ATG12 is a ubiquitin-like modifier and an essential component of the autophagic ATG8 lipidation machinery. Following activation by ATG7, ATG10 promotes its covalent conjugation to ATG5. The ATG12–ATG5 conjugate associates with ATG16L1 and provides E3-like activity for LC3/GABARAP lipidation on forming autophagic membranes; ATG12 recruits the E2 enzyme ATG3. ATG12 also forms a distinct covalent conjugate with ATG3 in mammalian cells. Alternative ATG12-containing assemblies contribute to autophagosome maturation, mitochondrial homeostasis and context-dependent antiviral signaling. The protein acts in the cytosol and on membranes through its interaction partners.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0034045 phagophore assembly site membrane | IBA GO_REF:0000033 | MODIFY | Summary: The obsolete PAS-membrane term is better represented by phagophore membrane. Reason: Live QuickGO confirms GO:0034045 is obsolete and explicitly recommends GO:7770114 for nascent phagophore membrane. ATG12-containing conjugation machinery is recruited to that membrane through ATG16L1 and partners; an intrinsic transmembrane domain is not required. Human endogenous ATG12 colocalization in PMID:24954904 and membrane recruitment in PMID:32960676 support the physical location. Preserve the original source ID and update only its review. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Actual PTHR13385 v19 root is ancestral to human O94817 leaf PTN002491519. Matching current IBD verified; target experimental grounding is expected, not circular. Proposed replacements: phagophore membrane Supporting Evidence: PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | ACCEPT | Summary: ATG12 contributes the conjugation machinery for autophagosome assembly and macroautophagy. Reason: The ATG12–ATG5–ATG16L1 complex promotes ATG8-family lipidation on forming autophagic membranes. ATG12 supplies the ATG3-binding surface and a contribution to E3-like activity, so it performs molecular work in autophagosome construction rather than merely being necessary for a downstream phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Actual PTHR13385 v19 root is ancestral to human O94817 leaf PTN002491519. Matching current IBD verified; target experimental grounding is expected, not circular. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0031386 protein tag activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATG12 acts as a covalently conjugated ubiquitin-like protein tag. Reason: ATG12 is attached to ATG5 through its terminal glycine and creates a functional ligase/cofactor surface. It is not confined to a single known substrate: mammalian ATG12–ATG3 conjugation was independently established. The protein-tag definition covers conjugated modifiers and does not require reversible multi-substrate ubiquitin-like turnover. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Actual PTHR13385 v19 root is ancestral to human O94817 leaf PTN002491519. Matching current IBD verified; target experimental grounding is expected, not circular. Supporting Evidence: 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. PMID:20723759 Overall, these data support that ATG12 forms a covalent complex with ATG3 and that this complex represents the second (with ATG12-ATG5 being the first) of several potential ATG12 conjugation targets. |
| GO:0000421 autophagosome membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ATG12-containing machinery associates with autophagic membranes. Reason: The inherited autophagosome-membrane claim is consistent with endogenous ATG12 colocalization on GFP-LC3-negative and positive forming autophagosomes and with the ATG12–ATG5/TECPR1 maturation complex. Phagophore membrane is additionally available as a current term; no exclusive restriction to either stage follows from the evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Actual PTHR13385 v19 root is ancestral to human O94817 leaf PTN002491519. Matching current IBD verified; target experimental grounding is expected, not circular. Supporting Evidence: PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0019776 Atg8-family ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Atg8-family ligase activity with a contributes_to qualifier, which is exactly right for a subunit of an E3-like conjugate. Reason: Neither ATG12 nor ATG5 has ligase activity alone; the conjugate does. The contributes_to qualifier is used correctly here and is the model for how the equivalent annotations on ATG5 and ATG16L1 should read. ATG12 makes a specific and identifiable contribution: the high-affinity ATG3-binding surface is exclusive to ATG12, so it is the subunit that engages the E2 carrying the ATG8 protein. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Actual PTHR13385 v19 root is ancestral to human O94817 leaf PTN002491519. Matching current IBD verified; target experimental grounding is expected, not circular. Supporting Evidence: PMID:23202584 The autophagy factor ATG12~ATG5 conjugate exhibits E3 ligase-like activity which facilitates the lipidation of members of the LC3 family. PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12, suggesting a different role of the continuous patch in E3 activity. |
