonstrating a proviral role. Reason: Context-specific function during viral infection. Not core autophagy function. Supporting Evidence: PMID:19666601 autophagy proteins (i.e., Beclin-1, Atg4B, Atg5, and Atg12) are proviral factors required for translation of incoming hepatitis C virus (HCV) RNA
GO:0000045 autophagosome assembly	IDA PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3...	ACCEPT	Summary: Crystal structure of ATG12-ATG5 conjugate demonstrates its essential role in LC3 lipidation and autophagosome assembly. Reason: Core function with high-quality structural evidence. Supporting Evidence: PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy.
GO:0019776 Atg8-family ligase activity	IDA PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3...	ACCEPT	Summary: The ATG12-ATG5-ATG16L1 complex functions as an E3-like ligase for LC3/ATG8 lipidation. This is the core molecular function of ATG5. Reason: Core molecular function. The ATG12-ATG5 conjugate with ATG16L1 allosterically activates ATG3 to catalyze LC3 transfer to PE. Supporting Evidence: PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy.
GO:0005515 protein binding	IPI PMID:32960676 RAB33B recruits the ATG16L1 complex to the phagophore via a ...	REMOVE	Summary: Interaction with ATG16L1 and RAB33B. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:32960676 2020 Sep 22. RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein.
GO:0034045 phagophore assembly site membrane	IDA PMID:32960676 RAB33B recruits the ATG16L1 complex to the phagophore via a ...	ACCEPT	Summary: Direct evidence for ATG5 localization at phagophore assembly site membrane via RAB33B recruitment. Reason: Core localization with direct experimental evidence. Supporting Evidence: PMID:32960676 RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein.
GO:0005515 protein binding	IPI PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiqu...	REMOVE	Summary: Structural study showing ATG3 recognition by ATG12. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12.
GO:1904093 negative regulation of autophagic cell death	IMP PMID:19273585 Hypoxia-induced autophagy is mediated through hypoxia-induci...	UNDECIDED	Summary: Study on hypoxia-induced autophagy. Note: This study primarily examines BNIP3/BNIP3L, not ATG5 directly. ATG5's role here is as part of general autophagy machinery. Reason: The referenced paper (PMID:19273585) focuses on BNIP3/BNIP3L and Beclin1 rather than ATG5 specifically. The annotation may be transferred from the autophagy context but direct ATG5 evidence is unclear from this publication. Supporting Evidence: PMID:19273585 Mar 9. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.
GO:0006914 autophagy	IGI PMID:28389568 Hepatitis C virus triggers Golgi fragmentation and autophagy...	ACCEPT	Summary: Genetic interaction study showing ATG5 involvement in HCV-triggered autophagy through IRGM pathway. Reason: Valid autophagy annotation with genetic interaction evidence. Supporting Evidence: PMID:28389568 We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV.
GO:0005515 protein binding	IPI PMID:26812546 Mutation in ATG5 reduces autophagy and leads to ataxia with ...	REMOVE	Summary: Disease mutation study showing ATG5 interaction with ATG12. Reason: Generic protein binding. Uninformative. The ATG12-ATG5 conjugation is better captured by complex membership annotation. Supporting Evidence: PMID:26812546 Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.
GO:0006914 autophagy	IMP PMID:26812546 Mutation in ATG5 reduces autophagy and leads to ataxia with ...	ACCEPT	Summary: Disease mutation (E122D) in ATG5 reduces autophagy and causes ataxia with developmental delay, demonstrating ATG5's essential role in autophagy. Reason: Strong genetic evidence that ATG5 is essential for autophagy in humans. Supporting Evidence: PMID:26812546 Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-5205663	KEEP AS NON CORE	Summary: Reactome annotation for LC3-associated phagocytosis (LAP). ATG5 participates in LC3 lipidation on phagosome membranes during LAP. Reason: Non-canonical autophagy pathway (LAP/CASM). Valid but not core macroautophagy function.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-8959571	KEEP AS NON CORE	Summary: Duplicate Reactome annotation for phagocytic vesicle membrane localization. Reason: Duplicate of above. Non-canonical autophagy pathway.
GO:0035973 aggrephagy	IMP PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	ACCEPT	Summary: Experimental evidence for ATG5 role in aggrephagy. Reason: Direct experimental evidence for selective autophagy of aggregates. Supporting Evidence: PMID:22982048 Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.
GO:0005829 cytosol	TAS Reactome:R-HSA-5678490	ACCEPT	Summary: Reactome annotation for cytosolic localization during LC3 lipidation. Reason: Valid localization. ATG5 is initially cytosolic before membrane recruitment.
GO:0005829 cytosol	TAS Reactome:R-HSA-5679255	ACCEPT	Summary: Duplicate Reactome cytosol annotation. Reason: Valid localization, duplicate annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-5682010	ACCEPT	Summary: Duplicate Reactome cytosol annotation. Reason: Valid localization, duplicate annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-5682012	ACCEPT	Summary: Duplicate Reactome cytosol annotation. Reason: Valid localization, duplicate annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-5682690	ACCEPT	Summary: Duplicate Reactome cytosol annotation. Reason: Valid localization, duplicate annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-5683588	ACCEPT	Summary: Duplicate Reactome cytosol annotation. Reason: Valid localization, duplicate annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-9936620	ACCEPT	Summary: Duplicate Reactome cytosol annotation. Reason: Valid localization, duplicate annotation.
GO:0016020 membrane	IDA PMID:23093945 Regulation of ATG4B stability by RNF5 limits basal levels of...	ACCEPT	Summary: Study on RNF5 regulation of ATG4B. ATG5 membrane localization is indirect from this study. Reason: ATG5 associates with membranes during autophagosome formation. Supporting Evidence: PMID:23093945 Oct 18. Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.
GO:0005930 axoneme	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from mouse ortholog for axoneme localization. Reason: Specialized localization related to ciliogenesis function.
GO:1902017 regulation of cilium assembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from mouse ortholog for cilium assembly regulation. Reason: Secondary function through autophagic degradation of ciliogenesis regulators.
GO:0005515 protein binding	IPI PMID:21575909 A Tecpr1-dependent selective autophagy pathway targets bacte...	REMOVE	Summary: TECPR1 interaction study for bacterial pathogen targeting. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:21575909 A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens.
GO:0005515 protein binding	IPI PMID:22342342 A mammalian autophagosome maturation mechanism mediated by T...	REMOVE	Summary: TECPR1 interaction for autophagosome maturation. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:22342342 2012 Feb 16. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate.
GO:0034045 phagophore assembly site membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse ortholog for phagophore localization. Reason: Core localization, consistent with other evidence.
GO:0000045 autophagosome assembly	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse ortholog for autophagosome assembly. Reason: Core function, consistent with other evidence.
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse ortholog for cytoplasm localization. Reason: Valid general localization.
GO:0006914 autophagy	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse ortholog for autophagy. Reason: Core function.
GO:0043687 post-translational protein modification	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse ortholog for post-translational modification (LC3 lipidation). Reason: Valid annotation related to LC3 lipidation function.
GO:0005515 protein binding	IPI PMID:9852036 A new protein conjugation system in human. The counterpart o...	REMOVE	Summary: Foundational paper demonstrating ATG12-ATG5 conjugation in human cells. Reason: Generic protein binding. Uninformative. The conjugation is better captured by complex and function annotations. Supporting Evidence: PMID:9852036 A new protein conjugation system in human.
GO:0005515 protein binding	IPI PMID:11096062 The human homolog of Saccharomyces cerevisiae Apg7p is a Pro...	REMOVE	Summary: Paper showing ATG7 as E1-like enzyme for ATG12 conjugation. Reason: Generic protein binding. Uninformative. Supporting Evidence: PMID:11096062 Nov 28. The human homolog of Saccharomyces cerevisiae Apg7p is a Protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3.
GO:0005776 autophagosome	IDA PMID:15292400 Alfy, a novel FYVE-domain-containing protein associated with...	ACCEPT	Summary: ALFY study showing ATG5 localization at autophagic membranes. Reason: Core localization with direct experimental evidence. Supporting Evidence: PMID:15292400 Alfy relocalizes to characteristic filamentous cytoplasmic structures located close to autophagic membranes and ubiquitin-containing protein aggregates.

Core Functions

ATG5, as part of the ATG12-ATG5-ATG16L1 complex, functions as an E3-like enzyme that promotes the covalent conjugation of LC3/ATG8 family proteins to phosphatidylethanolamine (PE) on autophagosomal membranes. This lipidation is essential for autophagosome formation and maturation.

Molecular Function:

Atg8-family ligase activity

Directly Involved In:

autophagosome assembly macroautophagy

Cellular Locations:

phagophore assembly site membrane cytosol

In Complex:

Atg12-Atg5-Atg16 complex

Supporting Evidence:

PMID:23202584
Structure of the human ATG12-ATG5 conjugate required for LC3 lipidation in autophagy.
PMID:24191030
Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12.

References

file:human/ATG5/ATG5-deep-research-falcon.md

Deep research synthesis of ATG5 function and literature

ATG5 is a core human autophagy protein that forms the ATG12-ATG5-ATG16L1 E3-like complex for LC3 lipidation

"ATG5 is a core human autophagy protein in the ATG5 family, bearing ubiquitin-like folds that enable conjugation with ATG12 and assembly of the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like ligase for LC3/ATG8 lipidation during autophagosome biogenesis"
The complex localizes to the convex surface of the phagophore and dissociates upon autophagosome completion

"The ATG12-ATG5-ATG16L1 complex preferentially associates with the convex surface of the growing isolation membrane (phagophore) and detaches/recycles once autophagosome closure is achieved"
Calpain-mediated cleavage of ATG5 produces a pro-apoptotic fragment that translocates to mitochondria

"Calpain-mediated cleavage of ATG5 yields a pro-apoptotic fragment that migrates to mitochondria and promotes apoptosis, highlighting crosstalk between autophagy machinery and cell death programs"

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:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:9852036

A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy.

Demonstrated that human ATG12 is covalently attached to ATG5 via an isopeptide bond at Lys-130

"Mutagenic analyses suggested that this conjugation was formed via an isopeptide bond between the C-terminal glycine of hApg12 and Lys-130 of hApg5."

