{"gene":"ATG13","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2009,"finding":"ATG13 forms a stable ~3-MDa complex with ULK1 and FIP200 in mammalian cells; this complex is constitutively assembled regardless of nutrient conditions (unlike the yeast counterpart). mTORC1 is incorporated into the ULK1-ATG13-FIP200 complex through ULK1 in a nutrient-dependent manner and directly phosphorylates both ULK1 and ATG13 to suppress autophagy. ATG13 localizes to the autophagosomal isolation membrane and is essential for autophagosome formation.","method":"Co-immunoprecipitation, gel filtration, siRNA knockdown, immunofluorescence, rapamycin and starvation experiments, in-cell phosphorylation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods, replicated independently in at least two concurrent papers (PMID:19211835 and PMID:19258318)","pmids":["19211835","19258318"],"is_preprint":false},{"year":2009,"finding":"FIP200 and ATG13 each enhance ULK1 kinase activity individually, but both are required for maximal ULK1 kinase activity stimulation, as demonstrated in cellular experiments and a de novo in vitro reconstituted reaction. ATG13 and FIP200 are also critical for correct localization of ULK1 to the pre-autophagosome and for ULK1 protein stability.","method":"In vitro kinase reconstitution assay, cellular co-immunoprecipitation, ULK1 localization by fluorescence microscopy, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of kinase activity plus cellular validation in a single rigorous study","pmids":["19258318"],"is_preprint":false},{"year":2009,"finding":"ATG101, a novel mammalian protein with no yeast homolog, directly interacts with ATG13 and associates with the ULK-ATG13-FIP200 complex. In ATG13 siRNA-treated cells, ATG101 is present only as a monomer, establishing ATG13 as the scaffold for ATG101 incorporation. ATG101 stabilizes ATG13 and ULK1 basal phosphorylation; its depletion blocks autophagosome formation.","method":"Co-immunoprecipitation, siRNA knockdown, GFP-tagged protein localization, western blot","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, localization data, functional KD phenotype, replicated across two independent groups (PMID:19597335 and PMID:19287211)","pmids":["19597335","19287211"],"is_preprint":false},{"year":2009,"finding":"ATG101 stabilizes ATG13 from proteasomal degradation and interacts with ULK1 in an ATG13-dependent manner, placing ATG13 as the bridge between ATG101 and ULK1 in the initiation complex.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, siRNA knockdown, western blot","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, Co-IP with functional follow-up but limited orthogonal methods","pmids":["19287211"],"is_preprint":false},{"year":2004,"finding":"In yeast, the Atg1-Atg13 signaling complex governs retrograde transport of Atg9 and Atg23 from the pre-autophagosomal structure (PAS); Atg1 kinase activity is required specifically for Atg23 retrieval, while Atg9 recycling additionally requires Atg18 and Atg2.","method":"Genetic epistasis, fluorescence microscopy of Atg9/Atg23 trafficking, Atg1 kinase-dead mutants","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with live-cell trafficking analysis and kinase-dead mutants in yeast","pmids":["14723849"],"is_preprint":false},{"year":2005,"finding":"In yeast, Atg17 physically associates with the Atg1-Atg13 complex; Atg17 binding to Atg1 requires Atg13 as an intermediary (Atg17-Atg1 interaction is lost in atg13Δ cells). A point mutation in Atg17 (C24R) reduces Atg13 affinity, impairs Atg1 kinase activity, and causes autophagy defects, demonstrating that Atg17-Atg13 complex formation is required for normal autophagosome formation and Atg1 activation.","method":"Two-hybrid, co-immunoprecipitation, atg13Δ epistasis, Atg17 point mutant analysis, autophagy assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis plus point-mutant functional analysis","pmids":["15743910"],"is_preprint":false},{"year":2009,"finding":"In Drosophila, Atg1 and Atg13 form a complex; Atg13 phosphorylation is greatest under autophagic (starvation) conditions rather than being inhibitory as in yeast, and phosphorylation does not prevent Atg1-Atg13 association. Atg13 stimulates Atg1 autophagic activity and Atg1's inhibition of TOR signaling, in part by disrupting normal TOR trafficking. Excess Atg13 paradoxically inhibits autophagosome expansion.","method":"Genetic knockout, in vivo co-immunoprecipitation, epistasis, phosphorylation analysis in TOR/Atg1 kinase-dependent conditions","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO of both Atg1 and Atg13 with epistasis, reciprocal Co-IP, and phosphorylation analysis in Drosophila","pmids":["19225150"],"is_preprint":false},{"year":2009,"finding":"In yeast, both the Tor and PKA signaling pathways independently phosphorylate Atg13 to regulate autophagy. PKA directly phosphorylates Atg13 at sites distinct from Tor phosphorylation sites, and these PKA phosphorylation events regulate Atg13 localization to the preautophagosomal structure (PAS).","method":"In vitro kinase assay (PKA phosphorylation of Atg13), phosphorylation-site mutant analysis, PAS localization by fluorescence microscopy, genetic pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay demonstrating direct PKA phosphorylation plus mutant localization studies","pmids":["19805182"],"is_preprint":false},{"year":2010,"finding":"In yeast, TORC1 directly phosphorylates Atg13 on at least eight serine residues. Expression of an unphosphorylatable Atg13 mutant (Atg13-8SA) bypasses the TORC1 pathway to induce autophagy in vegetatively growing cells, demonstrating that Atg13 dephosphorylation is a molecular switch for autophagy induction and Atg1 complex formation.","method":"In vitro TORC1 kinase assay, site-directed mutagenesis (8SA mutant), autophagy reporter assays, Atg1 complex formation analysis, PAS organization assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus bypass-of-pathway mutagenesis with multiple functional readouts","pmids":["20383061"],"is_preprint":false},{"year":2011,"finding":"The Hsp90-Cdc37 chaperone complex stabilizes and activates ULK1, which in turn phosphorylates ATG13 causing its release from ULK1 and recruitment to damaged mitochondria. Hsp90-Cdc37, ULK1, and ATG13 phosphorylation are all required for efficient mitochondrial clearance (mitophagy).","method":"Co-immunoprecipitation, pharmacological Hsp90 inhibition, phosphorylation analysis, mitochondrial clearance assays, siRNA knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional KD/inhibition with specific mitophagy phenotype, direct phosphorylation consequence shown","pmids":["21855797"],"is_preprint":false},{"year":2011,"finding":"ATG13 function in autophagy strictly depends on FIP200 binding; an ATG13-deficient cell line demonstrates that ATG13 is indispensable for autophagy induction. Furthermore, a short C-terminal peptide motif of ATG13 mediates ULK1/2 binding, but a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity, indicating ATG13 has ULK1/2-independent functions mediated through FIP200.","method":"ATG13 knockout cells, domain-deletion and point-mutant reconstitution, autophagy flux assays, co-immunoprecipitation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells reconstituted with domain mutants plus multiple autophagy readouts, replicated in two studies (PMID:22024743 and PMID:26213203)","pmids":["22024743","26213203"],"is_preprint":false},{"year":2013,"finding":"The N-terminal domain of Atg13 adopts a HORMA (Hop1, Rev7, Mad2) fold revealed at 2.3-Å resolution by X-ray crystallography. This HORMA domain is required for autophagy and for recruitment of the PI 3-kinase subunit Atg14 to the PAS, but is not required for Atg1 interaction or Atg13 recruitment to the PAS. Two conserved Arg residues in the HORMA domain (putative phosphate sensors) are essential for autophagy and Atg14 recruitment.","method":"X-ray crystallography (2.3 Å), yeast mutant analysis, autophagy assays, Atg14 localization assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at high resolution combined with site-directed mutagenesis and multiple functional assays in yeast","pmids":["23509291"],"is_preprint":false},{"year":2013,"finding":"ATG13 interacts with all three human LC3 isoforms (LC3A, LC3B, LC3C) via its LIR (LC3-interacting region) motif. Crystal structures of LC3A and LC3C complexed with the ATG13 LIR reveal that the side-chain of Lys49 in LC3 acts as a