ATG3 is the E2-like conjugating enzyme of the Atg8/LC3 ubiquitin-like conjugation system of macroautophagy. It receives Atg8-family proteins (MAP1LC3A/B/C, GABARAP, GABARAPL1, GABARAPL2) from the E1-like enzyme ATG7 as a thioester on its active-site Cys264 and, together with the E3-like ATG12~ATG5-ATG16L1 complex, transfers them to the head group of phosphatidylethanolamine in the phagophore membrane (LC3 lipidation), a step needed for phagophore expansion and autophagosome formation. Binding of ATG3 to ATG7 and to ATG12 of the E3 uses overlapping sites in its flexible region, so the enzyme cycles between E1 and E3. An N-terminal amphipathic helix senses membrane curvature and lipid-packing defects and, with an adjacent conserved region, restricts lipidation to highly curved, anionic membranes; a noncanonical LIR in the flexible region contacts LC3. ATG3 is a soluble cytosolic protein. It can also conjugate ATG12 to its own Lys243 (shown in mouse cells), and the ATG12-ATG3 conjugate influences mitochondrial homeostasis and endolysosomal trafficking rather than starvation-induced autophagy. Caspase-8 cleaves ATG3 at a LETD motif during death-receptor signalling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000305307 (donors include yeast Atg3, fly Atg3, mouse Atg3 and human ATG3). Reason: ATG3 executes a step of autophagosome assembly: it catalyses the conjugation of Atg8-family proteins to PE on the expanding phagophore, the lipidation step required for phagophore expansion. This is the core process of the gene and is conserved across the ATG3 subfamily from yeast to human. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation PMID:33446636 While the lipidation of LC3B was absent in Atg3−/− MEFs, the expression of hAtg3 rescued not only LC3B–PE conjugation, but also starvation-induced autophagic flux |
| GO:0000045 autophagosome assembly | IEA GO_REF:0000107 | ACCEPT | Summary: IEA Ensembl Compara transfer from mouse Atg3. Reason: ATG3 executes a step of autophagosome assembly: it catalyses the conjugation of Atg8-family proteins to PE on the expanding phagophore, the lipidation step required for phagophore expansion. This is the core process of the gene and is conserved across the ATG3 subfamily from yeast to human. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation file:human/ATG3/ATG3-uniprot.txt Belongs to the ATG3 family. |
| GO:0000045 autophagosome assembly | IMP PMID:33446636 An N-terminal conserved region in human Atg3 couples membran... | ACCEPT | Summary: IMP from Ye et al. 2021: human ATG3 rescues LC3B lipidation and starvation-induced autophagic flux in Atg3-/- MEFs, whereas N-terminal mutants do not. Reason: ATG3 executes a step of autophagosome assembly: it catalyses the conjugation of Atg8-family proteins to PE on the expanding phagophore, the lipidation step required for phagophore expansion. This is the core process of the gene and is conserved across the ATG3 subfamily from yeast to human. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation PMID:33446636 While the lipidation of LC3B was absent in Atg3−/− MEFs, the expression of hAtg3 rescued not only LC3B–PE conjugation, but also starvation-induced autophagic flux |
| GO:0000045 autophagosome assembly | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer from an ATG3 ortholog in the same PANTHER subfamily (PTHR12866:SF2). Reason: ATG3 executes a step of autophagosome assembly: it catalyses the conjugation of Atg8-family proteins to PE on the expanding phagophore, the lipidation step required for phagophore expansion. This is the core process of the gene and is conserved across the ATG3 subfamily from yeast to human. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation file:human/ATG3/ATG3-uniprot.txt Belongs to the ATG3 family. |
| GO:0000045 autophagosome assembly | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer from an ATG3 ortholog in the same PANTHER subfamily (PTHR12866:SF2). Reason: ATG3 executes a step of autophagosome assembly: it catalyses the conjugation of Atg8-family proteins to PE on the expanding phagophore, the lipidation step required for phagophore expansion. This is the core process of the gene and is conserved across the ATG3 subfamily from yeast to human. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation file:human/ATG3/ATG3-uniprot.txt Belongs to the ATG3 family. |