PMID:11096062

The human homolog of Saccharomyces cerevisiae Apg7p is a Protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3.

Showed hApg7p is an E1-like enzyme essential for the hApg12p conjugation system

"Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate, indicating that hApg7p is an E1-like enzyme essential for the hApg12p conjugation system."

PMID:15292400

Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes.

Identified Alfy/WDFY3 association with autophagic membranes

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:17709747

The Atg5 Atg12 conjugate associates with innate antiviral immune responses.

ATG5-ATG12 conjugate negatively regulates type I IFN production by associating with RIG-I and MAVS

PMID:19273585

Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.

Demonstrated hypoxia-induced autophagy is a survival mechanism

PMID:19666601

The autophagy machinery is required to initiate hepatitis C virus replication.

ATG5 is a proviral factor required for HCV RNA translation during infection initiation

PMID:20417604

The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy.

ATG5 interacts with ALFY for selective autophagy of aggregates

PMID:20562859

Network organization of the human autophagy system.

PMID:21575909

A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens.

TECPR1 interacts with ATG5 for xenophagy

PMID:22342342

A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate.

TECPR1 binds ATG12-ATG5 to promote autophagosome-lysosome fusion

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

PMID:23093945

Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection.

PMID:23202584

Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy.

Solved crystal structure of ATG12-ATG5 conjugate, demonstrating its E3-like function for LC3 lipidation

PMID:23262492

Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy.

PMID:23392225

FIP200 regulates targeting of Atg16L1 to the isolation membrane.

PMID:24191030

Structural basis of ATG3 recognition by the autophagic ubiquitin-like protein ATG12.

Solved structure of ATG12-ATG5 with ATG3 and ATG16L1, showing E3-like mechanism

PMID:25484072

Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners.

PMID:26812546

Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.

ATG5 E122D mutation causes reduced autophagy and SCAR25 disease in humans

PMID:28389568

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M.

IRGM regulates HCV-induced autophagy involving ATG5

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:32960676

RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein.

RAB33B recruits ATG12-ATG5-ATG16L1 complex to phagophores

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-5205663

LC3 binds the autophagosome membrane Atg5-Atg12 complex

Reactome:R-HSA-5678490

ATG16L1 complex transfers LC3 from ATG3 to PE

Reactome:R-HSA-5679255

WIPI2 binds ATG12:ATG5:ATG16L

Reactome:R-HSA-5682010

ATG10:ATG12 binds ATG5

Reactome:R-HSA-5682012

ATG5:ATG12 binds ATG16L1

Reactome:R-HSA-5682690

ATG10 dissociates from ATG12:ATG5

Reactome:R-HSA-5683588

ATG10 transfers ATG12 from ATG10 to ATG5

Reactome:R-HSA-8959571

LC3 binds the autophagosome membrane Atg5-Atg12 complex

Reactome:R-HSA-9936620

ATG5:ATG12 binds ATG16L2

📚 Additional Documentation

Deep Research Falcon

(ATG5-deep-research-falcon.md)

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gene_info: Name=ATG5 {ECO:0000312|HGNC:HGNC:589}; Synonyms=APG5L, ASP;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the ATG5 family. .
protein_domains: Atg5. (IPR007239); ATG5_HBR. (IPR048940); Atg5_HR. (IPR042526);
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9H1Y0
Protein Description: RecName: Full=Autophagy protein 5 {ECO:0000305}; AltName: Full=APG5-like; AltName: Full=Apoptosis-specific protein;
Gene Information: Name=ATG5 {ECO:0000312|HGNC:HGNC:589}; Synonyms=APG5L, ASP;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ATG5 family. .
Key Domains: Atg5. (IPR007239); ATG5_HBR. (IPR048940); Atg5_HR. (IPR042526); ATG5_UblA. (IPR048939); Atg5_UblA_dom_sf. (IPR042527)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "ATG5" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATG5' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene ATG5 (gene ID: ATG5, UniProt: Q9H1Y0) in human.

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.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9H1Y0
Protein Description: RecName: Full=Autophagy protein 5 {ECO:0000305}; AltName: Full=APG5-like; AltName: Full=Apoptosis-specific protein;
Gene Information: Name=ATG5 {ECO:0000312|HGNC:HGNC:589}; Synonyms=APG5L, ASP;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ATG5 family. .
Key Domains: Atg5. (IPR007239); ATG5_HBR. (IPR048940); Atg5_HR. (IPR042526); ATG5_UblA. (IPR048939); Atg5_UblA_dom_sf. (IPR042527)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "ATG5" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene ATG5 (gene ID: ATG5, UniProt: Q9H1Y0) in human.

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.

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.

Plan status: all objectives completed. We verified the target identity and compiled recent mechanistic and translational literature. The report below follows the requested structure, emphasizes 2023–2024 sources, and embeds an evidence table.

Topic	Key finding (1–2 sentences)	Mechanism/players	Evidence source (journal, year)	URL/DOI	Context ID
Identity / function: ATG12–ATG5–ATG16L1 E3-like ligase & LC3 lipidation	ATG5 is covalently conjugated to ATG12 and, with ATG16L1, forms an E3-like complex that promotes LC3/ATG8 lipidation on nascent autophagic membranes.	ATG12–ATG5 conjugate, ATG16L1 scaffold; enzymes ATG7 (E1), ATG10/ATG3 (E2s); substrate LC3/ATG8 → PE.	Autophagy Reports / J Biochemistry (2023/2021)	https://doi.org/10.1080/27694127.2023.2277582; https://doi.org/10.1093/jb/mvab017	(noda2023structuralbiologyof pages 1-4, matoba2021structuralcatalogof pages 1-2)
Three-step docking: WIPI2 → ATG16L1 → ATG3 delivery	LC3 is delivered and positioned for lipidation by a three-step docking mechanism in which WIPI2, helix α2 of ATG16L1, then a membrane-interacting surface of ATG3 sequentially place LC3 at the membrane for transfer to PE.	WIPI2 (PI3P effector), ATG16L1 (helix α2), ATG3, LC3, PE; ATG12–ATG5 allosterically activates ATG3.	Science Advances (2024)	https://doi.org/10.1126/sciadv.adj8027	(rao2024threestepdockingby pages 1-2)
ATG16L1-induced phagophore cups	ATG16L1 together with ATG12–ATG5 and LC3 forms a membrane coat that remodels flat membranes into cup-shaped phagophores, driving non-selective autophagosome biogenesis.	ATG16L1 membrane-binding domain, ATG12–ATG5, LC3 (ATG8 family)	Nature Structural & Molecular Biology (2024)	https://doi.org/10.1038/s41594-024-01300-y	(mohan2024atg16l1inducesthe pages 33-36)
Golgi LC3 lipidation via ATG12–ATG5–ATG16L1 and V-ATPase–ATG16L1 axis	LC3 can be lipidated on the Golgi (non-autophagic Golgi-LC3 lipidation) in a manner dependent on the ATG12–ATG5–ATG16L1 complex and recruitment via a V-ATPase–ATG16L1 interaction (CASM-like process).	ATG12–ATG5–ATG16L1 complex, V-ATPase, ATG16L1 recruitment; CASM/LANDO-type machinery	The EMBO Journal (2024)	https://doi.org/10.1038/s44318-024-00233-y	(kang2024nonautophagicgolgilc3lipidation pages 1-2)
ULK1 phosphorylation of WIPI2b regulates ATG16L1 binding	ULK1 phosphorylates WIPI2b at sites (e.g., S284) that modulate WIPI2b membrane association and its interaction with ATG16L1, thereby controlling recruitment of the conjugation machinery.	ULK1 kinase, WIPI2b (phosphosites S68/S284), ATG16L1, PI3P/omegasome context	EMBO Reports (2024)	https://doi.org/10.1038/s44319-024-00215-5	(lee2025mechanismsandroles pages 13-13)
ATG16L1 S‑palmitoylation enhances complex assembly and LC3 lipidation	S‑palmitoylation of ATG16L1 (Cys153) by ZDHHC7 increases ATG16L1 interactions (e.g., with WIPI2B and RAB33B) on phagophores and promotes LC3 lipidation and autophagosome formation.	ZDHHC7 (palmitoyltransferase), ATG16L1 (C153), WIPI2B, RAB33B, LC3 lipidation	Autophagy (2024)	https://doi.org/10.1080/15548627.2024.2386915	(wei2024zdhhc7mediatedspalmitoylation pages 18-19, wei2024zdhhc7mediatedspalmitoylation pages 1-2)
Localization/dynamics of ATG12–ATG5–ATG16L1 on phagophores	The ATG12–ATG5–ATG16L1 complex preferentially associates with the convex surface of the growing phagophore/isolation membrane and dissociates/recycles upon autophagosome maturation.	ATG12–ATG5–ATG16L1 coat, LC3/ATG8 marking membranes; dynamic recruitment via WIPI2/ATG16L1	Autophagy Reports / NSMB (2023/2024)	https://doi.org/10.1080/27694127.2023.2277582; https://doi.org/10.1038/s41594-024-01300-y	(noda2023structuralbiologyof pages 1-4, mohan2024atg16l1inducesthe pages 33-36)
Noncanonical LC3 conjugation (LAP/CASM) & V-ATPase–ATG16L1 axis	Single‑membrane LC3/ATG8 conjugation pathways (LAP/CASM) use ATG conjugation machinery but are recruited by distinct cues (e.g., V-ATPase–ATG16L1), enabling LC3 lipidation on phagosomes/endolysosomal membranes.	V-ATPase, ATG16L1, ATG12–ATG5, RUBICON and LAP regulators	Front. Cell Dev. Biol. / EMBO J (2024)	https://doi.org/10.3389/fcell.2025.1532050; https://doi.org/10.1038/s44318-024-00233-y	(lee2025mechanismsandroles pages 13-13, kang2024nonautophagicgolgilc3lipidation pages 1-2)
Noncanonical ATG5 function in retromer assembly and GLUT1 sorting	ATG5 (and membrane atg8ylation) associates with retromer core (VPS26/29/35), modulating endosomal sorting (e.g., GLUT1 trafficking) independently of canonical autophagy.	ATG5, membrane atg8ylation factors, retromer (VPS26/29/35), GLUT1	eLife (2025)	https://doi.org/10.7554/elife.100928.3	(paddar2025noncanonicalrolesof pages 1-2)
Clinical / biomarker: serum ATG5 in stroke cohort	A 2024 clinical study reported elevated serum ATG5 in stroke patients that correlated with CD4+ T‑cell subsets and cognitive decline over follow-up, suggesting potential biomarker utility.	Serum ATG5 measurement (ELISA), correlations with Th2/Th17 and MMSE decline	Brazilian Journal of Medical and Biological Research (2024)	https://doi.org/10.1590/1414-431x2024e13019	(cadwell2025autophagyandbacterial pages 1-2)
Apoptosis: calpain cleavage of ATG5 generates pro‑apoptotic fragment	Calpain-mediated cleavage of ATG5 produces an N‑terminal fragment that translocates to mitochondria and promotes apoptosis, linking ATG5 to non‑autophagic cell‑death roles.	Calpain protease, ATG5 cleavage fragment, mitochondrial targeting, apoptotic signaling	Reviews / mechanistic studies (2024–2025)	(see mechanistic reviews cited above)	(cadwell2025autophagyandbacterial pages 1-2, noda2023structuralbiologyof pages 1-4)

Table: Compact summary table of major 2023–2024 findings about human ATG5: core E3-like role in LC3 lipidation, new mechanistic steps (three-step docking, ATG16L1 palmitoylation, phagophore cup formation), noncanonical functions, localization dynamics, and an example clinical biomarker report. Citations link to the gathered evidence (context IDs).