gatekeeper regulating LIR binding; mutation of Lys49 in LC3A significantly reduces LC3A-positive puncta formation.","method":"X-ray crystallography (LC3-ATG13 LIR complex structures), in vitro binding assays, cell-based LC3 puncta formation assay with Lys49 mutants","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of complexes plus mutagenesis validated in cells","pmids":["24290141"],"is_preprint":false},{"year":2015,"finding":"The N-terminal HORMA domain of Atg13 directly binds Atg9 (a multispanning membrane protein on Atg9 vesicles). HORMA domain mutants unable to interact with Atg9 impair PAS localization of Atg9 vesicles and cause severe defects in starvation-induced autophagy. Thus, the Atg13 HORMA domain recruits Atg9 vesicles to the PAS as a mechanistically distinct step from complex scaffold formation by the C-terminal disordered region.","method":"Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy of Atg9 localization, autophagy assays with HORMA domain point mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP plus point-mutant functional analysis with localization and autophagy readouts","pmids":["25737544"],"is_preprint":false},{"year":2015,"finding":"The human ATG13 HORMA domain and the full-length HORMA-domain-only protein ATG101 form a heterodimer whose crystal structure reveals an architecture conserved with the Mad2 conformational heterodimer and S. pombe Atg13-Atg101. The WF finger motif essential for ATG101 function is sequestered in a hydrophobic pocket, suggesting regulated exposure. Conserved hydrophobic pockets in the dimer surface are suggestive of additional protein-interaction sites.","method":"X-ray crystallography of human ATG13-ATG101 HORMA heterodimer","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with structural-functional analysis of the WF finger and interaction surfaces","pmids":["26299944"],"is_preprint":false},{"year":2016,"finding":"mTOR directly phosphorylates ATG13 on Ser-258, while Ser-224 is modulated by the AMPK pathway. In ATG13-knockout cells reconstituted with unphosphorylatable ATG13, ULK1 kinase activity is more potent and starvation-induced ATG13/ULK1 translocation and autophagy are accelerated. Thus, ATG13 phosphorylation by mTOR and AMPK inhibits autophagy initiation.","method":"In vitro mTOR kinase assay, ATG13-KO cell reconstitution with phospho-mutants, ULK1 kinase activity assays, translocation analysis by imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay showing direct mTOR phosphorylation, KO reconstitution with phospho-mutants and multiple functional readouts","pmids":["26801615"],"is_preprint":false},{"year":2016,"finding":"Atg13 contains a large intrinsically disordered region (IDR) with two distinct binding sites for Atg17 that mediate intercomplex linkages between Atg17-Atg29-Atg31 subcomplexes, driving supramolecular self-assembly of multiple Atg1 complexes. This assembly promotes Atg1 autophosphorylation, Atg9 vesicle recruitment, and Atg9 phosphorylation by Atg1.","method":"X-ray crystallography, NMR, in vitro reconstitution of Atg1 complex assembly, yeast PAS organization assays, high-speed atomic force microscopy","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural and biochemical reconstitution plus in vivo PAS assays with multiple orthogonal methods","pmids":["27404361"],"is_preprint":false},{"year":2016,"finding":"PP2A phosphatases (PP2A-Cdc55 and PP2A-Rts1), activated upon TORC1 inactivation, are required for sufficient Atg13 dephosphorylation and consequent autophagy induction. Overexpression of non-phosphorylatable Atg13 suppresses autophagy defects in PP2A mutants, placing PP2A-mediated Atg13 dephosphorylation upstream of Atg1 kinase activation and PAS formation.","method":"PP2A deletion mutant analysis, Atg13 phosphorylation-state western blot, PAS formation assay, epistasis with non-phosphorylatable Atg13","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with phospho-mutant bypass and multiple autophagy readouts, single lab","pmids":["27973551"],"is_preprint":false},{"year":2011,"finding":"Atg13 promotes formation of a specific Atg1-Atg1 self-interaction in yeast. This Atg1 homodimerization is correlated with autophagy induction, is required for Atg1 kinase activity, and facilitates autophosphorylation of Thr-226 in the Atg1 activation loop. Disruption of the Atg1-Atg1 complex results in diminished autophagy and Atg1 activity.","method":"Co-immunoprecipitation of Atg1-Atg1 complex, in vitro kinase assay, heterologous dimerization domain fusion, phosphorylation-site mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase assay plus heterologous dimerization rescue, single lab","pmids":["21712380"],"is_preprint":false},{"year":2018,"finding":"The C-terminal intrinsically disordered region (IDR) of yeast Atg13 directly binds phospholipid membranes via electrostatic interactions (positively charged residues) and hydrophobic insertion of a Phe residue. Two sets of IDR residues mediating phospholipid binding overlap with the Vac8-binding domain, making Atg13 binding to phospholipids and Vac8 mutually exclusive; both interactions are required for efficient autophagy.","method":"Lipid-binding assays, isothermal titration calorimetry (ITC), circular dichroism, mutagenesis of binding residues, yeast autophagy assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical binding assays (ITC + lipid binding) combined with mutagenesis and functional yeast assays","pmids":["31352862"],"is_preprint":false},{"year":2018,"finding":"The dynamic Atg13-free conformation of the Atg1 EAT domain is required for phagophore expansion. Atg1 is present on autophagic puncta at ~twice the stoichiometry of Atg13. An EAT domain mutant (ATG1DD) that selectively disrupts the Atg13-free state shows reduced PAS formation and fails to support phagophore expansion, demonstrating a second EAT domain function independent of Atg13.","method":"Crystal structure analysis, isothermal titration calorimetry, quantitative and superresolution microscopy, structure-based mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-informed mutagenesis validated by quantitative/superresolution microscopy and ITC","pmids":["29540529"],"is_preprint":false},{"year":2020,"finding":"LUBAC (E3 ubiquitin ligase complex, via RNF31/HOIP) mediates linear ubiquitination of ATG13 at the phagophore. OTULIN deubiquitinase counteracts this modification. In OTULIN-knockdown cells, excessively ubiquitinated ATG13 accumulates at the phagophore and blocks autophagosome maturation. LUBAC activity promotes autophagy initiation, while OTULIN is required for maturation.","method":"siRNA knockdown, co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-based ubiquitination assays plus KD with defined maturation phenotype, single lab","pmids":["32543267"],"is_preprint":false},{"year":2020,"finding":"CDK1/cyclin B phosphorylates both ULK1 and ATG13 during mitosis. CDK1-induced ULK1-ATG13 phosphorylation promotes mitotic autophagy and cell cycle progression. Double knockout of ULK1 and ATG13 blocks cell cycle progression and decreases cancer cell proliferation in cell line and mouse models.","method":"Mass spectrometry phospho-mapping, site-directed mutagenesis, CDK1 kinase assays, ULK1/ATG13 double-KO cells and mouse xenograft models","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mass spectrometry plus in vitro CDK1 kinase assay plus mutagenesis plus in vivo tumor model","pmids":["32516310"],"is_preprint":false},{"year":2021,"finding":"ATG9A interacts with the ATG13-ATG101 dimer independently of ULK1, as shown by split-mVenus and knockout/reconstitution approaches. Deletion of ATG13 or ATG101 causes aberrant accumulation of ATG9A at stalled p62/ubiquitin clusters, rescuable by a ULK1 binding-deficient ATG13 mutant, establishing a ULK1-independent ATG13-ATG101-ATG9A axis that regulates ATG9A distribution.","method":"BioID quantitative proteomics, knockout/reconstitution, split-mVenus protein-protein interaction assay, fluorescence microscopy","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — BioID plus split-mVenus plus KO/reconstitution with mutant rescue, multiple orthogonal methods","pmids":["34369648"],"is_preprint":false},{"year":2022,"finding":"In yeast, Mec1 (DNA damage sensor kinase) directly binds Atg13 through a Mec1-Binding Region (MBR) on Atg13 and an Atg13-Binding Region (ABR) on Mec1. Disruption of MBR or ABR impairs recruitment of both Mec1 and Atg13 to the PAS and blocks glucose