| GO:0034727 piecemeal microautophagy of the nucleus | IBA GO_REF:0000033 | UNDECIDED | Summary: Conservation of ATG12-dependent piecemeal micronucleophagy in humans remains unresolved. Reason: The actual root IBD lies on the target lineage, and full yeast PMID:18701704 demonstrates ATG12 participation in PMN through the core conjugation machinery. GO:0034727 currently means degradation of a cell nucleus by microautophagy and does not require named yeast junction proteins in its definition. Lack of a yeast-like vacuole or identified NVJ1 ortholog is insufficient to establish loss. The conserved lipidation machinery could contribute, but macroautophagic nucleophagy alone would not establish this route. Await the already queued ATG2A route adjudication; no duplicate report requested. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000333039 UNRESOLVED Verified root IBD and human target ancestry. Yeast source PMID:18701704 directly tests ATG12; whether the same microautophagic nuclear route occurs in the target context remains unresolved. Supporting Evidence: PMID:18701704 We found that the core autophagy genes ATG3, 4, 5, 7, 10, 12 , and 16 are all required for efficient degradation of GFP-Osh1 |
| GO:0061723 glycophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ATG12 can contribute the lipidation machinery executing glycogen-selective autophagy. Reason: Live source tracing identifies fly Atg12 Q9VTU1 IMP PMID:24265594 and root IBD PTN000333039 on the human lineage. Full source FigureS1 explicitly includes Atg12 RNAi among perturbations that block starvation-induced glycogen-rich muscle autophagosomes. ATG12 contributes the E3-like conjugation machinery used to construct these membranes; it need not bind glycogen directly to participate. Retain this selective-cargo context as an inherited noncore function while the queued WIPI2 comparative report is available for later cross-check. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Exact current root IBD and target descent verified; fly source IMP PMID:24265594 independently read, with ATG12 specifically in FigureS1. General machinery can execute selective autophagy without conferring cargo specificity. Supporting Evidence: PMID:24265594 (D) Atg5 RNAi, (E) Atg12 RNAi, (F) Atg2 RNAi, (G) Atg9 RNAi, (H) Atg16 RNAi, (I) Atg3 RNAi, (J) Atg6 RNAi, (K) Atg18 RNAi, and (L) CG1347 RNAi all block autophagosome formation due to starvation +CQ treatment. |
| GO:0097352 autophagosome maturation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The ATG12–ATG5 conjugate supports TECPR1-dependent autophagosome maturation. Reason: Full PMID:22342342 identifies a TECPR1–ATG12–ATG5 complex distinct from ATG16L1 assemblies. Fig7 demonstrates that ATG12 conjugation enables TECPR1 lipid binding, supplying a molecular contribution to the maturation machinery rather than only a knockout phenotype. Retain this alternative-complex context without asserting independent fusion catalysis by ATG12. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Current ancestral maturation IBD is on the target path; independent human TECPR1/ATG12–ATG5 biochemistry corroborates the biological contribution. Supporting Evidence: PMID:22342342 indicating that Atg12 conjugation is required for the PtdIns(3)P binding of Atg5-TECPR1. |
| GO:0034274 Atg12-Atg5-Atg16 complex | IBA GO_REF:0000033 | ACCEPT | Summary: ATG12 is a core component of the ATG12–ATG5–ATG16 complex. Reason: The covalent ATG12–ATG5 conjugate associates with ATG16L1 to form the autophagic lipidation complex. This assembly is experimentally and phylogenetically supported; it does not imply that every ATG12 molecule is permanently bound to ATG5 or ATG16L1, because alternative ATG3 and TECPR1 assemblies exist. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Actual PTHR13385 v19 root is ancestral to human O94817 leaf PTN002491519. Matching current IBD verified; target experimental grounding is expected, not circular. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 |
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ATG12 contributes autophagic machinery used in mitochondrial turnover. Reason: The inherited mitophagy assertion is compatible with direct participation of the lipidation complex in autophagosome construction. Full PMID:20723759 additionally connects ATG12–ATG3 conjugation with mitochondrial mass, fusion and modestly altered mitophagy; these assays are predominantly mouse/cross-species mammalian evidence and do not make every mitochondrial phenotype synonymous with mitophagy. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000333039 SUPPORTS TRANSFER Current mitophagy IBD is ancestral to the exact target; general autophagic conjugation work is compatible with selective mitochondrial turnover. Supporting Evidence: PMID:20723759 Overall, these data support that ATG12 forms a covalent complex with ATG3 and that this complex represents the second (with ATG12-ATG5 being the first) of several potential ATG12 conjugation targets. |