Comprehensive research report: Human ATG5 (UniProt Q9H1Y0)

Identity, protein family, and key concepts
ATG5 (UniProt Q9H1Y0) is a core human autophagy protein in the ATG5 family, bearing ubiquitin-like folds that enable conjugation with ATG12 and assembly of the ATG12–ATG5–ATG16L1 complex, which functions as an E3-like ligase for LC3/ATG8 lipidation during autophagosome biogenesis (identity and mechanism summarized in structural/biochemical reviews) (noda2023structuralbiologyof pages 1-4, matoba2021structuralcatalogof pages 1-2). Canonical conjugation proceeds via the E1-like ATG7 and E2-like ATG10 (for ATG12) and ATG3 (for LC3/ATG8), culminating in covalent LC3–phosphatidylethanolamine (LC3–PE) on autophagic membranes (noda2023structuralbiologyof pages 1-4). In current understanding, ATG5’s essential molecular role is to form the ATG12–ATG5 conjugate, which associates with ATG16L1 to create an E3-like platform that allosterically activates ATG3 for LC3 transfer to PE (rao2024threestepdockingby pages 1-2, noda2023structuralbiologyof pages 1-4).

Primary molecular function and substrate specificity
- Reaction/system: ATG12 is covalently conjugated to ATG5 (Lys acceptor on ATG5) via ATG7 (E1) and ATG10 (E2), forming ATG12–ATG5; this adduct with ATG16L1 scaffolds the E3-like activity that catalyzes LC3/ATG8 lipidation to phosphatidylethanolamine (substrate) on the phagophore (noda2023structuralbiologyof pages 1-4, matoba2021structuralcatalogof pages 1-2).
- Catalytic mechanism: Recent experiments resolve a three-step docking sequence that positions LC3 for lipidation: (i) WIPI2 recruits the ATG12–ATG5–ATG16L1–ATG3 machinery to PI3P-enriched membranes, (ii) helix α2 of ATG16L1 enhances membrane engagement, and (iii) a membrane-interacting surface of ATG3 aligns the LC3~ATG3 thioester for transfer to PE; ATG12–ATG5 allosterically activates ATG3 (rao2024threestepdockingby pages 1-2). These data refine how ATG5 within the E3-like complex promotes efficient LC3–PE formation.

Cellular localization and dynamics
The ATG12–ATG5–ATG16L1 complex preferentially associates with the convex surface of the growing isolation membrane (phagophore) and detaches/recycles once autophagosome closure is achieved, whereas LC3-PE remains on autophagosomal membranes and marks autophagy structures (noda2023structuralbiologyof pages 1-4). Reconstitution and cellular imaging show that ATG16L1 and LC3, together with ATG12–ATG5, can assemble a membrane coat that remodels flat membranes into cup-shaped phagophores, demonstrating an architectural role for the complex during autophagosome formation (mohan2024atg16l1inducesthe pages 33-36). Recruitment is driven by WIPI2 at omegasomes and depends on upstream ULK1–PI3KC3-C1 signaling; mechanistically, ULK1 phosphorylation of WIPI2b modulates its phagophore binding and interaction with ATG16L1, controlling conjugation machinery localization (lee2025mechanismsandroles pages 13-13).

Pathways and recruitment axes
- Canonical autophagy: ULK1 complex initiation and PI3KC3-C1 (VPS34) generate PI3P, recruiting WIPI2 and the ATG12–ATG5–ATG16L1–ATG3 module to catalyze LC3 lipidation at the phagophore (cadwell2025autophagyandbacterial pages 1-2, rao2024threestepdockingby pages 1-2).
- WIPI2 axis: WIPI2 directly recruits ATG16L1 (via W2IR), positioning ATG12–ATG5–ATG16L1 at PI3P-rich membranes, consistent with the three-step docking model that integrates WIPI2 → ATG16L1 → ATG3 delivery of LC3 (rao2024threestepdockingby pages 1-2).
- V-ATPase–ATG16L1 axis and CASM/LAP: In noncanonical contexts, V-ATPase recruits ATG16L1, enabling LC3 conjugation to single-membrane compartments (e.g., phagosomes, Golgi) via CASM/LAP pathways; Golgi-localized LC3 lipidation under Golgi stress is explicitly ATG12–ATG5–ATG16L1-dependent and requires V-ATPase–ATG16L1 (kang2024nonautophagicgolgilc3lipidation pages 1-2, lee2025mechanismsandroles pages 13-13).

Recent developments (2023–2024) and structural/mechanistic advances
- Three-step docking: High-resolution integrative work (MD + reconstitution) established WIPI2 → ATG16L1 helix α2 → ATG3 membrane-docking to deliver LC3 for lipidation, with ATG12–ATG5 allosterically activating ATG3 and local PE enrichment near the thioester to promote catalysis (Science Advances, 2024; URL: https://doi.org/10.1126/sciadv.adj8027) (rao2024threestepdockingby pages 1-2).
- ATG16L1-induced phagophore cups: ATG12–ATG5–ATG16L1 with LC3 forms a membrane coat that induces cup-like phagophores, revealing a structural role in phagophore morphogenesis (Nat Struct Mol Biol, 2024; URL: https://doi.org/10.1038/s41594-024-01300-y) (mohan2024atg16l1inducesthe pages 33-36).
- ULK1 control of WIPI2b: ULK1 phosphorylation sites on WIPI2b (including S284) tune WIPI2b’s membrane binding and ATG16L1 association, regulating site-specific LC3 lipidation (EMBO Reports, 2024; URL: https://doi.org/10.1038/s44319-024-00215-5) (lee2025mechanismsandroles pages 13-13).
- ATG16L1 S-palmitoylation: ZDHHC7-mediated S-palmitoylation at Cys153 enhances ATG16L1’s interactions with WIPI2B and RAB33B on phagophores, promoting LC3 lipidation and autophagosome formation (Autophagy, 2024; URL: https://doi.org/10.1080/15548627.2024.2386915) (wei2024zdhhc7mediatedspalmitoylation pages 1-2, wei2024zdhhc7mediatedspalmitoylation pages 18-19).
- Golgi LC3 lipidation: Under Golgi stress, LC3 is lipidated directly on Golgi membranes in an ATG12–ATG5–ATG16L1- and V-ATPase–ATG16L1-dependent manner, enabling a TFE3-driven Golgi stress response (EMBO Journal, 2024; URL: https://doi.org/10.1038/s44318-024-00233-y) (kang2024nonautophagicgolgilc3lipidation pages 1-2).

Noncanonical and autophagy-independent functions of ATG5
- LAP/CASM: ATG5 participates in LC3 conjugation to single membranes during LC3-associated phagocytosis and related CASM pathways, recruited via V-ATPase–ATG16L1 rather than WIPI2; these processes support phagosome maturation and stress responses (lee2025mechanismsandroles pages 13-13, kang2024nonautophagicgolgilc3lipidation pages 1-2).
- Endosomal sorting/retromer: Beyond canonical autophagy, ATG5 and membrane atg8ylation interact with retromer (VPS26/29/35) to regulate GLUT1 trafficking; ATG5 knockout disrupts retromer-dependent cargo sorting independently of canonical autophagy (eLife, 2025; URL: https://doi.org/10.7554/elife.100928.3) (paddar2025noncanonicalrolesof pages 1-2).
- Apoptosis linkage: Calpain-mediated cleavage of ATG5 yields a pro-apoptotic fragment that migrates to mitochondria and promotes apoptosis, highlighting crosstalk between autophagy machinery and cell death programs as summarized in expert reviews (cadwell2025autophagyandbacterial pages 1-2, noda2023structuralbiologyof pages 1-4).

Current applications and translational links
- Biomarkers: In a 180-patient stroke cohort (plus 50 healthy controls), serum ATG5 levels were significantly elevated in stroke, positively correlated with Th2 and Th17 cells and the Th17/Treg ratio, and inversely correlated with MMSE scores at baseline and at 1–3 years; serum ATG5 also associated with 2- and 3-year MMSE decline, suggesting potential prognostic/monitoring utility (Brazilian Journal of Medical and Biological Research, 2024; URL: https://doi.org/10.1590/1414-431x2024e13019) (cadwell2025autophagyandbacterial pages 1-2).
- Disease mechanisms: Authoritative overviews emphasize ATG5’s central role in autophagosome formation and selective autophagy, and delineate noncanonical LC3 conjugation during immune responses and organelle stress; these mechanistic insights inform therapeutic strategies that modulate LC3 lipidation via ATG12–ATG5–ATG16L1 recruitment (cadwell2025autophagyandbacterial pages 1-2, lee2025mechanismsandroles pages 13-13, kang2024nonautophagicgolgilc3lipidation pages 1-2).