starvation-induced autophagy, placing this direct Mec1-Atg13 interaction upstream of PAS assembly.","method":"In vitro direct binding assay, deletion/point mutant analysis, PAS localization by fluorescence microscopy, autophagy assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding plus mutant-based epistasis with localization and functional readouts","pmids":["36574691"],"is_preprint":false},{"year":2022,"finding":"In yeast, autophagy termination during persistent starvation is mediated by re-phosphorylation of Atg13 by the Atg1 protein kinase (also modulated by PP2C phosphatases), leading to PAS dispersal. A vacuolar membrane protein Tag1 is required for this termination; tag1Δ cells show defective Atg13 re-phosphorylation and persistent PAS.","method":"Genetic screen, Atg13 phosphorylation western blot analysis, PAS microscopy in tag1Δ and Atg1 kinase-dead mutants","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen plus phosphorylation analysis plus microscopy, single lab","pmids":["33536246"],"is_preprint":false},{"year":2022,"finding":"Cdc14 phosphatase dephosphorylates Atg13 in a spatiotemporally controlled manner during meiotic anaphase I and II (following Cdc14 relocalization from nucleolus to cytoplasm), stimulating Atg1 kinase activity and autophagy to support meiotic progression and sporulation.","method":"In vitro Cdc14 phosphatase assay, subcellular localization analysis, meiotic autophagy assays, Atg13 phosphorylation state analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphatase assay plus spatiotemporal localization evidence plus functional meiotic autophagy readouts","pmids":["35238874"],"is_preprint":false},{"year":2022,"finding":"Comprehensive phospho-mapping identifies 48 in vivo phosphorylation sites on yeast Atg13. Reciprocal phospho-mimetic and phospho-deficient mutants reveal that dynamic phospho-regulation of Atg13 is critical: insufficient or excessive autophagy from disrupted regulation are both detrimental to cell survival. Atg11 is found to contribute to bulk autophagy even during nitrogen starvation by cooperating with Atg1 in driving phase separation of the PAS.","method":"In vivo phosphoproteomics (MS), reciprocal phospho-mutant (mimetic and non-phosphorylatable) analysis, PAS formation assays, epistasis with Atg11","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mass spectrometry phospho-mapping plus reciprocal mutagenesis plus epistasis, multiple orthogonal readouts","pmids":["38233718"],"is_preprint":false},{"year":2023,"finding":"PM2.5-induced downregulation of ALKBH5 promotes m6A methylation of ATG13 mRNA at site 767, enhancing ATG13 expression and ULK complex-regulated autophagy and epithelial inflammation in lung cells.","method":"m6A methylation analysis (MeRIP), ALKBH5 knockout mice, ATG13 m6A site mutagenesis, western blot, NF-κB/NLRP3 signaling readouts","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct m6A mapping plus KO mouse model plus site-specific mutagenesis, single lab","pmids":["37295326"],"is_preprint":false},{"year":2022,"finding":"LPS induces proteasomal degradation of ATG13 in hepatic stellate cells via p38 MAPK activation. Atg13 knockdown markedly inhibits autophagy and promotes LPS-induced inflammation. Ubiquitination of ATG13 leading to proteasomal degradation is dependent on p38 MAPK, positioning Atg13 as a mediator between autophagy and proteasomal pathways.","method":"Co-immunoprecipitation (ubiquitination assay), p38 MAPK inhibition, siRNA knockdown, proteasome inhibitor treatment, western blot","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP ubiquitination assay with pharmacological and siRNA perturbations, single lab","pmids":["36148140"],"is_preprint":false},{"year":2021,"finding":"ERK1/2 associates with ATG13 and FIP200 upon glucose starvation; ATG13 and FIP200 contain ERK consensus phosphorylation sites. Phospho-defective ATG13 mutants block glucose starvation-induced autophagy and sensitize renal cells to hypoglycemia-induced death, while phospho-mimetic ATG13 mutants induce autophagy and protect cells.","method":"Co-immunoprecipitation (ERK1/2-ATG13 interaction), phospho-defective/mimetic mutant reconstitution, autophagy flux assays, cell viability assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus phospho-mutant reconstitution, single lab, limited orthogonal methods","pmids":["33682133"],"is_preprint":false},{"year":2021,"finding":"HSBP1 (a small coiled-coil protein) physically interacts with FIP200 and ATG13 (binding via FIP200). HSBP1 depletion reduces stability of ULK kinase complex subunits and impairs autophagy induction. The FIP200-ATG13 subcomplex negatively regulates HSBP1's pro-picornaviral function during infections.","method":"Co-immunoprecipitation, siRNA/CRISPR knockdown/knockout, autophagy induction assays, viral replication assays","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus KD/KO with autophagy and viral replication phenotypes, single lab","pmids":["34869056"],"is_preprint":false},{"year":2020,"finding":"Live imaging and mathematical modeling of ATG13 translocation reveal that in nonselective autophagy ATG13 recruitment follows a normal distribution of intensity/duration, while mitophagy involves multiple, oscillatory ATG13 translocations whose number is directly proportional to the diameter of targeted mitochondrial fragments, consistent with successive phagophore nucleation events.","method":"Live fluorescence imaging, mathematical modeling, wortmannin perturbation, ivermectin-induced mitophagy model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — live imaging with mathematical modeling validated by chemical perturbation, single lab","pmids":["32320309"],"is_preprint":false},{"year":2025,"finding":"AlphaFold-based structure prediction and in vitro validation establish that the intrinsically disordered region of ATG13 engages the bases of two UBL domains in the FIP200 dimer via two phenylalanines, and also binds the tandem MIT domain of ULK1, yielding a 1:1:2 stoichiometry for the ULK1-ATG13-FIP200 core complex. Each pairwise interaction (ULK1-ATG13, ATG13-FIP200) additively contributes to autophagic flux.","method":"AlphaFold structure prediction, in vitro binding assays with point mutants, co-immunoprecipitation in cells, autophagy flux assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structure-guided mutagenesis, direct in vitro binding validation, and cell-based functional assays with additive mutant analysis","pmids":["40552710"],"is_preprint":false},{"year":2024,"finding":"The RNA-binding protein YBX3 interacts with and stabilizes ATG13 mRNA via its 3' UTR, increasing ATG13 protein expression. YBX3 depletion reduces ATG13 mRNA and protein levels in multiple human cell lines, identifying posttranscriptional mRNA stabilization as a regulatory mechanism for ATG13 abundance.","method":"RNA immunoprecipitation (RIP), mRNA stability assays, 3' UTR reporter assays, YBX3 depletion with western blot/qPCR readouts","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus 3' UTR functional assay plus protein/mRNA measurement across multiple cell lines, single lab","pmids":["39414370"],"is_preprint":false},{"year":2025,"finding":"ATG13:ATG101 HORMA dimer forms a tight complex with WIPI3 (and WIPI2). Bound to WIPIs, ATG13:ATG101 aligns with membranes and inserts the ATG101 WF finger into the membrane. A PVP motif within the ULK1 IDR docks onto the ATG13:ATG101 HORMA surface, bringing the ULK1 kinase domain near the membrane for substrate phosphorylation. WIPI3:ATG13 engagement is required for ATG16L1 phosphorylation by ULK1, ATG13 puncta formation, and bulk autophagic flux.","method":"Biochemical reconstitution, molecular dynamics simulations, cell-based autophagy and phosphorylation assays, pulldown assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution plus MD simulations plus multiple cell-based functional assays; preprint but mechanistically novel","pmids":["bio_10.1101_2025.11.07.687251"],"is_preprint":true},{"year":2025,"finding":"ULK1 phosphorylates ATG101, triggering ATG101 homo-dimerization that dramatically accelerates ATG101 association with ATG13 and ATG9A to form the ATG9A-ATG13-ATG101 initiation complex. ATG101 dimers create a positive autocatalytic feedback propagating activation independently of further ULK1 activity, and this memory of activation persists for hours after dephosphorylation.","method":"Interaction kinetics measurements, biochemical reconstitution, ULK1 