| GO:0000407 phagophore assembly site | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PTN000305307, yeast Atg3 donor) placing ATG3 activity at the phagophore assembly site. Reason: ATG3 acts where Atg8-family lipidation occurs, at the forming phagophore; in human ATG3 an N-terminal curvature-sensing amphipathic helix is proposed to target the enzyme to the highly curved phagophore rim. Accepted as an inherited location, though human-specific localization data are limited and the term reflects the yeast PAS concept. Supporting Evidence: PMID:33446636 N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore |
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA placing ATG3 in autophagy of mitochondrion (PAINT node PANTHER:PTN000305308). Reason: autophagy of mitochondrion uses the core autophagosome-formation machinery, and ATG3 performs the Atg8-lipidation step within it, so participation is genuine rather than merely necessity. These selective-autophagy processes are, however, specific uses of the general autophagosome assembly function rather than distinct ATG3 functions, and the experimental grounding comes from non-human donors (yeast/fly). Kept as non-core. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:0005515 protein binding | IPI PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | REMOVE | Summary: IPI binding of ATG3 to O94817 from PMID:11825910. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | REMOVE | Summary: IPI binding of ATG3 to P60520 from PMID:11825910. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:12890687 The mouse APG10 homologue, an E2-like enzyme for Apg12p conj... | REMOVE | Summary: IPI binding of ATG3 to Q9H492 from PMID:12890687. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:15355958 Human light chain 3/MAP1LC3B is cleaved at its carboxyl-term... | REMOVE | Summary: IPI binding of ATG3 to Q9GZQ8 from PMID:15355958. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:16303767 Phosphatidylserine in addition to phosphatidylethanolamine i... | REMOVE | Summary: IPI binding of ATG3 to O95166 from PMID:16303767. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:16303767 Phosphatidylserine in addition to phosphatidylethanolamine i... | REMOVE | Summary: IPI binding of ATG3 to P60520 from PMID:16303767. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:16303767 Phosphatidylserine in addition to phosphatidylethanolamine i... | REMOVE | Summary: IPI binding of ATG3 to Q9GZQ8 from PMID:16303767. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:18083104 Homeostatic levels of p62 control cytoplasmic inclusion body... | REMOVE | Summary: IPI binding of ATG3 to Q9GZQ8 from PMID:18083104. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI binding of ATG3 to O94817 from PMID:20562859. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI binding of ATG3 to O95166 from PMID:20562859. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI binding of ATG3 to P60520 from PMID:20562859. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI binding of ATG3 to Q7Z6L1 from PMID:20562859. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI binding of ATG3 to Q9GZQ8 from PMID:20562859. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: IPI binding of ATG3 to Q9H0R8 from PMID:20562859. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:23202584 Structure of the human ATG12~ATG5 conjugate required for LC3... | REMOVE | Summary: IPI binding of ATG3 to O94817 from PMID:23202584. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:24186333 Binding to E1 and E3 is mutually exclusive for the human aut... | MODIFY | Summary: IPI interaction of ATG3 with ATG7 (O95352) from PMID:24186333. ATG7 is the E1-like enzyme that loads Atg8-family proteins onto the ATG3 active-site cysteine. Reason: The ATG3-ATG7 E1-E2 interaction is functional and well established in human proteins; bare protein binding is uninformative, so the row is refined to GO:0044388 small protein activating enzyme binding (ATG7 is an E1 for the ubiquitin-like Atg8 and ATG12 modifiers), matching the refinement proposed for the GO:0019899 enzyme binding row. Proposed replacements: small protein activating enzyme binding Supporting Evidence: PMID:26043688 Transfer of GABARAP thioester from the E1 ATG7 to the E2 ATG3 requires the interaction between the N-terminal domain of ATG7 and the flexible region (FR) of ATG3 PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0005515 protein binding | IPI PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiqu... | REMOVE | Summary: IPI binding of ATG3 to O94817, Q676U5, Q9H1Y0 from PMID:24191030. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:26043688 Identification and characterization of the linear region of ... | MODIFY | Summary: IPI interaction of ATG3 with ATG7 (O95352) from PMID:26043688. ATG7 is the E1-like enzyme that loads Atg8-family proteins onto the ATG3 active-site cysteine. Reason: The ATG3-ATG7 E1-E2 interaction is functional and well established in human proteins; bare protein binding is uninformative, so the row is refined to GO:0044388 small protein activating enzyme binding (ATG7 is an E1 for the ubiquitin-like Atg8 and ATG12 modifiers), matching the refinement proposed for the GO:0019899 enzyme binding row. Proposed replacements: small protein activating enzyme binding Supporting Evidence: PMID:26043688 Transfer of GABARAP thioester from the E1 ATG7 to the E2 ATG3 requires the interaction between the N-terminal domain of ATG7 and the flexible region (FR) of ATG3 PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI binding of ATG3 to O94817 from PMID:32296183. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI binding of ATG3 to Q70IA6 from PMID:32296183. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI binding of ATG3 to P62879 from PMID:32814053. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI binding of ATG3 to O94817 from PMID:33961781. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI binding of ATG3 to P60520 from PMID:33961781. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI binding of ATG3 to O94817 from PMID:35271311. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI binding of ATG3 to P60520 from PMID:35271311. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI binding of ATG3 to Q9GZQ8 from PMID:35271311. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:37252361 Semisynthetic LC3 Probes for Autophagy Pathways Reveal a Non... | REMOVE | Summary: IPI binding of ATG3 to O95166, O95352, Q9H492 from PMID:37252361. Reason: Bare GO:0005515 protein binding is uninformative under the project protein-binding policy. Removal does not dispute the reported interaction; the functionally relevant interactions of ATG3 (with its Atg8-family substrates, the ATG12~ATG5-ATG16L1 E3 and the E1 ATG7) are captured by GO:0141046 Atg8-family conjugating enzyme activity and, for ATG7, by GO:0044388 small protein activating enzyme binding. |
| GO:0005515 protein binding | IPI PMID:37252361 Semisynthetic LC3 Probes for Autophagy Pathways Reveal a Non... | MODIFY | Summary: IPI interaction of ATG3 with ATG7 (O95352) from PMID:37252361. ATG7 is the E1-like enzyme that loads Atg8-family proteins onto the ATG3 active-site cysteine. Reason: The ATG3-ATG7 E1-E2 interaction is functional and well established in human proteins; bare protein binding is uninformative, so the row is refined to GO:0044388 small protein activating enzyme binding (ATG7 is an E1 for the ubiquitin-like Atg8 and ATG12 modifiers), matching the refinement proposed for the GO:0019899 enzyme binding row. Proposed replacements: small protein activating enzyme binding Supporting Evidence: PMID:26043688 Transfer of GABARAP thioester from the E1 ATG7 to the E2 ATG3 requires the interaction between the N-terminal domain of ATG7 and the flexible region (FR) of ATG3 PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0005737 cytoplasm | IDA PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | MODIFY | Summary: IDA cytoplasm (PMID:11825910). Reason: Correct but general; ATG3 is a soluble cytosolic enzyme that is recruited to phagophore membranes, and the gene already carries GO:0005829 cytosol from IBA, IDA (HPA) and Reactome. Proposed replacements: cytosol Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11825910}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: IEA cytoplasm (GO_REF:0000044). Reason: Correct but general; ATG3 is a soluble cytosolic enzyme that is recruited to phagophore membranes, and the gene already carries GO:0005829 cytosol from IBA, IDA (HPA) and Reactome. Proposed replacements: cytosol Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11825910}. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN000305308 (yeast, fly and human ATG3 donors). Reason: ATG3 is a soluble cytosolic E2 that is loaded by ATG7 in the cytosol. Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11825910}. Reactome:R-HSA-5681981 The activated LC3 protein is transferred to Cys-263 of ATG3 through a thioester bond |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA cytosol (GO_REF:0000052). Reason: ATG3 is a soluble cytosolic protein; supported by immunolocalization and biochemical fractionation. Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11825910}. |