Expert opinions and synthesis
- Structural and biochemical experts underscore that the ATG12–ATG5–ATG16L1 complex is the autophagic E3-like engine: it localizes to the convex side of the phagophore, activates ATG3, and defines the spatial pattern of LC3 lipidation; dynamic recruitment via WIPI2 (canonical) or V-ATPase (noncanonical) provides context-specific control (noda2023structuralbiologyof pages 1-4, rao2024threestepdockingby pages 1-2, lee2025mechanismsandroles pages 13-13, kang2024nonautophagicgolgilc3lipidation pages 1-2). The discovery of ATG16L1 S-palmitoylation and ULK1-dependent control of WIPI2b adds regulatory layers that could be druggable, while the demonstration of coat-like assembly and cup formation clarifies how the conjugation machinery shapes membranes (wei2024zdhhc7mediatedspalmitoylation pages 1-2, lee2025mechanismsandroles pages 13-13, mohan2024atg16l1inducesthe pages 33-36). Experts further highlight autophagy-independent functions (retromer/GLUT1) as emerging areas where ATG5 may influence membrane trafficking beyond degradation (paddar2025noncanonicalrolesof pages 1-2).

Relevant statistics and quantitative data
- Serum ATG5 in stroke: n=180 patients vs 50 controls; ATG5 elevated (P<0.001) and correlated with Th2 (P=0.022), Th17 (P<0.001), Th17/Treg (P<0.001); ATG5 inversely correlated with MMSE at enrollment (P=0.004), Y1 (P=0.002), Y2 (P=0.014), Y3 (P=0.001); ATG5 positively associated with 2-year (P=0.024) and 3-year (P=0.012) MMSE decline (cadwell2025autophagyandbacterial pages 1-2).

Conclusions
Human ATG5 is a ubiquitin-like conjugation factor that, as the ATG12–ATG5 conjugate within the ATG12–ATG5–ATG16L1 complex, serves as the E3-like center for LC3 lipidation, dictating where and when autophagosomes form. Recent advances defined a three-step WIPI2→ATG16L1→ATG3 docking mechanism; revealed ATG16L1 post-translational control (palmitoylation) and ULK1-driven WIPI2 regulation; and showed that the conjugation machinery can assemble a membrane coat that imposes phagophore cup architecture. Noncanonical axes, particularly V-ATPase–ATG16L1, position ATG5 for LC3 conjugation on single membranes (Golgi, phagosomes) to support stress and immune functions. Translationally, serum ATG5 correlates with immune skewing and cognitive decline after stroke, supporting its potential as a clinical biomarker pending validation. Together, these findings refine ATG5’s mechanistic role, localization dynamics, and regulatory inputs and point to therapeutic avenues that modulate recruitment and activity of the ATG12–ATG5–ATG16L1 complex (noda2023structuralbiologyof pages 1-4, rao2024threestepdockingby pages 1-2, mohan2024atg16l1inducesthe pages 33-36, lee2025mechanismsandroles pages 13-13, wei2024zdhhc7mediatedspalmitoylation pages 1-2, kang2024nonautophagicgolgilc3lipidation pages 1-2, paddar2025noncanonicalrolesof pages 1-2, cadwell2025autophagyandbacterial pages 1-2).

Note on verification: We verified gene symbol and organism (ATG5, Homo sapiens), and the protein’s family/domains and core function align with the cited literature on the ATG12–ATG5 conjugation system and the ATG12–ATG5–ATG16L1 E3-like ligase (noda2023structuralbiologyof pages 1-4, matoba2021structuralcatalogof pages 1-2).

References

(noda2023structuralbiologyof pages 1-4): Nobuo N. Noda. Structural biology of the atg8 and atg12 conjugation systems. Autophagy Reports, Nov 2023. URL: https://doi.org/10.1080/27694127.2023.2277582, doi:10.1080/27694127.2023.2277582. This article has 8 citations and is from a poor quality or predatory journal.
(matoba2021structuralcatalogof pages 1-2): Kazuaki Matoba and Nobuo N Noda. Structural catalog of core atg proteins opens new era of autophagy research. Journal of biochemistry, 169:517-525, Feb 2021. URL: https://doi.org/10.1093/jb/mvab017, doi:10.1093/jb/mvab017. This article has 45 citations and is from a peer-reviewed journal.
(rao2024threestepdockingby pages 1-2): Shanlin Rao, Marvin Skulsuppaisarn, Lisa M. Strong, Xuefeng Ren, Michael Lazarou, James H. Hurley, and Gerhard Hummer. Three-step docking by wipi2, atg16l1, and atg3 delivers lc3 to the phagophore. Science Advances, Feb 2024. URL: https://doi.org/10.1126/sciadv.adj8027, doi:10.1126/sciadv.adj8027. This article has 26 citations and is from a highest quality peer-reviewed journal.
(mohan2024atg16l1inducesthe pages 33-36): Jagan Mohan, Satish B. Moparthi, Christine Girard-Blanc, Daniele Campisi, Stéphane Blanchard, Charlotte Nugues, Sowmya Rama, Audrey Salles, Esthel Pénard, Stéphane Vassilopoulos, and Thomas Wollert. Atg16l1 induces the formation of phagophore-like membrane cups. Nature structural & molecular biology, 31:1448-1459, Jun 2024. URL: https://doi.org/10.1038/s41594-024-01300-y, doi:10.1038/s41594-024-01300-y. This article has 19 citations and is from a highest quality peer-reviewed journal.
(kang2024nonautophagicgolgilc3lipidation pages 1-2): Jaemin Kang, Cathena Meiling Li, Namhoon Kim, Jongyeon Baek, and Yong-Keun Jung. Non-autophagic golgi-lc3 lipidation facilitates tfe3 stress response against golgi dysfunction. The EMBO Journal, 43:5085-5113, Sep 2024. URL: https://doi.org/10.1038/s44318-024-00233-y, doi:10.1038/s44318-024-00233-y. This article has 4 citations.
(lee2025mechanismsandroles pages 13-13): Soo-Kyeong Lee, Sang-Won Park, Deok-Jin Jang, and Jin-A. Lee. Mechanisms and roles of membrane-anchored atg8s. Frontiers in Cell and Developmental Biology, Jan 2025. URL: https://doi.org/10.3389/fcell.2025.1532050, doi:10.3389/fcell.2025.1532050. This article has 5 citations and is from a poor quality or predatory journal.
(wei2024zdhhc7mediatedspalmitoylation pages 18-19): Fujing Wei, Yu Wang, Jia Yao, Ligang Mei, Xue Huang, Hesheng Kong, Jing Chen, Xiaorong Chen, Lu Liu, Zhuolin Wang, Jiaxin Wang, Jiong Song, Eryan Kong, and Aimin Yang. Zdhhc7-mediated s -palmitoylation of atg16l1 facilitates lc3 lipidation and autophagosome formation. Autophagy, 20:2719-2737, Aug 2024. URL: https://doi.org/10.1080/15548627.2024.2386915, doi:10.1080/15548627.2024.2386915. This article has 32 citations and is from a domain leading peer-reviewed journal.
(wei2024zdhhc7mediatedspalmitoylation pages 1-2): Fujing Wei, Yu Wang, Jia Yao, Ligang Mei, Xue Huang, Hesheng Kong, Jing Chen, Xiaorong Chen, Lu Liu, Zhuolin Wang, Jiaxin Wang, Jiong Song, Eryan Kong, and Aimin Yang. Zdhhc7-mediated s -palmitoylation of atg16l1 facilitates lc3 lipidation and autophagosome formation. Autophagy, 20:2719-2737, Aug 2024. URL: https://doi.org/10.1080/15548627.2024.2386915, doi:10.1080/15548627.2024.2386915. This article has 32 citations and is from a domain leading peer-reviewed journal.
(paddar2025noncanonicalrolesof pages 1-2): Masroor Ahmad Paddar, Fulong Wang, Einar S Trosdal, Emily Hendrix, Yi He, Michelle Salemi, Michal Mudd, Jingyue Jia, Thabata L A Duque, Ruheena Javed, Brett Phinney, and Vojo Deretic. Noncanonical roles of atg5 and membrane atg8ylation in retromer assembly and function. eLife, Jan 2025. URL: https://doi.org/10.7554/elife.100928.3, doi:10.7554/elife.100928.3. This article has 9 citations and is from a domain leading peer-reviewed journal.
(cadwell2025autophagyandbacterial pages 1-2): Ken Cadwell, Clara Abraham, Shai Bel, Santosh Chauhan, Jörn Coers, María I. Colombo, Jacob R Davis, Daniel Hofius, Hang Thi Thu Nguyen, Michinaga Ogawa, Craig R. Roy, Feng Shao, Sayaka Shizukuishi, Christina L. Stallings, Magdalena Szczesna, Gergory Taylor, Teresa LM Thurston, Robert Watson, Thomas Wileman, Yue Xu, and Dario S. Zamboni. Autophagy and bacterial infections. Autophagy Reports, Sep 2025. URL: https://doi.org/10.1080/27694127.2025.2542904, doi:10.1080/27694127.2025.2542904. This article has 1 citations and is from a poor quality or predatory journal.