in vitro phosphorylation assay, homo-dimerization analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biochemical reconstitution and kinetics in a preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.06.27.661946"],"is_preprint":true},{"year":2009,"finding":"In C. elegans, the divergent ATG13 homolog EPG-1 (encoded by epg-1) directly interacts with the C. elegans Atg1 homolog UNC-51 and is required for autophagy-regulated processes including degradation of aggregate-prone proteins and survival under starvation.","method":"Genetic loss-of-function, co-immunoprecipitation (EPG-1 with UNC-51), autophagy phenotype assays in C. elegans","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus genetic KO phenotype in C. elegans, single lab","pmids":["19377305"],"is_preprint":false},{"year":2012,"finding":"In C. elegans, EPG-9 (ATG101 homolog) directly interacts with EPG-1 (ATG13 homolog) and is essential for autophagic degradation of protein aggregates and animal survival under starvation, establishing a conserved ATG101-ATG13 interaction across metazoans.","method":"Direct in vitro binding assay, genetic loss-of-function in C. elegans, autophagy phenotype assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro binding plus genetic KO in C. elegans, single lab","pmids":["22885670"],"is_preprint":false},{"year":2024,"finding":"Transmembrane mitophagy receptors BNIP3 and NIX can initiate autophagosome biogenesis via a WIPI-ATG13 complex independently of the FIP200/ULK1 complex, establishing that ATG13 participates in a ULK1-independent membrane recruitment pathway for selective mitophagy.","method":"Biochemical reconstitution, knockout/rescue experiments, localization assays, autophagy flux measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — reconstitution and cell-based assays in a preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2024.08.28.609967"],"is_preprint":true}],"current_model":"ATG13 is a central scaffold of the autophagy initiation machinery that constitutively assembles with ULK1/2, FIP200, and ATG101 into a ~3-MDa complex; mTORC1 (phosphorylating ATG13 at Ser-258) and AMPK (at Ser-224) suppress autophagy by phosphorylating ATG13, while dephosphorylation by PP2A activates autophagy, with PKA and CDK1 providing additional independent phospho-regulatory inputs. Structurally, ATG13 contains an N-terminal HORMA domain (whose conserved Arg residues recruit PI3-kinase subunit Atg14 and whose surface engages ATG101 in a regulated Mad2-like heterodimer) and a large intrinsically disordered C-terminal region that binds ULK1, FIP200, Atg17, Atg8/LC3 via a LIR motif, and negatively charged phospholipid membranes; the ATG13:ATG101 HORMA dimer further binds WIPI2/3 to anchor the complex to PI3P-enriched membranes and position ULK1 for substrate phosphorylation. ATG13 also recruits Atg9 vesicles to the PAS via its HORMA domain and, independently of ULK1, forms an ATG13-ATG101 subcomplex that regulates ATG9A distribution; LUBAC-mediated linear ubiquitination and proteasomal (p38 MAPK-dependent) degradation of ATG13 provide additional post-translational control, while YBX3 stabilizes ATG13 mRNA to maintain protein levels."},"narrative":{"mechanistic_narrative":"ATG13 is a central scaffold of the autophagy initiation machinery, assembling with ULK1/2 and FIP200 into a constitutive ~3-MDa complex whose activity is gated by nutrient signaling and which is essential for autophagosome formation [PMID:19211835, PMID:19258318]. ATG13 and FIP200 together stimulate ULK1 kinase activity and direct ULK1 to the pre-autophagosomal structure, and ATG13 also serves as the obligate bridge that incorporates ATG101 into the complex and stabilizes it [PMID:19258318, PMID:19597335, PMID:19287211]. Architecturally the protein is bipartite: an N-terminal HORMA domain whose conserved Arg residues recruit the PI3-kinase subunit Atg14 and which directly binds Atg9 vesicles to deliver them to the PAS, and a large C-terminal intrinsically disordered region that engages ULK1, FIP200, Atg17, LC3 via a LIR motif, and acidic phospholipid membranes [PMID:23509291, PMID:24290141, PMID:25737544, PMID:31352862, PMID:40552710]. The ATG13 HORMA domain pairs with ATG101 in a Mad2-like conformational heterodimer that anchors the complex to PI3P-enriched membranes through WIPI3/WIPI2 binding and positions the ULK1 kinase domain for substrate phosphorylation [PMID:26299944, PMID:bio_10.1101_2025.11.07.687251]. ATG13 activity is set by reversible phosphorylation: mTORC1 (Ser-258) and AMPK (Ser-224) phosphorylate ATG13 to inhibit initiation, while dephosphorylation switches autophagy on, with additional kinase inputs from PKA, CDK1/cyclin B during mitosis, and Mec1 coupling autophagy to nutrient and DNA-damage states [PMID:26801615, PMID:19805182, PMID:32516310, PMID:36574691]. Beyond the canonical complex, an ATG13-ATG101 subcomplex regulates ATG9A distribution independently of ULK1, and ATG13 abundance is further controlled post-translationally by linear ubiquitination and proteasomal degradation and post-transcriptionally by mRNA stabilization [PMID:34369648, PMID:32543267, PMID:36148140, PMID:39414370]. ATG13 function is broadly conserved from yeast Atg13 through Drosophila and C. elegans EPG-1 [PMID:15743910, PMID:19225150, PMID:19377305].","teleology":[{"year":2009,"claim":"Established the mammalian autophagy initiation complex and its nutrient control: whether ATG13 acted within a stable complex and how nutrients controlled it was unknown; the work defined a constitutive ULK1-ATG13-FIP200 assembly directly phosphorylated by mTORC1.","evidence":"Co-IP, gel filtration, siRNA, rapamycin/starvation and in-cell phosphorylation in mammalian cells","pmids":["19211835","19258318"],"confidence":"High","gaps":["Did not resolve the structural basis of subunit contacts","Did not identify the specific mTORC1 phosphosites"]},{"year":2009,"claim":"Defined ATG13/FIP200 as activators of ULK1: it was unclear how the complex tuned kinase output; reconstitution showed both subunits are required for maximal ULK1 activity, localization, and stability.","evidence":"In vitro kinase reconstitution plus cellular Co-IP and microscopy","pmids":["19258318"],"confidence":"High","gaps":["Mechanism of kinase stimulation not structurally defined"]},{"year":2009,"claim":"Placed ATG13 as the scaffold for ATG101 incorporation: the metazoan-specific ATG101 lacked a known assembly route; ATG13 was shown to be required for ATG101 to join and stabilize the complex.","evidence":"Reciprocal Co-IP, siRNA, localization and proteasome-inhibition assays in mammalian cells","pmids":["19597335","19287211"],"confidence":"High","gaps":["Structural basis of the ATG13-ATG101 interface not yet defined","How ATG101 reciprocally stabilizes ATG13 mechanistically unresolved"]},{"year":2010,"claim":"Demonstrated Atg13 dephosphorylation as the molecular switch for autophagy: it was unclear whether TORC1 phosphorylation directly gated Atg1 complex assembly; an unphosphorylatable mutant bypassed TORC1 to induce autophagy.","evidence":"In vitro TORC1 kinase assay and 8SA-mutant bypass in yeast","pmids":["20383061"],"confidence":"High","gaps":["Phosphatase responsible for dephosphorylation not identified here","Direct mammalian sites not yet mapped"]},{"year":2013,"claim":"Revealed the HORMA fold as a distinct functional module: domain assignment for ATG13's N-terminus was unknown; crystallography defined a HORMA domain with conserved Arg residues required for Atg14 recruitment but not Atg1 binding.","evidence":"X-ray crystallography (2.3 Å) plus yeast mutant and localization assays","pmids":["23509291"],"confidence":"High","gaps":["Whether the Arg residues bind phosphate directly was not demonstrated","HORMA conformational dynamics not characterized"]},{"year":2013,"claim":"Identified ATG13 as a direct LC3-family interactor: it was unknown whether ATG13 itself binds Atg8-family proteins; structures showed LIR-mediated binding to LC3A/B/C gated by an LC3 Lys49 gatekeeper.","evidence":"Crystal structures of LC3-ATG13 LIR complexes and cell-based puncta assays","pmids":["24290141"],"confidence":"High","gaps":["Functional role of the LIR in autophagosome formation not fully dissected","Isoform selectivity in vivo not resolved"]},{"year":2015,"claim":"Assigned the HORMA domain a vesicle-recruitment role: how Atg9 vesicles reach the PAS was unclear; the Atg13 HORMA domain was shown to directly bind Atg9 and deliver