| GO:0000045 autophagosome assembly | IEA GO_REF:0000120 | ACCEPT | Summary: ATG12 contributes the conjugation machinery for autophagosome assembly and macroautophagy. Reason: The ATG12–ATG5–ATG16L1 complex promotes ATG8-family lipidation on forming autophagic membranes. ATG12 supplies the ATG3-binding surface and a contribution to E3-like activity, so it performs molecular work in autophagosome construction rather than merely being necessary for a downstream phenotype. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0006914 autophagy | IEA GO_REF:0000117 | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000117 | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0034045 phagophore assembly site membrane | IEA GO_REF:0000120 | MODIFY | Summary: The obsolete PAS-membrane term is better represented by phagophore membrane. Reason: Live QuickGO confirms GO:0034045 is obsolete and explicitly recommends GO:7770114 for nascent phagophore membrane. ATG12-containing conjugation machinery is recruited to that membrane through ATG16L1 and partners; an intrinsic transmembrane domain is not required. Human endogenous ATG12 colocalization in PMID:24954904 and membrane recruitment in PMID:32960676 support the physical location. Preserve the original source ID and update only its review. Proposed replacements: phagophore membrane Supporting Evidence: PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: Autophagy-network associations include the conjugation machinery and TECPR1. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0005515 protein binding | IPI PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: Structural and biochemical data locate ATG3 recruitment on the ATG12 surface of the E3-like conjugate. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: Proteome-scale binary interaction mapping does not by itself identify a new ATG12 molecular function. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: Binary interactome mapping does not by itself identify a new ATG12 molecular function. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: Affinity-purification interactome associations do not by themselves identify a new ATG12 molecular function. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: Endogenous-tagging interaction data do not by themselves identify a new ATG12 molecular function. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0016236 macroautophagy | IEA GO_REF:0000107 | ACCEPT | Summary: ATG12 contributes the conjugation machinery for autophagosome assembly and macroautophagy. Reason: The ATG12–ATG5–ATG16L1 complex promotes ATG8-family lipidation on forming autophagic membranes. ATG12 supplies the ATG3-binding surface and a contribution to E3-like activity, so it performs molecular work in autophagosome construction rather than merely being necessary for a downstream phenotype. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0032480 negative regulation of type I interferon production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATG12 conjugate can suppress innate antiviral signaling. Reason: Full PMID:17709747 directly tests ATG12 in HEK293 cells: conjugate formation suppresses RIG-I/MDA5-dependent reporter signaling, whereas conjugation-deficient ATG5 fails to suppress it. The broad innate-response parent is therefore as valid as type-I-IFN and antiviral-defense children. Source PMID:19666601 instead measures HCV translation/infection and is not by itself an immune-suppression assay; the independent PMID:17709747 evidence supports the biological claim without conflating proviral replication with host-defense inhibition. Supporting Evidence: PMID:17709747 Similar suppression was observed with Atg12 alone, but not with Atg5-K130R |
| GO:0034274 Atg12-Atg5-Atg16 complex | IEA GO_REF:0000107 | ACCEPT | Summary: ATG12 is a core component of the ATG12–ATG5–ATG16 complex. Reason: The covalent ATG12–ATG5 conjugate associates with ATG16L1 to form the autophagic lipidation complex. This assembly is experimentally and phylogenetically supported; it does not imply that every ATG12 molecule is permanently bound to ATG5 or ATG16L1, because alternative ATG3 and TECPR1 assemblies exist. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 |