| GO:0005829 cytosol | IDA PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | ACCEPT | Summary: IDA cytosol (PMID:11825910). Reason: ATG3 is a soluble cytosolic protein; supported by immunolocalization and biochemical fractionation. Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11825910}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5678490 | ACCEPT | Summary: TAS from Reactome reaction Reactome:R-HSA-5678490 in the LC3 lipidation pathway, which places the ATG7/ATG3/LC3 reactions in the cytosol. Reason: The E1-E2 loading reactions of ATG3 take place in the cytosol before membrane transfer; consistent with the IDA and IBA support for cytosol. Supporting Evidence: Reactome:R-HSA-5678490 mediating the transfer of LC3 ubiquitin-like proteins from the E2-like enzyme ATG3 to phosphatidylethanolamine (PE) in the expanding membrane |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5681981 | ACCEPT | Summary: TAS from Reactome reaction Reactome:R-HSA-5681981 in the LC3 lipidation pathway, which places the ATG7/ATG3/LC3 reactions in the cytosol. Reason: The E1-E2 loading reactions of ATG3 take place in the cytosol before membrane transfer; consistent with the IDA and IBA support for cytosol. Supporting Evidence: Reactome:R-HSA-5681981 The activated LC3 protein is transferred to Cys-263 of ATG3 through a thioester bond |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5682896 | ACCEPT | Summary: TAS from Reactome reaction Reactome:R-HSA-5682896 in the LC3 lipidation pathway, which places the ATG7/ATG3/LC3 reactions in the cytosol. Reason: The E1-E2 loading reactions of ATG3 take place in the cytosol before membrane transfer; consistent with the IDA and IBA support for cytosol. Supporting Evidence: Reactome:R-HSA-5682896 The ATG7 dimer with bound LC3 binds ATG3. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5683593 | ACCEPT | Summary: TAS from Reactome reaction Reactome:R-HSA-5683593 in the LC3 lipidation pathway, which places the ATG7/ATG3/LC3 reactions in the cytosol. Reason: The E1-E2 loading reactions of ATG3 take place in the cytosol before membrane transfer; consistent with the IDA and IBA support for cytosol. Supporting Evidence: Reactome:R-HSA-5683593 ATG7 dissociates from the ATG3-LC3 conjugate |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: IDA plasma membrane from Human Protein Atlas immunofluorescence (GO_REF:0000052). Reason: ATG3 is a cytosolic enzyme whose membrane associations are with highly curved, anionic phagophore/autophagosome precursor membranes. No functional study places ATG3 activity at the plasma membrane; a single antibody-based imaging screen signal is not sufficient to make this a location of the gene product's function. Supporting Evidence: PMID:29142222 ATG3 interacts more strongly with negatively-charged phospholipid vesicles or nanotubes than with electrically neutral model membranes PMID:33446636 N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore |
| GO:0006612 protein targeting to membrane | ISS GO_REF:0000024 | MODIFY | Summary: ISS from yeast Atg3 (P40344) for protein targeting to membrane. Reason: ATG3 brings Atg8-family proteins to membranes by covalently attaching them to PE; this is better described as Atg8-family lipidation, GO:0006501 C-terminal protein lipidation, than as generic protein targeting to membrane (which implies a targeting/sorting machinery role). Yeast and human Atg3 are in the same PANTHER subfamily, and the human activity is established directly. The replacement is the genus rather than the precomposed GO:0061739 (projects/INVOLVED_IN_PRECOMPOSITION.md); the autophagosome-assembly context is carried by the module metazoan_autophagosome_biogenesis#atg3_e2 and the core functions. Proposed replacements: C-terminal protein lipidation Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:0006914 autophagy | IEA GO_REF:0000120 | MODIFY | Summary: IEA autophagy (combined automated methods, ARBA plus Ensembl Compara). Reason: True but general; the specific process ATG3 executes is GO:0000045 autophagosome assembly, which the gene already carries with IMP and IBA support. Proposed replacements: autophagosome assembly Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:0016567 protein ubiquitination | IDA PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | MODIFY | Summary: IDA protein ubiquitination from Tanida et al. 2002 (cloning of human ATG3 as Atg8-homologue E2). Reason: ATG3 does not conjugate ubiquitin; the paper shows it is the E2 for the ubiquitin-like Atg8 homologues, whose final acceptor is phosphatidylethanolamine, not a protein. The process the curator captured is the Atg8-family lipidation reaction, GO:0006501 C-terminal protein lipidation. The replacement is the genus rather than the precomposed GO:0061739 (projects/INVOLVED_IN_PRECOMPOSITION.md); the autophagosome-assembly context is carried by the module metazoan_autophagosome_biogenesis#atg3_e2 and the core functions. Proposed replacements: C-terminal protein lipidation Supporting Evidence: PMID:11825910 hApg3p is an E2-like enzyme essential for three human Apg8p homologues PMID:16303767 formed an E2-substrate intermediate with hAtg3 via a thioester bond dependent on ATP and hAtg7 |