vesicles, distinct from C-terminal scaffolding.","evidence":"Yeast two-hybrid, Co-IP, localization and HORMA point-mutant autophagy assays","pmids":["25737544"],"confidence":"High","gaps":["Atg9 binding surface on HORMA not structurally mapped","Coordination with ATG101 in vesicle recruitment not addressed"]},{"year":2015,"claim":"Defined the ATG13-ATG101 HORMA heterodimer architecture: how the two HORMA proteins assemble was unknown; the structure revealed a Mad2-like dimer with a sequestered WF finger suggesting regulated exposure.","evidence":"X-ray crystallography of the human ATG13-ATG101 HORMA heterodimer","pmids":["26299944"],"confidence":"High","gaps":["Trigger for WF finger exposure not identified","Functional partners docking on the hydrophobic pockets not yet found"]},{"year":2016,"claim":"Mapped the inhibitory mammalian phosphosites: the direct mTOR/AMPK targets on ATG13 were undefined; Ser-258 (mTOR) and Ser-224 (AMPK) were shown to suppress autophagy via ULK1 activity.","evidence":"In vitro mTOR kinase assay and ATG13-KO reconstitution with phospho-mutants","pmids":["26801615"],"confidence":"High","gaps":["Phosphatase reversing these sites in mammals not identified here","Full mammalian phosphosite map incomplete"]},{"year":2016,"claim":"Showed the IDR drives supramolecular complex self-assembly: how Atg1 complexes oligomerize at the PAS was unclear; the Atg13 IDR was found to carry two Atg17 sites linking subcomplexes and promoting Atg1 autophosphorylation and Atg9 recruitment.","evidence":"Crystallography, NMR, in vitro reconstitution, PAS assays, and HS-AFM in yeast","pmids":["27404361"],"confidence":"High","gaps":["Whether mammalian ATG13 IDR mediates equivalent multimerization not tested here"]},{"year":2018,"claim":"Defined direct membrane engagement by the IDR: it was unknown whether Atg13 itself contacts lipid; the C-terminal IDR was shown to bind phospholipids electrostatically and via a Phe insertion, mutually exclusive with Vac8.","evidence":"ITC, lipid-binding, CD, and mutagenesis with yeast autophagy assays","pmids":["31352862"],"confidence":"High","gaps":["In vivo membrane-binding kinetics not resolved","Mammalian conservation of the membrane-binding residues not addressed"]},{"year":2009,"claim":"Established additional independent phospho-inputs: beyond TOR, whether other kinases regulate Atg13 was unknown; PKA was shown to directly phosphorylate Atg13 at distinct sites controlling PAS localization.","evidence":"In vitro PKA kinase assay, phospho-site mutants, PAS localization in yeast","pmids":["19805182"],"confidence":"High","gaps":["Integration of PKA and TOR inputs not quantified","Mammalian PKA control of ATG13 not established here"]},{"year":2016,"claim":"Identified the activating phosphatase: how dephosphorylation is achieved after TORC1 inactivation was unclear; PP2A-Cdc55/Rts1 were shown to be required for Atg13 dephosphorylation and autophagy induction.","evidence":"PP2A deletion-mutant epistasis with non-phosphorylatable Atg13 in yeast","pmids":["27973551"],"confidence":"Medium","gaps":["Single-lab study","Direct PP2A action on Atg13 not shown by in vitro phosphatase assay","Mammalian phosphatase counterpart not identified"]},{"year":2011,"claim":"Linked ATG13 phosphorylation to selective mitophagy: how ATG13 contributes to mitochondrial clearance was unknown; Hsp90-Cdc37-stabilized ULK1 phosphorylates ATG13 driving its release and recruitment to damaged mitochondria.","evidence":"Co-IP, Hsp90 inhibition, phosphorylation and mitochondrial clearance assays","pmids":["21855797"],"confidence":"High","gaps":["Phosphosite mediating release not mapped","Mitochondrial receptor coupling not defined here"]},{"year":2011,"claim":"Connected ATG13 to Atg1 homodimerization: the mechanism by which Atg13 activates Atg1 was unclear; Atg13 was shown to promote an Atg1-Atg1 self-interaction required for kinase activity and activation-loop autophosphorylation.","evidence":"Co-IP, in vitro kinase assay, heterologous dimerization rescue in yeast","pmids":["21712380"],"confidence":"Medium","gaps":["Single lab","Structural basis of the dimer not resolved","Conservation in mammalian ULK1 not tested"]},{"year":2011,"claim":"Separated FIP200- and ULK1-dependent functions: whether ATG13 acts solely through ULK1 was unknown; KO reconstitution showed FIP200 binding is essential while ULK1-binding-deficient ATG13 partially rescues, revealing ULK1-independent roles.","evidence":"ATG13-KO cells with domain-mutant reconstitution and flux assays","pmids":["22024743","26213203"],"confidence":"High","gaps":["Molecular nature of the ULK1-independent FIP200 function not defined here"]},{"year":2020,"claim":"Added cell-cycle phospho-control: whether autophagy initiation is coupled to mitosis was unknown; CDK1/cyclin B was shown to phosphorylate ULK1 and ATG13 to promote mitotic autophagy and proliferation.","evidence":"MS phospho-mapping, CDK1 kinase assay, ULK1/ATG13 double-KO cells and xenografts","pmids":["32516310"],"confidence":"High","gaps":["Substrate consequences of mitotic ATG13 phosphosites not detailed","Relationship to mTOR/AMPK sites unresolved"]},{"year":2020,"claim":"Revealed ubiquitin control at the phagophore: how ATG13 is modified during maturation was unknown; LUBAC linear-ubiquitinates ATG13 (countered by OTULIN) to balance initiation versus maturation.","evidence":"siRNA, Co-IP, co-localization and ubiquitination assays","pmids":["32543267"],"confidence":"Medium","gaps":["Single lab","Ubiquitinated lysines not mapped","Mechanism linking ubiquitination to maturation block unclear"]},{"year":2021,"claim":"Defined a ULK1-independent ATG13-ATG101-ATG9A axis: whether the HORMA dimer functions outside the ULK1 complex was unknown; the dimer was shown to bind ATG9A independently of ULK1 and regulate its distribution.","evidence":"BioID, split-mVenus, KO/reconstitution with ULK1-binding-deficient mutant rescue","pmids":["34369648"],"confidence":"High","gaps":["Functional output of altered ATG9A distribution incompletely defined","Direct ATG9A-HORMA contact not structurally resolved"]},{"year":2022,"claim":"Coupled DNA-damage sensing to PAS assembly: whether Mec1 acts directly on Atg13 was unknown; a direct Mec1-Atg13 interaction via defined MBR/ABR regions was shown to be required for PAS recruitment and starvation autophagy.","evidence":"In vitro binding, deletion/point mutants, PAS localization and autophagy assays in yeast","pmids":["36574691"],"confidence":"High","gaps":["Whether Mec1 phosphorylates Atg13 at the PAS not established","Mammalian conservation unaddressed"]},{"year":2022,"claim":"Defined autophagy termination via Atg13 re-phosphorylation: how prolonged autophagy is switched off was unknown; Atg1-mediated Atg13 re-phosphorylation (with PP2C and the vacuolar protein Tag1) was shown to disperse the PAS.","evidence":"Genetic screen, phosphorylation western blots, PAS microscopy in tag1Δ/kinase-dead mutants","pmids":["33536246"],"confidence":"Medium","gaps":["Single lab","Tag1 mechanism of action on Atg13 unresolved","Mammalian termination pathway not defined"]},{"year":2022,"claim":"Extended phosphatase control to meiosis: developmental regulation of Atg13 was unknown; Cdc14 was shown to dephosphorylate Atg13 in a spatiotemporal manner during meiotic anaphase to stimulate autophagy.","evidence":"In vitro Cdc14 phosphatase assay, localization and meiotic autophagy assays in yeast","pmids":["35238874"],"confidence":"High","gaps":["Cdc14 target sites on Atg13 not mapped","Relationship to PP2A control unclear"]},{"year":2022,"claim":"Provided a comprehensive phospho-map and a balance principle: the full phospho-regulatory landscape was undefined; 48 Atg13 sites were mapped and reciprocal mutants showed both insufficient and excessive autophagy are detrimental.","evidence":"In vivo phosphoproteomics, reciprocal phospho-mutants, PAS assays, Atg11 epistasis in yeast","pmids":["38233718"],"confidence":"High","gaps":["Kinase/phosphatase assignment for individual sites incomplete","Mammalian equivalence of the 48-site map unknown"]},{"year":2025,"claim":"Defined the core complex stoichiometry and interfaces: precise architecture of the ULK1-ATG13-FIP200 core was unknown; structure prediction plus validation established a 1:1:2 complex with ATG13 IDR engaging FIP200 UBL bases and the ULK1 MIT domain.","evidence":"AlphaFold prediction, in vitro binding with point mutants, cellular Co-IP and flux assays","pmids":["40552710"],"confidence":"High","gaps":["Full-length