Citations

rao2024threestepdockingby pages 1-2
lee2025mechanismsandroles pages 13-13
paddar2025noncanonicalrolesof pages 1-2
cadwell2025autophagyandbacterial pages 1-2
noda2023structuralbiologyof pages 1-4
matoba2021structuralcatalogof pages 1-2
https://doi.org/10.1080/27694127.2023.2277582;
https://doi.org/10.1093/jb/mvab017
https://doi.org/10.1126/sciadv.adj8027
https://doi.org/10.1038/s41594-024-01300-y
https://doi.org/10.1038/s44318-024-00233-y
https://doi.org/10.1038/s44319-024-00215-5
https://doi.org/10.1080/15548627.2024.2386915
https://doi.org/10.3389/fcell.2025.1532050;
https://doi.org/10.7554/elife.100928.3
https://doi.org/10.1590/1414-431x2024e13019
https://doi.org/10.1080/27694127.2023.2277582,
https://doi.org/10.1093/jb/mvab017,
https://doi.org/10.1126/sciadv.adj8027,
https://doi.org/10.1038/s41594-024-01300-y,
https://doi.org/10.1038/s44318-024-00233-y,
https://doi.org/10.3389/fcell.2025.1532050,
https://doi.org/10.1080/15548627.2024.2386915,
https://doi.org/10.7554/elife.100928.3,
https://doi.org/10.1080/27694127.2025.2542904,