| GO:0045824 negative regulation of innate immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATG12 conjugate can suppress innate antiviral signaling. Reason: Full PMID:17709747 directly tests ATG12 in HEK293 cells: conjugate formation suppresses RIG-I/MDA5-dependent reporter signaling, whereas conjugation-deficient ATG5 fails to suppress it. The broad innate-response parent is therefore as valid as type-I-IFN and antiviral-defense children. Source PMID:19666601 instead measures HCV translation/infection and is not by itself an immune-suppression assay; the independent PMID:17709747 evidence supports the biological claim without conflating proviral replication with host-defense inhibition. Supporting Evidence: PMID:17709747 Similar suppression was observed with Atg12 alone, but not with Atg5-K130R |
| GO:0050687 negative regulation of defense response to virus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATG12 conjugate can suppress innate antiviral signaling. Reason: Full PMID:17709747 directly tests ATG12 in HEK293 cells: conjugate formation suppresses RIG-I/MDA5-dependent reporter signaling, whereas conjugation-deficient ATG5 fails to suppress it. The broad innate-response parent is therefore as valid as type-I-IFN and antiviral-defense children. Source PMID:19666601 instead measures HCV translation/infection and is not by itself an immune-suppression assay; the independent PMID:17709747 evidence supports the biological claim without conflating proviral replication with host-defense inhibition. Supporting Evidence: PMID:17709747 Similar suppression was observed with Atg12 alone, but not with Atg5-K130R |
| GO:1990234 transferase complex | IEA GO_REF:0000107 | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0034045 phagophore assembly site membrane | EXP PMID:22342342 A mammalian autophagosome maturation mechanism mediated by T... | MODIFY | Summary: The obsolete PAS-membrane term is better represented by phagophore membrane. Reason: Live QuickGO confirms GO:0034045 is obsolete and explicitly recommends GO:7770114 for nascent phagophore membrane. ATG12-containing conjugation machinery is recruited to that membrane through ATG16L1 and partners; an intrinsic transmembrane domain is not required. Human endogenous ATG12 colocalization in PMID:24954904 and membrane recruitment in PMID:32960676 support the physical location. Preserve the original source ID and update only its review. Proposed replacements: phagophore membrane Supporting Evidence: PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0016236 macroautophagy | IMP PMID:25484072 Insights into autophagosome maturation revealed by the struc... | ACCEPT | Summary: ATG12 contributes the conjugation machinery for autophagosome assembly and macroautophagy. Reason: The ATG12–ATG5–ATG16L1 complex promotes ATG8-family lipidation on forming autophagic membranes. ATG12 supplies the ATG3-binding surface and a contribution to E3-like activity, so it performs molecular work in autophagosome construction rather than merely being necessary for a downstream phenotype. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0032991 protein-containing complex | NAS PMID:25484072 Insights into autophagosome maturation revealed by the struc... | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0034274 Atg12-Atg5-Atg16 complex | IPI PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3... | ACCEPT | Summary: ATG12 is a core component of the ATG12–ATG5–ATG16 complex. Reason: The covalent ATG12–ATG5 conjugate associates with ATG16L1 to form the autophagic lipidation complex. This assembly is experimentally and phylogenetically supported; it does not imply that every ATG12 molecule is permanently bound to ATG5 or ATG16L1, because alternative ATG3 and TECPR1 assemblies exist. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 |
| 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: ATG12 conjugate can suppress innate antiviral signaling. Reason: Full PMID:17709747 directly tests ATG12 in HEK293 cells: conjugate formation suppresses RIG-I/MDA5-dependent reporter signaling, whereas conjugation-deficient ATG5 fails to suppress it. The broad innate-response parent is therefore as valid as type-I-IFN and antiviral-defense children. Source PMID:19666601 instead measures HCV translation/infection and is not by itself an immune-suppression assay; the independent PMID:17709747 evidence supports the biological claim without conflating proviral replication with host-defense inhibition. Supporting Evidence: PMID:17709747 Similar suppression was observed with Atg12 alone, but not with Atg5-K130R |
| GO:1901096 regulation of autophagosome maturation | IMP PMID:22342342 A mammalian autophagosome maturation mechanism mediated by T... | KEEP AS NON CORE | Summary: The ATG12–ATG5 conjugate supports TECPR1-dependent autophagosome maturation. Reason: Full PMID:22342342 identifies a TECPR1–ATG12–ATG5 complex distinct from ATG16L1 assemblies. Fig7 demonstrates that ATG12 conjugation enables TECPR1 lipid binding, supplying a molecular contribution to the maturation machinery rather than only a knockout phenotype. Retain this alternative-complex context without asserting independent fusion catalysis by ATG12. Supporting Evidence: PMID:22342342 indicating that Atg12 conjugation is required for the PtdIns(3)P binding of Atg5-TECPR1. |