experimental structure not determined","Dynamics of the IDR contacts not resolved"]},{"year":2025,"claim":"Defined membrane anchoring and kinase positioning by WIPI binding: how the HORMA dimer couples to PI3P membranes and orients ULK1 was unknown; ATG13:ATG101 was shown to bind WIPI3/WIPI2, insert the ATG101 WF finger into membrane, and dock a ULK1 PVP motif to position the kinase for ATG16L1 phosphorylation.","evidence":"Biochemical reconstitution, MD simulations, cell-based phosphorylation and flux assays (preprint)","pmids":["bio_10.1101_2025.11.07.687251"],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","In vivo confirmation of WF finger membrane insertion limited"]},{"year":2024,"claim":"Established post-transcriptional control of ATG13 abundance: how ATG13 protein levels are set was undefined; YBX3 was shown to bind and stabilize ATG13 mRNA via its 3' UTR.","evidence":"RIP, mRNA stability and 3' UTR reporter assays, YBX3 depletion across cell lines","pmids":["39414370"],"confidence":"Medium","gaps":["Single lab","Physiological contexts where this control dominates unclear"]},{"year":null,"claim":"How the many phospho-, ubiquitin-, and abundance-control inputs are integrated to set a quantitatively correct autophagic response in mammalian cells, and the mechanistic basis of the proposed ATG101-dimerization feedback memory, remain open.","evidence":"No single study in the corpus integrates the regulatory layers; the ATG101 autocatalytic feedback model rests on a preprint","pmids":[],"confidence":"Low","gaps":["Cross-talk between kinase/phosphatase, ubiquitin, and mRNA-stability inputs not reconciled","ATG101-dimerization memory model awaits peer review and in vivo validation","Mammalian phosphosite-specific kinase/phosphatase assignments incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,10,33]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9,32]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,10,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[22]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,8,15]}],"complexes":["ULK1-ATG13-FIP200 (ULK initiation complex)","ATG13-ATG101 HORMA heterodimer","Atg1-Atg13-Atg17 complex (yeast)"],"partners":["ULK1","FIP200","ATG101","ATG9A","WIPI3","WIPI2","LC3B","ATG17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75143","full_name":"Autophagy-related protein 13","aliases":[],"length_aa":517,"mass_kda":56.6,"function":"Autophagy factor required for autophagosome formation and mitophagy. Target of the TOR kinase signaling pathway that regulates autophagy through the control of the phosphorylation status of ATG13 and ULK1, and the regulation of the ATG13-ULK1-RB1CC1 complex. Through its regulation of ULK1 activity, plays a role in the regulation of the kinase activity of mTORC1 and cell proliferation","subcellular_location":"Cytoplasm, cytosol; Preautophagosomal structure","url":"https://www.uniprot.org/uniprotkb/O75143/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATG13","classification":"Not 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CHROMOSOME REGION, CANDIDATE GENE 8; SMCR8","url":"https://www.omim.org/entry/617074"},{"mim_id":"615089","title":"AUTOPHAGY-RELATED PROTEIN 101; ATG101","url":"https://www.omim.org/entry/615089"},{"mim_id":"615088","title":"AUTOPHAGY-RELATED 13; ATG13","url":"https://www.omim.org/entry/615088"},{"mim_id":"614260","title":"CHROMOSOME 9 OPEN READING FRAME 72; C9ORF72","url":"https://www.omim.org/entry/614260"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATG13"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0652"]},"alphafold":{"accession":"O75143","domains":[{"cath_id":"3.30.900.10","chopping":"8-190","consensus_level":"high","plddt":94.6643,"start":8,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75143","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75143-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75143-F1-predicted_aligned_error_v6.png","plddt_mean":63.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATG13","jax_strain_url":"https://www.jax.org/strain/search?query=ATG13"},"sequence":{"accession":"O75143","fasta_url":"https://rest.uniprot.org/uniprotkb/O75143.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75143/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75143"}},"corpus_meta":[{"pmid":"19211835","id":"PMC_19211835","title":"Nutrient-dependent mTORC1 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ATG13 localizes to the autophagosomal isolation membrane and is essential for autophagosome formation.\",\n      \"method\": \"Co-immunoprecipitation, gel filtration, siRNA knockdown, immunofluorescence, rapamycin and starvation experiments, in-cell phosphorylation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods, replicated independently in at least two concurrent papers (PMID:19211835 and PMID:19258318)\",\n      \"pmids\": [\"19211835\", \"19258318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FIP200 and ATG13 each enhance ULK1 kinase activity individually, but both are required for maximal ULK1 kinase activity stimulation, as demonstrated in cellular experiments and a de novo in vitro reconstituted reaction. ATG13 and FIP200 are also critical for correct localization of ULK1 to the pre-autophagosome and for ULK1 protein stability.\",\n      \"method\": \"In vitro kinase reconstitution assay, cellular co-immunoprecipitation, ULK1 localization by fluorescence microscopy, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of kinase activity plus cellular validation in a single rigorous study\",\n      \"pmids\": [\"19258318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATG101, a novel mammalian protein with no yeast homolog, directly interacts with ATG13 and associates with the ULK-ATG13-FIP200 complex. In ATG13 siRNA-treated cells, ATG101 is present only as a monomer, establishing ATG13 as the scaffold for ATG101 incorporation. ATG101 stabilizes ATG13 and ULK1 basal phosphorylation; its depletion blocks autophagosome formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, GFP-tagged protein localization, western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, localization data, functional KD phenotype, replicated across two independent groups (PMID:19597335 and PMID:19287211)\",\n      \"pmids\": [\"19597335\", \"19287211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATG101 stabilizes ATG13 from proteasomal degradation and interacts with ULK1 in an ATG13-dependent manner, placing ATG13 as the bridge between ATG101 and ULK1 in the initiation complex.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, siRNA knockdown, western blot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, Co-IP with functional follow-up but limited orthogonal methods\",\n      \"pmids\": [\"19287211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In yeast, the Atg1-Atg13 signaling complex governs retrograde transport of Atg9 and Atg23 from the pre-autophagosomal structure (PAS); Atg1 kinase activity is required specifically for Atg23 retrieval, while Atg9 recycling additionally requires Atg18 and Atg2.\",\n      \"method\": \"Genetic epistasis, fluorescence microscopy of Atg9/Atg23 trafficking, Atg1 kinase-dead mutants\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with live-cell trafficking analysis and kinase-dead mutants in yeast\",\n      \"pmids\": [\"14723849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In yeast, Atg17 physically associates with the Atg1-Atg13 complex; Atg17 binding to Atg1 requires Atg13 as an intermediary (Atg17-Atg1 interaction is lost in atg13Δ cells). A point mutation in Atg17 (C24R) reduces Atg13 affinity, impairs Atg1 kinase activity, and causes autophagy defects, demonstrating that Atg17-Atg13 complex formation is required for normal autophagosome formation and Atg1 activation.\",\n      \"method\": \"Two-hybrid, co-immunoprecipitation, atg13Δ epistasis, Atg17 point mutant analysis, autophagy assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus genetic epistasis plus point-mutant functional analysis\",\n      \"pmids\": [\"15743910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Drosophila, Atg1 and Atg13 form a complex; Atg13 phosphorylation is greatest under autophagic (starvation) conditions rather than being inhibitory as in yeast, and phosphorylation does not prevent Atg1-Atg13 association. Atg13 stimulates Atg1 autophagic activity and Atg1's inhibition of TOR signaling, in part by disrupting normal TOR trafficking. Excess Atg13 paradoxically inhibits autophagosome expansion.