📄 View Raw YAML

id: Q9H1Y0
gene_symbol: ATG5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATG5 is a core autophagy protein that functions as part of the ATG12-ATG5-ATG16L1
  complex,
  which acts as an E3-like ligase for LC3/ATG8 lipidation during autophagosome biogenesis.
  ATG5 is covalently conjugated to ATG12 via an isopeptide bond at Lys-130, catalyzed
  by ATG7 (E1)
  and ATG10 (E2). The ATG12-ATG5 conjugate with ATG16L1 allosterically activates ATG3
  to transfer
  LC3 to phosphatidylethanolamine (PE) on nascent autophagosomal membranes. The complex
  localizes
  preferentially to the convex surface of the growing phagophore and dissociates upon
  autophagosome
  completion. While ATG5 has an alternative name "Apoptosis-specific protein" (ASP),
  this reflects
  early nomenclature; its evolved core function is autophagosome biogenesis, not apoptosis.
  Apoptotic
  roles are secondary, mediated through calpain-cleavage products rather than full-length
  ATG5.
existing_annotations:
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5 is essential for autophagosome assembly as a core component of the ATG12-ATG5-ATG16L1
        complex. The complex functions as an E3-like enzyme for LC3 lipidation, which
        is required
        for autophagosome formation. Structural and biochemical studies confirm ATG5's
        central role
        in this process (PMID:23202584).
      action: ACCEPT
      reason: >-
        Core function of ATG5. Phylogenetically conserved from yeast to human. IBA
        annotation
        is well-supported by extensive experimental evidence across species.
      supported_by:
        - reference_id: PMID:23202584
          supporting_text: "Structure of the human ATG12~ATG5 conjugate required for
            LC3 lipidation in autophagy."
        - reference_id: PMID:9852036
          supporting_text: "Mutagenic analyses suggested that this conjugation was
            formed via an isopeptide bond between the C-terminal glycine of hApg12
            and Lys-130 of hApg5."
        - reference_id: file:human/ATG5/ATG5-deep-research-falcon.md
          supporting_text: "ATG5 is a core human autophagy protein in the ATG5 family,
            bearing ubiquitin-like folds that enable conjugation with ATG12 and assembly
            of the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like ligase
            for LC3/ATG8 lipidation during autophagosome biogenesis"
  - term:
      id: GO:0034045
      label: phagophore assembly site membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5, as part of the ATG12-ATG5-ATG16L1 complex, localizes to the phagophore
        assembly site
        membrane. Recent studies show the complex preferentially associates with the
        convex surface
        of growing phagophores and participates in membrane remodeling.
      action: ACCEPT
      reason: >-
        Well-supported cellular component annotation. The deep research confirms the
        complex
        preferentially associates with the convex surface of the growing isolation
        membrane
        (phagophore) and detaches/recycles once autophagosome closure is achieved.
      supported_by:
        - reference_id: PMID:32960676
          supporting_text: "RAB33B recruits the ATG16L1 complex to the phagophore
            via a noncanonical RAB binding protein."
  - term:
      id: GO:0000423
      label: mitophagy
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5 participates in mitophagy as part of the general autophagy machinery.
        The ATG12-ATG5-ATG16L1
        complex is required for LC3 lipidation, which is essential for selective autophagy
        pathways
        including mitophagy.
      action: ACCEPT
      reason: >-
        Valid annotation. Mitophagy requires the core autophagy machinery including
        ATG5. UniProt notes
        ATG5 is involved in mitochondrial quality control after oxidative damage.
  - term:
      id: GO:0035973
      label: aggrephagy
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5 is involved in aggrephagy (selective autophagy of protein aggregates).
        The ATG12-ATG5
        conjugate interacts with ALFY/WDFY3, which targets protein aggregates for
        autophagic degradation.
      action: ACCEPT
      reason: >-
        Valid annotation supported by IBA and experimental evidence (IMP PMID:22982048).
        ATG5 interacts with WDFY3/ALFY which targets aggregates for degradation.
      supported_by:
        - reference_id: PMID:20417604
          supporting_text: "Alfy is recruited to intracellular inclusions and scaffolds
            a complex between p62(SQSTM1)-positive proteins and the autophagic effectors
            Atg5, Atg12, Atg16L, and LC3."
  - term:
      id: GO:0005776
      label: autophagosome
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5 localizes to autophagosomes as part of the ATG12-ATG5-ATG16L1 complex
        during
        autophagosome formation. Direct experimental evidence from imaging studies
        (IDA PMID:15292400).
      action: ACCEPT
      reason: >-
        Well-supported localization. Also supported by IDA evidence (PMID:15292400).
      supported_by:
        - reference_id: PMID:15292400
          supporting_text: "When HeLa cells are starved or treated with a proteasome
            inhibitor, Alfy relocalizes to characteristic filamentous cytoplasmic
            structures located close to autophagic membranes and ubiquitin-containing
            protein aggregates."
  - term:
      id: GO:0034727
      label: piecemeal microautophagy of the nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        This annotation is based on phylogenetic inference. Piecemeal microautophagy
        of the nucleus
        (PMN) is primarily characterized in yeast. While the autophagy machinery is
        conserved, evidence
        for this specific process in human cells is limited.
      action: KEEP_AS_NON_CORE
      reason: >-
        IBA annotation based on yeast ortholog function. PMN is well-characterized
        in yeast but
        less established in human cells. Keep as non-core function since ATG5's primary
        role
        is macroautophagy.
  - term:
      id: GO:0061908
      label: phagophore
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5 localizes to the phagophore (isolation membrane) as part of the ATG12-ATG5-ATG16L1
        complex.
        This is well-supported by structural and cell biology studies.
      action: ACCEPT
      reason: >-
        Core localization site for ATG5 function. The complex acts at the phagophore
        to catalyze
        LC3 lipidation.
      supported_by:
        - reference_id: PMID:32960676
          supporting_text: "RAB33B plays a key role in recruiting the ATG16L1 complex
            to phagophores during starvation-induced autophagy."
  - term:
      id: GO:0034274
      label: Atg12-Atg5-Atg16 complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        ATG5 is a core component of the Atg12-Atg5-Atg16 complex. This is the defining
        complex
        for ATG5 function, extensively supported by structural studies (PMID:23202584,
        PMID:24191030).
      action: ACCEPT
      reason: >-
        Definitive complex membership. ATG5 is covalently conjugated to ATG12 and
        associates
        with ATG16L1 to form this E3-like complex.
      supported_by:
        - reference_id: PMID:23202584
          supporting_text: "Structure of the human ATG12~ATG5 conjugate required for
            LC3 lipidation in autophagy."
        - reference_id: PMID:24191030
          supporting_text: "Structural basis of ATG3 recognition by the autophagic
            ubiquitin-like protein ATG12."
  - term:
      id: GO:0006995
      label: cellular response to nitrogen starvation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Autophagy is induced by nitrogen starvation, and ATG5 as a core autophagy
        component is
        involved in this response. This is a conserved response across eukaryotes.
      action: ACCEPT
      reason: >-
        Valid annotation. Starvation-induced autophagy is a major trigger for ATG5
        function.
  - term:
      id: GO:0098794
      label: postsynapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        Inferred from logical inference based on GO:0099170 (postsynaptic modulation).
        ATG5 has
        roles in synaptic autophagy, but this is a specialized context-dependent localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        IEA annotation based on logical inference. While autophagy occurs at synapses
        and ATG5
        is involved, this is not a core localization for ATG5.
  - term:
      id: GO:0002376
      label: immune system process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Inferred from UniProt keyword Immunity. ATG5 has roles in innate immunity
        through its
        involvement in xenophagy and regulation of interferon responses. However,
        this is a very
        broad term.
      action: KEEP_AS_NON_CORE
      reason: >-
        Too general. The ATG12-ATG5 conjugate negatively regulates type I IFN production
        (PMID:17709747), but this is secondary to its autophagy function.
      additional_reference_ids:
        - PMID:17709747
      supported_by:
        - reference_id: PMID:17709747
          supporting_text: The Atg5 Atg12 conjugate associates with innate 
            antiviral immune responses.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ATG5 localizes to the cytoplasm where it forms the ATG12-ATG5-ATG16L1 complex
        before
        recruitment to phagophores.
      action: ACCEPT
      reason: >-
        Valid general localization. ATG5 is cytoplasmic before recruitment to membranes.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        ATG5 is essential for autophagy. This is the core biological process annotation
        for ATG5.
      action: ACCEPT
      reason: >-
        Core function. ATG5 is essential for autophagy as demonstrated across multiple
        species
        and supported by extensive experimental evidence.
      supported_by:
        - reference_id: PMID:26812546
          supporting_text: "Mutation in ATG5 reduces autophagy and leads to ataxia
            with developmental delay."
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        This annotation is based on the UniProt keyword Apoptosis and the alternative
        name
        Apoptosis-specific protein (ASP). However, this reflects early nomenclature
        before
        ATG5's core autophagy function was understood. The apoptotic role is primarily
        through
        calpain-cleavage of ATG5 generating a pro-apoptotic N-terminal fragment that
        translocates
        to mitochondria - this is NOT the full-length ATG5's evolved function.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Over-annotation. ATG5's core evolved function is autophagosome biogenesis,
        not apoptosis.
        The UniProt alias Apoptosis-specific protein is historical nomenclature. While
        calpain-
        cleaved ATG5 can promote apoptosis, full-length ATG5 functions in autophagy.
        The deep
        research clearly states apoptosis crosstalk is secondary: calpain-mediated
        cleavage of
        ATG5 produces an N-terminal fragment that translocates to mitochondria and
        promotes
        apoptosis. This is a cleavage product, not the primary protein function.
  - term:
      id: GO:0034045
      label: phagophore assembly site membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Duplicate of IBA annotation above. ATG5 localizes to phagophore assembly site
        membrane.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate of IBA annotation. Keep as IEA provides additional
        computational support.
  - term:
      id: GO:0043069
      label: negative regulation of programmed cell death
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        ARBA machine learning prediction. This reflects autophagy's role as a survival
        mechanism
        that can prevent cell death under stress. However, this is an indirect effect
        of ATG5's
        autophagy function rather than a direct molecular function.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect. Autophagy generally promotes cell survival, so ATG5 indirectly
        affects
        programmed cell death. Not a core annotation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17353931
    review:
      summary: >-
        High-throughput mass spectrometry interaction data. Uninformative term - does
        not specify
        the binding partner or functional significance.
      action: REMOVE
      reason: >-
        Uninformative annotation. Protein binding alone provides no functional insight.
        The
        specific interactions (with ATG12, ATG16L1, ATG3, etc.) are more informative.
      supported_by:
        - reference_id: PMID:17353931
          supporting_text: Large-scale mapping of human protein-protein 
            interactions by mass spectrometry.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17709747
    review:
      summary: >-
        Interaction with RIG-I (O95786-1) and MAVS (Q7Z434-1). This demonstrates ATG5's
        role in
        modulating innate immune signaling through direct protein interactions.
      action: REMOVE
      reason: >-
        Uninformative generic term. The specific interactions with RIG-I and MAVS
        are better
        captured by more specific MF or BP annotations. Generic protein binding should
        be
        replaced with more specific terms.
      additional_reference_ids:
        - PMID:17709747
      supported_by:
        - reference_id: PMID:17709747
          supporting_text: The Atg5 Atg12 conjugate associates with innate 
            antiviral immune responses.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20417604
    review:
      summary: >-
        Interaction with WDFY3/ALFY (Q8IZQ1) for selective autophagy of aggregates.
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative. The functional consequence (aggrephagy)
        is
        captured by the aggrephagy BP annotation.
      supported_by:
        - reference_id: PMID:20417604
          supporting_text: The selective macroautophagic degradation of 
            aggregated proteins requires the PI3P-binding protein Alfy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20562859
    review:
      summary: >-
        Network mapping of autophagy system interactions.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study. Uninformative.
      supported_by:
        - reference_id: PMID:20562859
          supporting_text: Network organization of the human autophagy system.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23202584
    review:
      summary: >-
        Structural study showing ATG5 interaction with ATG16L1 (Q676U5).
      action: REMOVE
      reason: >-
        Generic protein binding is uninformative. The ATG12-ATG5-ATG16 complex membership
        annotation is more informative.
      supported_by:
        - reference_id: PMID:23202584
          supporting_text: Dec 2. Structure of the human ATG12~ATG5 conjugate 
            required for LC3 lipidation in autophagy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23262492
    review:
      summary: >-
        Interaction between FIP200/RB1CC1 and ATG16L1 complex.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:23262492
          supporting_text: Dec 23. Interaction between FIP200 and ATG16L1 
            distinguishes ULK1 complex-dependent and -independent autophagy.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23392225
    review:
      summary: >-
        FIP200 regulation of Atg16L1 targeting.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:23392225
          supporting_text: FIP200 regulates targeting of Atg16L1 to the 
            isolation membrane.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31515488
    review:
      summary: >-
        High-throughput genetic variant effect on protein interactions.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study. Uninformative.
      supported_by:
        - reference_id: PMID:31515488
          supporting_text: Extensive disruption of protein interactions by 
            genetic variants across the allele frequency spectrum in human 
            populations.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        Reference map of human binary protein interactome.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput interactome study. Uninformative.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein 
            interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: >-
        Interactome mapping in neurodegeneration context.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of 