| GO:0019776 Atg8-family ligase activity | IEA GO_REF:0000107 | MODIFY | Summary: IEA transfer from mouse Atg3 (Q9CPX6) of Atg8-family ligase activity. Reason: ATG3 is the Atg8-family E2 (conjugating enzyme), not the E3; in current GO the E3 activity GO:0019776 Atg8-family ligase activity is carried by the ATG12~ATG5-ATG16L1 complex (cf. ATG5), whereas the E2 thioester-carrier/transfer step is GO:0141046 Atg8-family conjugating enzyme activity, which human ATG3 has by direct experiment. The mouse and human proteins are in the same PANTHER subfamily (PTHR12866:SF2), so the transfer is sound in essence and only the term needs correcting. Proposed replacements: Atg8-family conjugating enzyme activity Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane PMID:37252361 ATG3 performs the lipidation of LC3/GABARAP in conjunction with an E3-like enzyme complex of isopeptide-linked ATG5-ATG12 |
| GO:0019776 Atg8-family ligase activity | ISS GO_REF:0000024 | MODIFY | Summary: ISS transfer from mouse Atg3 (Q9CPX6) of Atg8-family ligase activity. Reason: ATG3 is the Atg8-family E2 (conjugating enzyme), not the E3; in current GO the E3 activity GO:0019776 Atg8-family ligase activity is carried by the ATG12~ATG5-ATG16L1 complex (cf. ATG5), whereas the E2 thioester-carrier/transfer step is GO:0141046 Atg8-family conjugating enzyme activity, which human ATG3 has by direct experiment. The mouse and human proteins are in the same PANTHER subfamily (PTHR12866:SF2), so the transfer is sound in essence and only the term needs correcting. Proposed replacements: Atg8-family conjugating enzyme activity Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane PMID:37252361 ATG3 performs the lipidation of LC3/GABARAP in conjunction with an E3-like enzyme complex of isopeptide-linked ATG5-ATG12 |
| GO:0019777 Atg12 transferase activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA transfer from mouse Atg3 (Q9CPX6) of Atg12 transferase activity, reflecting ATG3 autocatalytic conjugation of ATG12 to its own Lys243. Reason: Radoshevich et al. 2010 (mouse cells) showed that ATG12 becomes covalently attached to a single lysine of ATG3 in an ATG7-dependent reaction requiring ATG3's own E2 activity, so ATG3 transfers ATG12 (onto itself). Mouse and human ATG3 are in the same PANTHER subfamily and UniProt carries the statement by similarity; it is not yet shown experimentally for the human protein. The ATG12-ATG3 conjugate is not required for starvation-induced autophagy, so this is a non-core activity. Supporting Evidence: PMID:20723759 ATG12-ATG3 complex formation requires ATG7 as the E1 enzyme and ATG3 autocatalytic activity as the E2, resulting in the covalent linkage of ATG12 onto a single lysine on ATG3 file:human/ATG3/ATG3-uniprot.txt ATG12-conjugation plays a role in regulation of mitochondrial homeostasis and cell death, while it is not involved in phosphatidylethanolamine-conjugation to ATG8-like proteins and autophagy. |
| GO:0019777 Atg12 transferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from mouse Atg3 (Q9CPX6) of Atg12 transferase activity, reflecting ATG3 autocatalytic conjugation of ATG12 to its own Lys243. Reason: Radoshevich et al. 2010 (mouse cells) showed that ATG12 becomes covalently attached to a single lysine of ATG3 in an ATG7-dependent reaction requiring ATG3's own E2 activity, so ATG3 transfers ATG12 (onto itself). Mouse and human ATG3 are in the same PANTHER subfamily and UniProt carries the statement by similarity; it is not yet shown experimentally for the human protein. The ATG12-ATG3 conjugate is not required for starvation-induced autophagy, so this is a non-core activity. Supporting Evidence: PMID:20723759 ATG12-ATG3 complex formation requires ATG7 as the E1 enzyme and ATG3 autocatalytic activity as the E2, resulting in the covalent linkage of ATG12 onto a single lysine on ATG3 file:human/ATG3/ATG3-uniprot.txt ATG12-conjugation plays a role in regulation of mitochondrial homeostasis and cell death, while it is not involved in phosphatidylethanolamine-conjugation to ATG8-like proteins and autophagy. |