| GO:1904973 positive regulation of viral translation | IDA PMID:19666601 The autophagy machinery is required to initiate hepatitis C ... | KEEP AS NON CORE | Summary: ATG12-dependent autophagic machinery supports incoming HCV RNA translation. Reason: Full PMID:19666601 FigS4 tests ATG12 knockdown with replication-defective HCV IRES reporters, RNA abundance/transfection controls and cap-dependent translation controls. The effect concerns initiation of infection; established replication is largely spared. Retain this experimental regulatory phenotype as context-specific without claiming ATG12 is itself a ribosomal translation factor. Supporting Evidence: PMID:19666601 HCV IRES-dependent translation measured by Rluc activity was strongly reduced in Beclin-1, Atg4B, and Atg12-down-regulated cells as compared to control and GFP shRNA-expressing cells |
| GO:0005515 protein binding | IPI PMID:32960676 RAB33B recruits the ATG16L1 complex to the phagophore via a ... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: RAB33B recruits the conjugation complex through ATG16L1; this does not establish direct RAB33B binding by isolated ATG12. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0005515 protein binding | IPI PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiqu... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: The ATG3 recognition surface is experimentally mapped on ATG12, supporting its E3-complex contribution. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 |
| GO:0005515 protein binding | IPI PMID:26812546 Mutation in ATG5 reduces autophagy and leads to ataxia with ... | MODIFY | Summary: The interaction evidence identifies ATG12 covalent modifier activity. Reason: The source explicitly assays ATG12–ATG5 conjugation, which is more informative than generic protein binding. ATG12 supplies the covalently attached modifier, and the existing protein-tag term already captures that role; no duplicate NEW assertion is added. Proposed replacements: protein tag activity Supporting Evidence: 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. |
| GO:0005776 autophagosome | IDA PMID:24954904 WIPI2 links LC3 conjugation with PI3P, autophagosome formati... | ACCEPT | Summary: The broader annotation correctly captures ATG12 autophagic machinery. Reason: ATG12 is a cytoplasmic and membrane-associated subunit of protein-containing transferase assemblies that lipidate ATG8-family proteins during autophagy. Broad membrane, complex and autophagy categories remain correct alongside more specific child terms. Peripheral recruitment through partner proteins is genuine membrane association, and forming autophagosomes are part of the core operating location. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0030670 phagocytic vesicle membrane | TAS Reactome:R-HSA-5205663 | KEEP AS NON CORE | Summary: ATG12-containing conjugation machinery can associate with phagosomes. Reason: The cited Reactome event describes mitophagic autophagosomes and does not itself establish LC3-associated phagocytosis. Independent full PMID:19339495 Fig1D detects endogenous ATG12–ATG5 on purified mouse macrophage phagosomes, with cytosolic/ER contamination controls. This supplies relevant mammalian localization evidence supporting a conditional inherited phagosomal pool; it is not presented as a direct human fractionation assay. Supporting Evidence: PMID:19339495 ATG12 was detected as the ATG12–ATG5 conjugated form in both total lysate and phagosome fractions Reactome:R-HSA-5205663 The mitochondrion is engulfed after elongation of the isolation membrane. |
| GO:0030670 phagocytic vesicle membrane | TAS Reactome:R-HSA-8959571 | KEEP AS NON CORE | Summary: ATG12-containing conjugation machinery can associate with phagosomes. Reason: The cited Reactome event describes mitophagic autophagosomes and does not itself establish LC3-associated phagocytosis. Independent full PMID:19339495 Fig1D detects endogenous ATG12–ATG5 on purified mouse macrophage phagosomes, with cytosolic/ER contamination controls. This supplies relevant mammalian localization evidence supporting a conditional inherited phagosomal pool; it is not presented as a direct human fractionation assay. Supporting Evidence: PMID:19339495 ATG12 was detected as the ATG12–ATG5 conjugated form in both total lysate and phagosome fractions Reactome:R-HSA-5205663 The mitochondrion is engulfed after elongation of the isolation membrane. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5678490 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5679255 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5681980 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5682010 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5682012 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5682690 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5683588 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9020616 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9936620 | ACCEPT | Summary: Cytosol is a core location for the ATG12 conjugation machinery. Reason: The Reactome reaction places the ATG12-containing conjugation system in the cytosol, consistent with ATG7/ATG10-dependent conjugation and subsequent recruitment to autophagic membranes. A membrane-bound active fraction does not exclude cytosolic intermediates or complexes. Supporting Evidence: PMID:11096062 Overexpression of hApg7p enhances the formation of the hApg5p.hApg12p conjugate |