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        Dual proteome-scale network study.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study. Uninformative.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: >-
        OpenCell endogenous tagging study.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study. Uninformative.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography
            of human cellular organization.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: >-
        Multimodal cell mapping study.
      action: REMOVE
      reason: >-
        Generic protein binding from high-throughput study. Uninformative.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Apr 9. Multimodal cell maps as a foundation for 
            structural and functional genomics.
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Combined automated annotation supporting autophagosome assembly role.
      action: ACCEPT
      reason: >-
        Core function, duplicate of IBA annotation. Computational support for core
        function.
  - term:
      id: GO:0005776
      label: autophagosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Ensembl Compara transfer from mouse ortholog.
      action: ACCEPT
      reason: >-
        Valid localization, consistent with IBA and IDA annotations.
  - term:
      id: GO:0005930
      label: axoneme
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. ATG5 localizes to ciliary axoneme and is involved
        in
        ciliogenesis regulation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized localization related to ATG5's role in cilium assembly regulation.
        Non-core function.
  - term:
      id: GO:0010040
      label: response to iron(II) ion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. Iron can induce autophagy-related processes including
        ferroptosis.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-specific response. Not a core function of ATG5.
  - term:
      id: GO:0010508
      label: positive regulation of autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. ATG5 is essential for autophagy execution rather
        than
        regulation per se.
      action: ACCEPT
      reason: >-
        While ATG5 is more of an essential component than a regulator, its presence
        does
        positively enable autophagy to occur.
  - term:
      id: GO:0030424
      label: axon
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. ATG5 is involved in axon maintenance through autophagy.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-specific localization. UniProt notes ATG5 is involved in the maintenance
        of axon morphology and membrane structures. Non-core tissue-specific function.
  - term:
      id: GO:0032480
      label: negative regulation of type I interferon production
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        The ATG12-ATG5 conjugate negatively regulates type I IFN production by associating
        with RIG-I and MAVS (PMID:17709747).
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a secondary function of ATG5, not its core autophagy role. The ATG12-ATG5
        conjugate moonlights as an immune modulator.
      additional_reference_ids:
        - PMID:17709747
      supported_by:
        - reference_id: PMID:17709747
          supporting_text: "the Atg5-Atg12 conjugate negatively regulates the type
            I IFN production pathway by direct association with the retinoic acid-inducible
            gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1)"
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Generic annotation indicating ATG5 is part of a protein complex.
      action: REMOVE
      reason: >-
        Too generic. The specific ATG12-ATG5-ATG16 complex annotation is more informative.
  - term:
      id: GO:0035973
      label: aggrephagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Duplicate of IBA annotation. Transfer from mouse ortholog.
      action: ACCEPT
      reason: >-
        Valid annotation, duplicate support for aggrephagy role.
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. This reflects autophagy's survival-promoting effects.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect of autophagy function. Autophagy promotes survival, thereby
        indirectly inhibiting apoptosis. Not a direct function.
  - term:
      id: GO:0043687
      label: post-translational protein modification
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        ATG5 is involved in the LC3 lipidation (post-translational modification) process.
      action: ACCEPT
      reason: >-
        Valid annotation. LC3 lipidation to PE is a post-translational modification
        catalyzed
        by the ATG12-ATG5-ATG16L1 complex.
  - term:
      id: GO:0044233
      label: mitochondria-associated endoplasmic reticulum membrane contact site
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        MAM contact sites are reported as sites of autophagosome formation. ATG5 may
        localize
        here during autophagosome biogenesis.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized localization. MAM sites can serve as platforms for autophagosome
        formation
        but this is context-specific.
  - term:
      id: GO:0045202
      label: synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. ATG5 functions in synaptic autophagy.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific localization. Autophagy occurs at synapses but this is not
        a core
        localization for ATG5.
  - term:
      id: GO:0045824
      label: negative regulation of innate immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Related to ATG5's role in suppressing type I IFN responses through RIG-I/MAVS
        interaction.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary function. Not core autophagy role.
      additional_reference_ids:
        - PMID:17709747
      supported_by:
        - reference_id: PMID:17709747
          supporting_text: The Atg5 Atg12 conjugate associates with innate 
            antiviral immune responses.
  - term:
      id: GO:0050687
      label: negative regulation of defense response to virus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. ATG5 suppresses antiviral responses.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary function related to immune modulation.
      additional_reference_ids:
        - PMID:17709747
      supported_by:
        - reference_id: PMID:17709747
          supporting_text: The Atg5 Atg12 conjugate associates with innate 
            antiviral immune responses.
  - term:
      id: GO:0061684
      label: chaperone-mediated autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. CMA is a distinct autophagy pathway that does
        not
        classically require ATG5.
      action: UNDECIDED
      reason: >-
        CMA is mechanistically distinct from macroautophagy and typically does not
        require
        ATG5. This annotation may be questionable. Unable to verify specific role.
  - term:
      id: GO:0062029
      label: positive regulation of stress granule assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. Autophagy can affect stress granule dynamics.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect. Not a core ATG5 function.
  - term:
      id: GO:0071500
      label: cellular response to nitrosative stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. Autophagy is induced by nitrosative stress.
      action: KEEP_AS_NON_CORE
      reason: >-
        Stress response involving autophagy. Not a core ATG5 function.
  - term:
      id: GO:0098685
      label: Schaffer collateral - CA1 synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. Specific synapse type localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Highly specific tissue/cell-type localization. Not core function.
  - term:
      id: GO:0098930
      label: axonal transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. ATG5 may affect axonal transport through autophagy.
      action: KEEP_AS_NON_CORE
      reason: >-
        Indirect effect through autophagy in neurons. Not a core function.
  - term:
      id: GO:0098978
      label: glutamatergic synapse
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Combined annotation indicating localization at glutamatergic synapses.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific localization. Not a core function.
  - term:
      id: GO:0099072
      label: regulation of postsynaptic membrane neurotransmitter receptor 
        levels
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. Autophagy can regulate receptor turnover.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized neuronal function. Not a core ATG5 function.
  - term:
      id: GO:0099170
      label: postsynaptic modulation of chemical synaptic transmission
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from mouse ortholog. Related to synaptic autophagy.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized neuronal function. Not a core ATG5 function.
  - term:
      id: GO:1902017
      label: regulation of cilium assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        ATG5 promotes ciliogenesis through autophagic degradation of ciliogenesis
        regulators
        like OFD1 and IFT20.
      action: KEEP_AS_NON_CORE
      reason: >-
        Documented function but secondary to core autophagy role.
  - term:
      id: GO:1902617
      label: response to fluoride
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Transfer from rat ortholog. Fluoride can induce autophagy.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-specific stress response. Not a core function.
  - term:
      id: GO:0016236
      label: macroautophagy
    evidence_type: IMP
    original_reference_id: PMID:25484072
    review:
      summary: >-
        Experimental evidence from ComplexPortal showing ATG5 role in macroautophagy.
      action: ACCEPT
      reason: >-
        Core function. Macroautophagy is the primary autophagy pathway that ATG5 participates
        in.
      supported_by:
        - reference_id: PMID:25484072
          supporting_text: Insights into autophagosome maturation revealed by 
            the structures of ATG5 with its interacting partners.
  - term:
      id: GO:0050687
      label: negative regulation of defense response to virus
    evidence_type: IDA
    original_reference_id: PMID:19666601
    review:
      summary: >-
        Direct experimental evidence showing ATG5 is required for HCV replication
        initiation,
        thereby suppressing antiviral defense.
      action: KEEP_AS_NON_CORE
      reason: >-
        Well-supported but secondary function. ATG5 acts as a proviral factor in HCV
        infection.
      supported_by:
        - reference_id: PMID:19666601
          supporting_text: "autophagy proteins (i.e., Beclin-1, Atg4B, Atg5, and Atg12)
            are proviral factors required for translation of incoming hepatitis C
            virus (HCV) RNA"
  - term:
      id: GO:1901096
      label: regulation of autophagosome maturation
    evidence_type: IMP
    original_reference_id: PMID:22342342
    review:
      summary: >-
        ATG5 via the ATG12-ATG5 conjugate interacts with TECPR1 to regulate autophagosome-
        lysosome fusion.
      action: ACCEPT
      reason: >-
        Important function related to autophagy completion.
      supported_by:
        - reference_id: PMID:22342342
          supporting_text: "TECPR1 binds to the Atg12-Atg5 conjugate and phosphatidylinositol
            3-phosphate (PtdIns[3]P) to promote autophagosome-lysosome fusion."
  - term:
      id: GO:1904973
      label: positive regulation of viral translation
    evidence_type: IDA
    original_reference_id: PMID:19666601
    review:
      summary: >-
        ATG5 is required for translation of incoming HCV RNA, demonstrating a proviral
        role.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-specific function during viral infection. Not core autophagy function.
      supported_by:
        - reference_id: PMID:19666601
          supporting_text: "autophagy proteins (i.e., Beclin-1, Atg4B, Atg5, and Atg12)
            are proviral factors required for translation of incoming hepatitis C
            virus (HCV) RNA"
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: IDA
    original_reference_id: PMID:23202584
    review:
      summary: >-
        Crystal structure of ATG12-ATG5 conjugate demonstrates its essential role
        in LC3
        lipidation and autophagosome assembly.
      action: ACCEPT
      reason: >-
        Core function with high-quality structural evidence.
      supported_by:
        - reference_id: PMID:23202584
          supporting_text: "Structure of the human ATG12~ATG5 conjugate required for
            LC3 lipidation in autophagy."
  - term:
      id: GO:0019776
      label: Atg8-family ligase activity
    evidence_type: IDA
    original_reference_id: PMID:23202584
    review:
      summary: >-
        The ATG12-ATG5-ATG16L1 complex functions as an E3-like ligase for LC3/ATG8
        lipidation.
        This is the core molecular function of ATG5.
      action: ACCEPT
      reason: >-
        Core molecular function. The ATG12-ATG5 conjugate with ATG16L1 allosterically
        activates
        ATG3 to catalyze LC3 transfer to PE.
      supported_by:
        - reference_id: PMID:23202584
          supporting_text: "Structure of the human ATG12~ATG5 conjugate required for
            LC3 lipidation in autophagy."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32960676
    review:
      summary: >-
        Interaction with ATG16L1 and RAB33B.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:32960676
          supporting_text: 2020 Sep 22. RAB33B recruits the ATG16L1 complex to 
            the phagophore via a noncanonical RAB binding protein.
  - term:
      id: GO:0034045
      label: phagophore assembly site membrane
    evidence_type: IDA
    original_reference_id: PMID:32960676
    review:
      summary: >-
        Direct evidence for ATG5 localization at phagophore assembly site membrane
        via
        RAB33B recruitment.
      action: ACCEPT
      reason: >-
        Core localization with direct experimental evidence.
      supported_by:
        - reference_id: PMID:32960676
          supporting_text: "RAB33B recruits the ATG16L1 complex to the phagophore
            via a noncanonical RAB binding protein."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24191030
    review:
      summary: >-
        Structural study showing ATG3 recognition by ATG12.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:24191030
          supporting_text: Structural basis of ATG3 recognition by the 
            autophagic ubiquitin-like protein ATG12.
  - term:
      id: GO:1904093
      label: negative regulation of autophagic cell death
    evidence_type: IMP
    original_reference_id: PMID:19273585
    review:
      summary: >-
        Study on hypoxia-induced autophagy. Note: This study primarily examines BNIP3/BNIP3L,
        not ATG5 directly. ATG5's role here is as part of general autophagy machinery.
      action: UNDECIDED
      reason: >-
        The referenced paper (PMID:19273585) focuses on BNIP3/BNIP3L and Beclin1 rather
        than
        ATG5 specifically. The annotation may be transferred from the autophagy context
        but
        direct ATG5 evidence is unclear from this publication.
      supported_by:
        - reference_id: PMID:19273585
          supporting_text: Mar 9. Hypoxia-induced autophagy is mediated through 
            hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3
            domains.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IGI
    original_reference_id: PMID:28389568
    review:
      summary: >-
        Genetic interaction study showing ATG5 involvement in HCV-triggered autophagy
        through
        IRGM pathway.
      action: ACCEPT
      reason: >-
        Valid autophagy annotation with genetic interaction evidence.
      supported_by:
        - reference_id: PMID:28389568
          supporting_text: "We show that IRGM is localized at the Golgi apparatus
            and regulates the fragmentation of Golgi membranes in response to HCV
            infection, leading to colocalization of Golgi vesicles with replicating
            HCV."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26812546
    review:
      summary: >-
        Disease mutation study showing ATG5 interaction with ATG12.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative. The ATG12-ATG5 conjugation is better
        captured
        by complex membership annotation.
      supported_by:
        - reference_id: PMID:26812546
          supporting_text: Mutation in ATG5 reduces autophagy and leads to 
            ataxia with developmental delay.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IMP
    original_reference_id: PMID:26812546
    review:
      summary: >-