| GO:0019787 ubiquitin-like protein transferase activity | IDA PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | MODIFY | Summary: IDA from Tanida et al. 2002 (JBC), the cloning of human ATG3 as an E2 for GATE-16, GABARAP and MAP-LC3. Reason: Correct but general: the paper shows ATG3 forms Cys264 thioester intermediates with the three Atg8 homologues, which is precisely GO:0141046 Atg8-family conjugating enzyme activity (already carried by ATG3 with IDA/IMP/IBA support). Proposed replacements: Atg8-family conjugating enzyme activity Supporting Evidence: PMID:11825910 hApg3p is an E2-like enzyme essential for three human Apg8p homologues PMID:11825910 Cys(264) of hApg3p is an authentic active-site cysteine residue essential for the formation of hApg3p |
| GO:0019787 ubiquitin-like protein transferase activity | IEA GO_REF:0000120 | MODIFY | Summary: IEA (combined automated methods; InterPro IPR007135 Atg3/Atg10) mapping to ubiquitin-like protein transferase activity. Reason: True but general for an ATG3 subfamily member; the specific activity GO:0141046 Atg8-family conjugating enzyme activity is experimentally established for human ATG3. IPR007135 also covers ATG10, so the domain alone cannot give substrate specificity, but PANTHER PTHR12866:SF2 membership plus direct experiment does. Proposed replacements: Atg8-family conjugating enzyme activity Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt Belongs to the ATG3 family. PMID:11825910 hApg3p is an E2-like enzyme essential for three human Apg8p homologues |
| GO:0019899 enzyme binding | IPI PMID:11825910 Human Apg3p/Aut1p homologue is an authentic E2 enzyme for mu... | MODIFY | Summary: IPI enzyme binding with ATG7 (O95352) from Tanida et al. 2002. Reason: The ATG7-ATG3 E1-E2 complex is real and functional; GO:0044388 small protein activating enzyme binding names the partner class precisely (ATG7 is the E1-like activating enzyme for Atg8 and ATG12). Proposed replacements: small protein activating enzyme binding Supporting Evidence: PMID:11825910 hApg3p forms an E1.E2 complex with hApg7p as in the case of yeast Apg3p and Apg7p PMID:26043688 Transfer of GABARAP thioester from the E1 ATG7 to the E2 ATG3 requires the interaction between the N-terminal domain of ATG7 and the flexible region (FR) of ATG3 |
| GO:0034274 Atg12-Atg5-Atg16 complex | IDA PMID:24186333 Binding to E1 and E3 is mutually exclusive for the human aut... | MARK AS OVER ANNOTATED | Summary: IDA part_of Atg12-Atg5-Atg16 complex (PMID:24186333), based on ATG3 association with the ATG12~ATG5-ATG16L1 E3. Reason: ATG3 is the E2 that is recruited by ATG12 of the E3 and binds it transiently, in competition with ATG7; it cycles between E1 and E3 rather than being a stable subunit of the E3 complex. The interaction is functional and well supported, but being a substrate-carrying client of the complex is not membership in it. The E2-E3 relationship is better represented through the conjugating-enzyme activity. Supporting Evidence: PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0034274 Atg12-Atg5-Atg16 complex | IDA PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiqu... | MARK AS OVER ANNOTATED | Summary: IDA part_of Atg12-Atg5-Atg16 complex (PMID:24191030), based on ATG3 association with the ATG12~ATG5-ATG16L1 E3. Reason: ATG3 is the E2 that is recruited by ATG12 of the E3 and binds it transiently, in competition with ATG7; it cycles between E1 and E3 rather than being a stable subunit of the E3 complex. The interaction is functional and well supported, but being a substrate-carrying client of the complex is not membership in it. The E2-E3 relationship is better represented through the conjugating-enzyme activity. Supporting Evidence: PMID:24191030 A role of ATG12 in the E3 complex is to recruit the E2 enzyme ATG3 PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0034274 Atg12-Atg5-Atg16 complex | IDA PMID:37252361 Semisynthetic LC3 Probes for Autophagy Pathways Reveal a Non... | MARK AS OVER ANNOTATED | Summary: IDA part_of Atg12-Atg5-Atg16 complex (PMID:37252361), based on ATG3 association with the ATG12~ATG5-ATG16L1 E3. Reason: ATG3 is the E2 that is recruited by ATG12 of the E3 and binds it transiently, in competition with ATG7; it cycles between E1 and E3 rather than being a stable subunit of the E3 complex. The interaction is functional and well supported, but being a substrate-carrying client of the complex is not membership in it. The E2-E3 relationship is better represented through the conjugating-enzyme activity. Supporting Evidence: PMID:37252361 ATG3 performs the lipidation of LC3/GABARAP in conjunction with an E3-like enzyme complex of isopeptide-linked