| GO:0034045 phagophore assembly site membrane | ISS GO_REF:0000024 | MODIFY | Summary: The obsolete PAS-membrane term is better represented by phagophore membrane. Reason: Live QuickGO confirms GO:0034045 is obsolete and explicitly recommends GO:7770114 for nascent phagophore membrane. ATG12-containing conjugation machinery is recruited to that membrane through ATG16L1 and partners; an intrinsic transmembrane domain is not required. Human endogenous ATG12 colocalization in PMID:24954904 and membrane recruitment in PMID:32960676 support the physical location. Preserve the original source ID and update only its review. Proposed replacements: phagophore membrane Supporting Evidence: PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0000045 autophagosome assembly | ISS GO_REF:0000024 | ACCEPT | Summary: ATG12 contributes the conjugation machinery for autophagosome assembly and macroautophagy. Reason: The ATG12–ATG5–ATG16L1 complex promotes ATG8-family lipidation on forming autophagic membranes. ATG12 supplies the ATG3-binding surface and a contribution to E3-like activity, so it performs molecular work in autophagosome construction rather than merely being necessary for a downstream phenotype. Supporting Evidence: PMID:23202584 The ATG12~ATG5 conjugate interacts with the E2 enzyme ATG3 with high affinity through another surface location that is exclusive to ATG12 PMID:24954904 Endogenous WIPI2 colocalized with Atg16L1 (Figure 1I) and Atg12 (Figure 1J) on both GFP-LC3-negative and -positive autophagosomes. |
| GO:0005515 protein binding | IPI PMID:9852036 A new protein conjugation system in human. The counterpart o... | MODIFY | Summary: The interaction evidence identifies ATG12 covalent modifier activity. Reason: The source explicitly assays ATG12–ATG5 conjugation, which is more informative than generic protein binding. ATG12 supplies the covalently attached modifier, and the existing protein-tag term already captures that role; no duplicate NEW assertion is added. Proposed replacements: protein tag activity Supporting Evidence: 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. |
| GO:0005515 protein binding | IPI PMID:11096062 The human homolog of Saccharomyces cerevisiae Apg7p is a Pro... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: ATG7 recognizes/activates ATG12 as a conjugation substrate; ATG12 is not the E1 enzyme. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
| GO:0005515 protein binding | IPI PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | REMOVE | Summary: Generic protein binding does not specify ATG12 molecular work. Reason: ATG3 association links the two conjugation systems; ATG12 is not the ATG3 E2 enzyme. Remove this uninformative generic descriptor under the review specificity policy, not because the reported association is false. Preserve the source assertion and retain established modifier/ligase-complex functions and interaction evidence elsewhere. Do not infer an additional adaptor or catalytic activity solely from an interaction. |
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Download this section (compressed HTML)Q: Which nuclear microautophagy routes in human cells use the ATG12 conjugation machinery, as distinct from macroautophagic nucleophagy?
Q: How do ATG12–ATG5, ATG12–ATG3 and unconjugated ATG12 pools partition across membrane lipidation, mitochondrial homeostasis and immune signaling contexts?
Experiment: Test whether the ATG12-ATG5 conjugate can be replaced by a genetically encoded ATG12-ATG5 fusion in cells lacking ATG7 and ATG10, scoring canonical autophagy, TECPR1-dependent maturation and the antiviral phenotypes, to determine what the conjugation reaction itself contributes beyond producing the conjugate.
Experiment: Structure-guided separation of the two conjugate destinations: identify ATG12 or ATG5 surface mutations that abolish TECPR1 binding without affecting ATG16L1 binding, and the reverse, then assay autophagosome formation and autophagosome-lysosome fusion separately in each background.
Experiment: Co-immunoprecipitation and proximity labelling in cells infected with vesicular stomatitis virus and with hepatitis C virus, comparing conjugated and unconjugated ATG12, to establish whether the antiviral and proviral roles require the ATG5 conjugate or the free protein, which GOA currently does not distinguish.
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