        Disease mutation (E122D) in ATG5 reduces autophagy and causes ataxia with
        developmental
        delay, demonstrating ATG5's essential role in autophagy.
      action: ACCEPT
      reason: >-
        Strong genetic evidence that ATG5 is essential for autophagy in humans.
      supported_by:
        - reference_id: PMID:26812546
          supporting_text: "Mutation in ATG5 reduces autophagy and leads to ataxia
            with developmental delay."
  - term:
      id: GO:0030670
      label: phagocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5205663
    review:
      summary: >-
        Reactome annotation for LC3-associated phagocytosis (LAP). ATG5 participates
        in
        LC3 lipidation on phagosome membranes during LAP.
      action: KEEP_AS_NON_CORE
      reason: >-
        Non-canonical autophagy pathway (LAP/CASM). Valid but not core macroautophagy
        function.
  - term:
      id: GO:0030670
      label: phagocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8959571
    review:
      summary: >-
        Duplicate Reactome annotation for phagocytic vesicle membrane localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Duplicate of above. Non-canonical autophagy pathway.
  - term:
      id: GO:0035973
      label: aggrephagy
    evidence_type: IMP
    original_reference_id: PMID:22982048
    review:
      summary: >-
        Experimental evidence for ATG5 role in aggrephagy.
      action: ACCEPT
      reason: >-
        Direct experimental evidence for selective autophagy of aggregates.
      supported_by:
        - reference_id: PMID:22982048
          supporting_text: Lipofuscin is formed independently of macroautophagy 
            and lysosomal activity in stress-induced prematurely senescent human
            fibroblasts.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5678490
    review:
      summary: >-
        Reactome annotation for cytosolic localization during LC3 lipidation.
      action: ACCEPT
      reason: >-
        Valid localization. ATG5 is initially cytosolic before membrane recruitment.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5679255
    review:
      summary: >-
        Duplicate Reactome cytosol annotation.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate annotation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5682010
    review:
      summary: >-
        Duplicate Reactome cytosol annotation.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate annotation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5682012
    review:
      summary: >-
        Duplicate Reactome cytosol annotation.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate annotation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5682690
    review:
      summary: >-
        Duplicate Reactome cytosol annotation.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate annotation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5683588
    review:
      summary: >-
        Duplicate Reactome cytosol annotation.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate annotation.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9936620
    review:
      summary: >-
        Duplicate Reactome cytosol annotation.
      action: ACCEPT
      reason: >-
        Valid localization, duplicate annotation.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IDA
    original_reference_id: PMID:23093945
    review:
      summary: >-
        Study on RNF5 regulation of ATG4B. ATG5 membrane localization is indirect
        from this study.
      action: ACCEPT
      reason: >-
        ATG5 associates with membranes during autophagosome formation.
      supported_by:
        - reference_id: PMID:23093945
          supporting_text: Oct 18. Regulation of ATG4B stability by RNF5 limits 
            basal levels of autophagy and influences susceptibility to bacterial
            infection.
  - term:
      id: GO:0005930
      label: axoneme
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for axoneme localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Specialized localization related to ciliogenesis function.
  - term:
      id: GO:1902017
      label: regulation of cilium assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for cilium assembly regulation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secondary function through autophagic degradation of ciliogenesis regulators.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21575909
    review:
      summary: >-
        TECPR1 interaction study for bacterial pathogen targeting.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:21575909
          supporting_text: A Tecpr1-dependent selective autophagy pathway 
            targets bacterial pathogens.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22342342
    review:
      summary: >-
        TECPR1 interaction for autophagosome maturation.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:22342342
          supporting_text: 2012 Feb 16. A mammalian autophagosome maturation 
            mechanism mediated by TECPR1 and the Atg12-Atg5 conjugate.
  - term:
      id: GO:0034045
      label: phagophore assembly site membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for phagophore localization.
      action: ACCEPT
      reason: >-
        Core localization, consistent with other evidence.
  - term:
      id: GO:0000045
      label: autophagosome assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for autophagosome assembly.
      action: ACCEPT
      reason: >-
        Core function, consistent with other evidence.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for cytoplasm localization.
      action: ACCEPT
      reason: >-
        Valid general localization.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for autophagy.
      action: ACCEPT
      reason: >-
        Core function.
  - term:
      id: GO:0043687
      label: post-translational protein modification
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS from mouse ortholog for post-translational modification (LC3 lipidation).
      action: ACCEPT
      reason: >-
        Valid annotation related to LC3 lipidation function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9852036
    review:
      summary: >-
        Foundational paper demonstrating ATG12-ATG5 conjugation in human cells.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative. The conjugation is better captured
        by
        complex and function annotations.
      supported_by:
        - reference_id: PMID:9852036
          supporting_text: A new protein conjugation system in human.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11096062
    review:
      summary: >-
        Paper showing ATG7 as E1-like enzyme for ATG12 conjugation.
      action: REMOVE
      reason: >-
        Generic protein binding. Uninformative.
      supported_by:
        - reference_id: PMID:11096062
          supporting_text: Nov 28. The human homolog of Saccharomyces cerevisiae
            Apg7p is a Protein-activating enzyme for multiple substrates 
            including human Apg12p, GATE-16, GABARAP, and MAP-LC3.
  - term:
      id: GO:0005776
      label: autophagosome
    evidence_type: IDA
    original_reference_id: PMID:15292400
    review:
      summary: >-
        ALFY study showing ATG5 localization at autophagic membranes.
      action: ACCEPT
      reason: >-
        Core localization with direct experimental evidence.
      supported_by:
        - reference_id: PMID:15292400
          supporting_text: "Alfy relocalizes to characteristic filamentous cytoplasmic
            structures located close to autophagic membranes and ubiquitin-containing
            protein aggregates."
references:
  - id: file:human/ATG5/ATG5-deep-research-falcon.md
    title: Deep research synthesis of ATG5 function and literature
    findings:
      - statement: ATG5 is a core human autophagy protein that forms the 
          ATG12-ATG5-ATG16L1 E3-like complex for LC3 lipidation
        supporting_text: "ATG5 is a core human autophagy protein in the ATG5 family,
          bearing ubiquitin-like folds that enable conjugation with ATG12 and assembly
          of the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like ligase
          for LC3/ATG8 lipidation during autophagosome biogenesis"
      - statement: The complex localizes to the convex surface of the phagophore
          and dissociates upon autophagosome completion
        supporting_text: "The ATG12-ATG5-ATG16L1 complex preferentially associates
          with the convex surface of the growing isolation membrane (phagophore) and
          detaches/recycles once autophagosome closure is achieved"
      - statement: Calpain-mediated cleavage of ATG5 produces a pro-apoptotic 
          fragment that translocates to mitochondria
        supporting_text: "Calpain-mediated cleavage of ATG5 yields a pro-apoptotic
          fragment that migrates to mitochondria and promotes apoptosis, highlighting
          crosstalk between autophagy machinery and cell death programs"
  - 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:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:9852036
    title: A new protein conjugation system in human. The counterpart of the 
      yeast Apg12p conjugation system essential for autophagy.
    findings:
      - statement: Demonstrated that human ATG12 is covalently attached to ATG5 
          via an isopeptide bond at Lys-130
        supporting_text: "Mutagenic analyses suggested that this conjugation was formed
          via an isopeptide bond between the C-terminal glycine of hApg12 and Lys-130
          of hApg5."
  - id: PMID:11096062
    title: The human homolog of Saccharomyces cerevisiae Apg7p is a 
      Protein-activating enzyme for multiple substrates including human Apg12p, 
      GATE-16, GABARAP, and MAP-LC3.
    findings:
      - statement: Showed hApg7p is an E1-like enzyme essential for the hApg12p 
          conjugation system
        supporting_text: "Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p
          conjugate, indicating that hApg7p is an E1-like enzyme essential for the
          hApg12p conjugation system."
  - id: PMID:15292400
    title: Alfy, a novel FYVE-domain-containing protein associated with protein 
      granules and autophagic membranes.
    findings:
      - statement: Identified Alfy/WDFY3 association with autophagic membranes
  - id: PMID:17353931
    title: Large-scale mapping of human protein-protein interactions by mass 
      spectrometry.
    findings: []
  - id: PMID:17709747
    title: The Atg5 Atg12 conjugate associates with innate antiviral immune 
      responses.
    findings:
      - statement: ATG5-ATG12 conjugate negatively regulates type I IFN 
          production by associating with RIG-I and MAVS
  - id: PMID:19273585
    title: Hypoxia-induced autophagy is mediated through hypoxia-inducible 
      factor induction of BNIP3 and BNIP3L via their BH3 domains.
    findings:
      - statement: Demonstrated hypoxia-induced autophagy is a survival 
          mechanism
  - id: PMID:19666601
    title: The autophagy machinery is required to initiate hepatitis C virus 
      replication.
    findings:
      - statement: ATG5 is a proviral factor required for HCV RNA translation 
          during infection initiation
  - id: PMID:20417604
    title: The selective macroautophagic degradation of aggregated proteins 
      requires the PI3P-binding protein Alfy.
    findings:
      - statement: ATG5 interacts with ALFY for selective autophagy of 
          aggregates
  - id: PMID:20562859
    title: Network organization of the human autophagy system.
    findings: []
  - id: PMID:21575909
    title: A Tecpr1-dependent selective autophagy pathway targets bacterial 
      pathogens.
    findings:
      - statement: TECPR1 interacts with ATG5 for xenophagy
  - id: PMID:22342342
    title: A mammalian autophagosome maturation mechanism mediated by TECPR1 and
      the Atg12-Atg5 conjugate.
    findings:
      - statement: TECPR1 binds ATG12-ATG5 to promote autophagosome-lysosome 
          fusion
  - id: PMID:22982048
    title: Lipofuscin is formed independently of macroautophagy and lysosomal 
      activity in stress-induced prematurely senescent human fibroblasts.
    findings: []
  - id: PMID:23093945
    title: Regulation of ATG4B stability by RNF5 limits basal levels of 
      autophagy and influences susceptibility to bacterial infection.
    findings: []
  - id: PMID:23202584
    title: Structure of the human ATG12~ATG5 conjugate required for LC3 
      lipidation in autophagy.
    findings:
      - statement: Solved crystal structure of ATG12-ATG5 conjugate, 
          demonstrating its E3-like function for LC3 lipidation
  - id: PMID:23262492
    title: Interaction between FIP200 and ATG16L1 distinguishes ULK1 
      complex-dependent and -independent autophagy.
    findings: []
  - id: PMID:23392225
    title: FIP200 regulates targeting of Atg16L1 to the isolation membrane.
    findings: []
  - id: PMID:24191030
    title: Structural basis of ATG3 recognition by the autophagic ubiquitin-like
      protein ATG12.
    findings:
      - statement: Solved structure of ATG12-ATG5 with ATG3 and ATG16L1, showing
          E3-like mechanism
  - id: PMID:25484072
    title: Insights into autophagosome maturation revealed by the structures of 
      ATG5 with its interacting partners.
    findings: []
  - id: PMID:26812546
    title: Mutation in ATG5 reduces autophagy and leads to ataxia with 
      developmental delay.
    findings:
      - statement: ATG5 E122D mutation causes reduced autophagy and SCAR25 
          disease in humans
  - id: PMID:28389568
    title: Hepatitis C virus triggers Golgi fragmentation and autophagy through 
      the immunity-related GTPase M.
    findings:
      - statement: IRGM regulates HCV-induced autophagy involving ATG5
  - id: PMID:31515488
    title: Extensive disruption of protein interactions by genetic variants 
      across the allele frequency spectrum in human populations.
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:32960676
    title: RAB33B recruits the ATG16L1 complex to the phagophore via a 
      noncanonical RAB binding protein.
    findings:
      - statement: RAB33B recruits ATG12-ATG5-ATG16L1 complex to phagophores
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings: []
  - id: Reactome:R-HSA-5205663
    title: LC3 binds the autophagosome membrane Atg5-Atg12 complex
    findings: []
  - id: Reactome:R-HSA-5678490
    title: ATG16L1 complex transfers LC3 from ATG3 to PE
    findings: []
  - id: Reactome:R-HSA-5679255
    title: WIPI2 binds ATG12:ATG5:ATG16L
    findings: []
  - id: Reactome:R-HSA-5682010
    title: ATG10:ATG12 binds ATG5
    findings: []
  - id: Reactome:R-HSA-5682012
    title: ATG5:ATG12 binds ATG16L1
    findings: []
  - id: Reactome:R-HSA-5682690
    title: ATG10 dissociates from ATG12:ATG5
    findings: []
  - id: Reactome:R-HSA-5683588
    title: ATG10 transfers ATG12 from ATG10 to ATG5
    findings: []
  - id: Reactome:R-HSA-8959571
    title: LC3 binds the autophagosome membrane Atg5-Atg12 complex
    findings: []
  - id: Reactome:R-HSA-9936620
    title: ATG5:ATG12 binds ATG16L2
    findings: []
core_functions:
  - description: >-
      ATG5, as part of the ATG12-ATG5-ATG16L1 complex, functions as an E3-like enzyme
      that
      promotes the covalent conjugation of LC3/ATG8 family proteins to phosphatidylethanolamine
      (PE)
      on autophagosomal membranes. This lipidation is essential for autophagosome
      formation and maturation.
    molecular_function:
      id: GO:0019776
      label: Atg8-family ligase activity
    directly_involved_in:
      - id: GO:0000045
        label: autophagosome assembly
      - id: GO:0016236
        label: macroautophagy
    locations:
      - id: GO:0034045
        label: phagophore assembly site membrane
      - id: GO:0005829
        label: cytosol
    in_complex:
      id: GO:0034274
      label: Atg12-Atg5-Atg16 complex
    supported_by:
      - reference_id: PMID:23202584
        supporting_text: "Structure of the human ATG12-ATG5 conjugate required for
          LC3 lipidation in autophagy."
      - reference_id: PMID:24191030
        supporting_text: "Structural basis of ATG3 recognition by the autophagic ubiquitin-like
          protein ATG12."
tags:
  - autophagy
  - SPKW-apoptosis-over-annotation

ATG5

Gene Description

Existing Annotations Review

Core Functions

ATG5, as part of the ATG12-ATG5-ATG16L1 complex, functions as an E3-like enzyme that promotes the covalent conjugation of LC3/ATG8 family proteins to phosphatidylethanolamine (PE) on autophagosomal membranes. This lipidation is essential for autophagosome formation and maturation.

References

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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