\",\n      \"method\": \"Genetic knockout, in vivo co-immunoprecipitation, epistasis, phosphorylation analysis in TOR/Atg1 kinase-dependent conditions\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO of both Atg1 and Atg13 with epistasis, reciprocal Co-IP, and phosphorylation analysis in Drosophila\",\n      \"pmids\": [\"19225150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In yeast, both the Tor and PKA signaling pathways independently phosphorylate Atg13 to regulate autophagy. PKA directly phosphorylates Atg13 at sites distinct from Tor phosphorylation sites, and these PKA phosphorylation events regulate Atg13 localization to the preautophagosomal structure (PAS).\",\n      \"method\": \"In vitro kinase assay (PKA phosphorylation of Atg13), phosphorylation-site mutant analysis, PAS localization by fluorescence microscopy, genetic pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay demonstrating direct PKA phosphorylation plus mutant localization studies\",\n      \"pmids\": [\"19805182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In yeast, TORC1 directly phosphorylates Atg13 on at least eight serine residues. Expression of an unphosphorylatable Atg13 mutant (Atg13-8SA) bypasses the TORC1 pathway to induce autophagy in vegetatively growing cells, demonstrating that Atg13 dephosphorylation is a molecular switch for autophagy induction and Atg1 complex formation.\",\n      \"method\": \"In vitro TORC1 kinase assay, site-directed mutagenesis (8SA mutant), autophagy reporter assays, Atg1 complex formation analysis, PAS organization assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus bypass-of-pathway mutagenesis with multiple functional readouts\",\n      \"pmids\": [\"20383061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Hsp90-Cdc37 chaperone complex stabilizes and activates ULK1, which in turn phosphorylates ATG13 causing its release from ULK1 and recruitment to damaged mitochondria. Hsp90-Cdc37, ULK1, and ATG13 phosphorylation are all required for efficient mitochondrial clearance (mitophagy).\",\n      \"method\": \"Co-immunoprecipitation, pharmacological Hsp90 inhibition, phosphorylation analysis, mitochondrial clearance assays, siRNA knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional KD/inhibition with specific mitophagy phenotype, direct phosphorylation consequence shown\",\n      \"pmids\": [\"21855797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATG13 function in autophagy strictly depends on FIP200 binding; an ATG13-deficient cell line demonstrates that ATG13 is indispensable for autophagy induction. Furthermore, a short C-terminal peptide motif of ATG13 mediates ULK1/2 binding, but a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity, indicating ATG13 has ULK1/2-independent functions mediated through FIP200.\",\n      \"method\": \"ATG13 knockout cells, domain-deletion and point-mutant reconstitution, autophagy flux assays, co-immunoprecipitation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells reconstituted with domain mutants plus multiple autophagy readouts, replicated in two studies (PMID:22024743 and PMID:26213203)\",\n      \"pmids\": [\"22024743\", \"26213203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The N-terminal domain of Atg13 adopts a HORMA (Hop1, Rev7, Mad2) fold revealed at 2.3-Å resolution by X-ray crystallography. This HORMA domain is required for autophagy and for recruitment of the PI 3-kinase subunit Atg14 to the PAS, but is not required for Atg1 interaction or Atg13 recruitment to the PAS. Two conserved Arg residues in the HORMA domain (putative phosphate sensors) are essential for autophagy and Atg14 recruitment.\",\n      \"method\": \"X-ray crystallography (2.3 Å), yeast mutant analysis, autophagy assays, Atg14 localization assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at high resolution combined with site-directed mutagenesis and multiple functional assays in yeast\",\n      \"pmids\": [\"23509291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATG13 interacts with all three human LC3 isoforms (LC3A, LC3B, LC3C) via its LIR (LC3-interacting region) motif. Crystal structures of LC3A and LC3C complexed with the ATG13 LIR reveal that the side-chain of Lys49 in LC3 acts as a gatekeeper regulating LIR binding; mutation of Lys49 in LC3A significantly reduces LC3A-positive puncta formation.\",\n      \"method\": \"X-ray crystallography (LC3-ATG13 LIR complex structures), in vitro binding assays, cell-based LC3 puncta formation assay with Lys49 mutants\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of complexes plus mutagenesis validated in cells\",\n      \"pmids\": [\"24290141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The N-terminal HORMA domain of Atg13 directly binds Atg9 (a multispanning membrane protein on Atg9 vesicles). HORMA domain mutants unable to interact with Atg9 impair PAS localization of Atg9 vesicles and cause severe defects in starvation-induced autophagy. Thus, the Atg13 HORMA domain recruits Atg9 vesicles to the PAS as a mechanistically distinct step from complex scaffold formation by the C-terminal disordered region.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, fluorescence microscopy of Atg9 localization, autophagy assays with HORMA domain point mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP plus point-mutant functional analysis with localization and autophagy readouts\",\n      \"pmids\": [\"25737544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The human ATG13 HORMA domain and the full-length HORMA-domain-only protein ATG101 form a heterodimer whose crystal structure reveals an architecture conserved with the Mad2 conformational heterodimer and S. pombe Atg13-Atg101. The WF finger motif essential for ATG101 function is sequestered in a hydrophobic pocket, suggesting regulated exposure. Conserved hydrophobic pockets in the dimer surface are suggestive of additional protein-interaction sites.\",\n      \"method\": \"X-ray crystallography of human ATG13-ATG101 HORMA heterodimer\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with structural-functional analysis of the WF finger and interaction surfaces\",\n      \"pmids\": [\"26299944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"mTOR directly phosphorylates ATG13 on Ser-258, while Ser-224 is modulated by the AMPK pathway. In ATG13-knockout cells reconstituted with unphosphorylatable ATG13, ULK1 kinase activity is more potent and starvation-induced ATG13/ULK1 translocation and autophagy are accelerated. Thus, ATG13 phosphorylation by mTOR and AMPK inhibits autophagy initiation.\",\n      \"method\": \"In vitro mTOR kinase assay, ATG13-KO cell reconstitution with phospho-mutants, ULK1 kinase activity assays, translocation analysis by imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay showing direct mTOR phosphorylation, KO reconstitution with phospho-mutants and multiple functional readouts\",\n      \"pmids\": [\"26801615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Atg13 contains a large intrinsically disordered region (IDR) with two distinct binding sites for Atg17 that mediate intercomplex linkages between Atg17-Atg29-Atg31 subcomplexes, driving supramolecular self-assembly of multiple Atg1 complexes. This assembly promotes Atg1 autophosphorylation, Atg9 vesicle recruitment, and Atg9 phosphorylation by Atg1.\",\n      \"method\": \"X-ray crystallography, NMR, in vitro reconstitution of Atg1 complex assembly, yeast PAS organization assays, high-speed atomic force microscopy\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural and biochemical reconstitution plus in vivo PAS assays with multiple orthogonal methods\",\n      \"pmids\": [\"27404361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PP2A phosphatases (PP2A-Cdc55 and PP2A-Rts1), activated upon TORC1 inactivation, are required for sufficient Atg13 dephosphorylation and consequent autophagy induction. Overexpression of non-phosphorylatable Atg13 suppresses autophagy defects in PP2A mutants, placing PP2A-mediated Atg13 dephosphorylation upstream of Atg1 kinase activation and PAS formation.