ATG5-ATG12 PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA transfer from mouse Atg3 (Q9CPX6) of mitochondrial fragmentation involved in apoptotic process, presumably from Radoshevich et al. 2010. Reason: In mouse cells, loss of ATG12-ATG3 conjugation increased mitochondrial mass and fragmentation and reduced mitochondria-dependent cell death; the phenotype is indirect (attributed to altered mitochondrial homeostasis) and its direction does not show that ATG3 performs mitochondrial fragmentation. There is no experiment in human ATG3. This is a downstream phenotype of the ATG12-ATG3 conjugate rather than a process ATG3 executes. Supporting Evidence: PMID:20723759 disrupting ATG12 conjugation to ATG3 produces significant increases in mitochondrial mass and fragmentation |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse Atg3 (Q9CPX6) of mitochondrial fragmentation involved in apoptotic process, presumably from Radoshevich et al. 2010. Reason: In mouse cells, loss of ATG12-ATG3 conjugation increased mitochondrial mass and fragmentation and reduced mitochondria-dependent cell death; the phenotype is indirect (attributed to altered mitochondrial homeostasis) and its direction does not show that ATG3 performs mitochondrial fragmentation. There is no experiment in human ATG3. This is a downstream phenotype of the ATG12-ATG3 conjugate rather than a process ATG3 executes. Supporting Evidence: PMID:20723759 disrupting ATG12 conjugation to ATG3 produces significant increases in mitochondrial mass and fragmentation |
| GO:0044804 nucleophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA placing ATG3 in nucleophagy (PAINT node PANTHER:PTN000305307). Reason: nucleophagy uses the core autophagosome-formation machinery, and ATG3 performs the Atg8-lipidation step within it, so participation is genuine rather than merely necessity. These selective-autophagy processes are, however, specific uses of the general autophagosome assembly function rather than distinct ATG3 functions, and the experimental grounding comes from non-human donors (yeast/fly). Kept as non-core. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:0061723 glycophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA placing ATG3 in glycophagy (PAINT node PANTHER:PTN000305307). Reason: glycophagy uses the core autophagosome-formation machinery, and ATG3 performs the Atg8-lipidation step within it, so participation is genuine rather than merely necessity. These selective-autophagy processes are, however, specific uses of the general autophagosome assembly function rather than distinct ATG3 functions, and the experimental grounding comes from non-human donors (yeast/fly). Kept as non-core. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:0141046 Atg8-family conjugating enzyme activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN000305308 (PANTHER PTHR12866:SF2, ATG3 subfamily), with human ATG3 itself among the experimental donors. Reason: This is the defining activity of ATG3: an E2-like enzyme that receives Atg8-family proteins from ATG7 as a Cys264 thioester and transfers them to phosphatidylethanolamine with the help of the ATG12~ATG5-ATG16L1 E3. Human ATG3 has direct experimental evidence; the IBA additionally asserts that the activity is ancestral to the ATG3 subfamily, consistent with yeast Atg3 being the founding Atg8 E2. Supporting Evidence: file:human/ATG3/ATG3-uniprot.txt E2 conjugating enzyme that catalyzes the covalent conjugation of the C-terminal Gly of ATG8-like proteins (GABARAP, GABARAPL1, GABARAPL2 or MAP1LC3A) to the amino group of phosphatidylethanolamine (PE)-containing lipids in the membrane PMID:11825910 hApg3p is an E2-like enzyme essential for three human Apg8p homologues PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:0141046 Atg8-family conjugating enzyme activity | IDA PMID:12207896 Mammalian Apg12p, but not the Apg12p.Apg5p conjugate, facili... | ACCEPT | Summary: IDA from Tanida et al. 2002 (BBRC), which examined how ATG12 and the ATG12~ATG5 conjugate affect Apg7/Apg3-catalysed LC3 processing to LC3-II. Reason: The abstract states that Apg7p and Apg3p catalyse the conversion of LC3 to the membrane-bound LC3-II form; abstract-only cache, but the activity is well established for human ATG3 by several independent papers, so the curator's IDA is accepted. Supporting Evidence: PMID:12207896 The same Apg7p and Apg3p catalyze the processing of LC3 to a membrane-bound form, LC3-II PMID:11825910 hApg3p is an E2-like enzyme essential for three human Apg8p homologues |
| GO:0141046 Atg8-family conjugating enzyme activity | IDA PMID:24186333 Binding to E1 and E3 is mutually exclusive for the human aut... | ACCEPT | Summary: IDA from Qiu et al. 2013: identification of the E3-binding region of human ATG3; peptides from this region inhibit LC3 lipidation in vitro. Reason: In vitro reconstituted LC3 lipidation with human ATG7/ATG3/E3 directly measures the Atg8-family conjugating activity of ATG3. Supporting Evidence: PMID:24186333 the E3 competes with Atg7 for binding to Atg3, implying that Atg3 likely cycles back and forth between binding to Atg7 for loading with the UBL LC3 and binding to E3 to promote LC3 lipidation |
| GO:0141046 Atg8-family conjugating enzyme activity | IDA PMID:37252361 Semisynthetic LC3 Probes for Autophagy Pathways Reveal a Non... | ACCEPT | Summary: IDA from Farnung et al. 2023: activity-based LC3 probes and ATG3 KO/rescue show the noncanonical LIR of ATG3 is needed for ATG3~LC3 thioester formation and LC3 lipidation. Reason: Direct biochemical and cellular evidence for the human E2 activity, including ATG3~LC3 thioester formation. Supporting Evidence: PMID:37252361 LIRATG3 is required for LC3 lipidation and ATG3∼LC3 thioester formation PMID:37252361 ATG3 performs the lipidation of LC3/GABARAP in conjunction with an E3-like enzyme complex of isopeptide-linked ATG5-ATG12 |
| GO:0141046 Atg8-family conjugating enzyme activity | IMP PMID:24191030 Structural basis of ATG3 recognition by the autophagic ubiqu... | ACCEPT | Summary: IMP from Metlagel et al. 2013: mutation of ATG3 residues contacting ATG12 impairs E3 interaction and LC3 lipidation. Reason: Mutational analysis of human ATG3 links its E3-recruitment segment to its LC3 lipidation activity. Supporting Evidence: PMID:24191030 Mutational analyses of ATG3 confirm that four residues whose side chains make contacts with ATG12 are important for E3 interaction as well as LC3 lipidation |
| GO:0141046 Atg8-family conjugating enzyme activity | IMP PMID:33446636 An N-terminal conserved region in human Atg3 couples membran... | ACCEPT | Summary: IMP from Ye et al. 2021: N-terminal conserved-region mutants of human ATG3 lose LC3-PE conjugation activity in vitro and fail to rescue LC3B lipidation in Atg3-/- MEFs. Reason: Mutational and complementation data directly tie the activity to human ATG3. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation PMID:33446636 While the lipidation of LC3B was absent in Atg3−/− MEFs, the expression of hAtg3 rescued not only LC3B–PE conjugation, but also starvation-induced autophagic flux |
| GO:1902017 regulation of cilium assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA transfer from mouse Atg3 (Q9CPX6) of regulation of cilium assembly (autophagic removal of OFD1 from centriolar satellites promoting ciliogenesis). Reason: The effect on ciliogenesis is an indirect consequence of general autophagy: autophagic degradation of OFD1 requires the conjugation machinery, so loss of ATG3 (like loss of ATG5/ATG7) affects cilia. ATG3 does no cilium-specific work; this is necessity, not participation. No human ATG3 experiment supports it. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
| GO:1902017 regulation of cilium assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS transfer from mouse Atg3 (Q9CPX6) of regulation of cilium assembly (autophagic removal of OFD1 from centriolar satellites promoting ciliogenesis). Reason: The effect on ciliogenesis is an indirect consequence of general autophagy: autophagic degradation of OFD1 requires the conjugation machinery, so loss of ATG3 (like loss of ATG5/ATG7) affects cilia. ATG3 does no cilium-specific work; this is necessity, not participation. No human ATG3 experiment supports it. Supporting Evidence: PMID:33446636 During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation |
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Download this section (compressed HTML)Q: Should ATG3's transient association with the ATG12~ATG5-ATG16L1 E3 be represented as complex membership (GO:0034274), or only through the E2 activity and an E2-E3 binding relationship, given that ATG3 binding to E1 and E3 is mutually exclusive?
Q: Does human ATG3 form the ATG12-ATG3 conjugate under physiological conditions, and does it influence mitochondrial homeostasis as in mouse cells?
Experiment: Express a non-conjugatable ATG3 K243R variant in human ATG3-knockout cells and test ATG12-ATG3 formation, LC3 lipidation, mitochondrial morphology and PDCD6IP-dependent endolysosomal trafficking, to establish in human cells the ATG12-ATG3 functions currently inferred from mouse.
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