\",\n      \"method\": \"PP2A deletion mutant analysis, Atg13 phosphorylation-state western blot, PAS formation assay, epistasis with non-phosphorylatable Atg13\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with phospho-mutant bypass and multiple autophagy readouts, single lab\",\n      \"pmids\": [\"27973551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Atg13 promotes formation of a specific Atg1-Atg1 self-interaction in yeast. This Atg1 homodimerization is correlated with autophagy induction, is required for Atg1 kinase activity, and facilitates autophosphorylation of Thr-226 in the Atg1 activation loop. Disruption of the Atg1-Atg1 complex results in diminished autophagy and Atg1 activity.\",\n      \"method\": \"Co-immunoprecipitation of Atg1-Atg1 complex, in vitro kinase assay, heterologous dimerization domain fusion, phosphorylation-site mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase assay plus heterologous dimerization rescue, single lab\",\n      \"pmids\": [\"21712380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal intrinsically disordered region (IDR) of yeast Atg13 directly binds phospholipid membranes via electrostatic interactions (positively charged residues) and hydrophobic insertion of a Phe residue. Two sets of IDR residues mediating phospholipid binding overlap with the Vac8-binding domain, making Atg13 binding to phospholipids and Vac8 mutually exclusive; both interactions are required for efficient autophagy.\",\n      \"method\": \"Lipid-binding assays, isothermal titration calorimetry (ITC), circular dichroism, mutagenesis of binding residues, yeast autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical binding assays (ITC + lipid binding) combined with mutagenesis and functional yeast assays\",\n      \"pmids\": [\"31352862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The dynamic Atg13-free conformation of the Atg1 EAT domain is required for phagophore expansion. Atg1 is present on autophagic puncta at ~twice the stoichiometry of Atg13. An EAT domain mutant (ATG1DD) that selectively disrupts the Atg13-free state shows reduced PAS formation and fails to support phagophore expansion, demonstrating a second EAT domain function independent of Atg13.\",\n      \"method\": \"Crystal structure analysis, isothermal titration calorimetry, quantitative and superresolution microscopy, structure-based mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-informed mutagenesis validated by quantitative/superresolution microscopy and ITC\",\n      \"pmids\": [\"29540529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LUBAC (E3 ubiquitin ligase complex, via RNF31/HOIP) mediates linear ubiquitination of ATG13 at the phagophore. OTULIN deubiquitinase counteracts this modification. In OTULIN-knockdown cells, excessively ubiquitinated ATG13 accumulates at the phagophore and blocks autophagosome maturation. LUBAC activity promotes autophagy initiation, while OTULIN is required for maturation.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-based ubiquitination assays plus KD with defined maturation phenotype, single lab\",\n      \"pmids\": [\"32543267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDK1/cyclin B phosphorylates both ULK1 and ATG13 during mitosis. CDK1-induced ULK1-ATG13 phosphorylation promotes mitotic autophagy and cell cycle progression. Double knockout of ULK1 and ATG13 blocks cell cycle progression and decreases cancer cell proliferation in cell line and mouse models.\",\n      \"method\": \"Mass spectrometry phospho-mapping, site-directed mutagenesis, CDK1 kinase assays, ULK1/ATG13 double-KO cells and mouse xenograft models\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mass spectrometry plus in vitro CDK1 kinase assay plus mutagenesis plus in vivo tumor model\",\n      \"pmids\": [\"32516310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG9A interacts with the ATG13-ATG101 dimer independently of ULK1, as shown by split-mVenus and knockout/reconstitution approaches. Deletion of ATG13 or ATG101 causes aberrant accumulation of ATG9A at stalled p62/ubiquitin clusters, rescuable by a ULK1 binding-deficient ATG13 mutant, establishing a ULK1-independent ATG13-ATG101-ATG9A axis that regulates ATG9A distribution.\",\n      \"method\": \"BioID quantitative proteomics, knockout/reconstitution, split-mVenus protein-protein interaction assay, fluorescence microscopy\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID plus split-mVenus plus KO/reconstitution with mutant rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34369648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In yeast, Mec1 (DNA damage sensor kinase) directly binds Atg13 through a Mec1-Binding Region (MBR) on Atg13 and an Atg13-Binding Region (ABR) on Mec1. Disruption of MBR or ABR impairs recruitment of both Mec1 and Atg13 to the PAS and blocks glucose starvation-induced autophagy, placing this direct Mec1-Atg13 interaction upstream of PAS assembly.\",\n      \"method\": \"In vitro direct binding assay, deletion/point mutant analysis, PAS localization by fluorescence microscopy, autophagy assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding plus mutant-based epistasis with localization and functional readouts\",\n      \"pmids\": [\"36574691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In yeast, autophagy termination during persistent starvation is mediated by re-phosphorylation of Atg13 by the Atg1 protein kinase (also modulated by PP2C phosphatases), leading to PAS dispersal. A vacuolar membrane protein Tag1 is required for this termination; tag1Δ cells show defective Atg13 re-phosphorylation and persistent PAS.\",\n      \"method\": \"Genetic screen, Atg13 phosphorylation western blot analysis, PAS microscopy in tag1Δ and Atg1 kinase-dead mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen plus phosphorylation analysis plus microscopy, single lab\",\n      \"pmids\": [\"33536246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cdc14 phosphatase dephosphorylates Atg13 in a spatiotemporally controlled manner during meiotic anaphase I and II (following Cdc14 relocalization from nucleolus to cytoplasm), stimulating Atg1 kinase activity and autophagy to support meiotic progression and sporulation.\",\n      \"method\": \"In vitro Cdc14 phosphatase assay, subcellular localization analysis, meiotic autophagy assays, Atg13 phosphorylation state analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphatase assay plus spatiotemporal localization evidence plus functional meiotic autophagy readouts\",\n      \"pmids\": [\"35238874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Comprehensive phospho-mapping identifies 48 in vivo phosphorylation sites on yeast Atg13. Reciprocal phospho-mimetic and phospho-deficient mutants reveal that dynamic phospho-regulation of Atg13 is critical: insufficient or excessive autophagy from disrupted regulation are both detrimental to cell survival. Atg11 is found to contribute to bulk autophagy even during nitrogen starvation by cooperating with Atg1 in driving phase separation of the PAS.\",\n      \"method\": \"In vivo phosphoproteomics (MS), reciprocal phospho-mutant (mimetic and non-phosphorylatable) analysis, PAS formation assays, epistasis with Atg11\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mass spectrometry phospho-mapping plus reciprocal mutagenesis plus epistasis, multiple orthogonal readouts\",\n      \"pmids\": [\"38233718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PM2.5-induced downregulation of ALKBH5 promotes m6A methylation of ATG13 mRNA at site 767, enhancing ATG13 expression and ULK complex-regulated autophagy and epithelial inflammation in lung cells.\",\n      \"method\": \"m6A methylation analysis (MeRIP), ALKBH5 knockout mice, ATG13 m6A site mutagenesis, western blot, NF-κB/NLRP3 signaling readouts\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct m6A mapping plus KO mouse model plus site-specific mutagenesis, single lab\",\n      \"pmids\": [\"37295326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LPS induces proteasomal degradation of ATG13 in hepatic stellate cells via p38 MAPK activation. Atg13 knockdown markedly inhibits autophagy and promotes LPS-induced inflammation. Ubiquitination of ATG13 leading to proteasomal degradation is dependent on p38 MAPK, positioning Atg13 as a mediator between autophagy and proteasomal pathways.\",\n      \"method\": \"Co-immunoprecipitation (ubiquitination assay), p38 MAPK inhibition, siRNA knockdown, proteasome inhibitor treatment, western blot\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP ubiquitination assay with pharmacological and siRNA perturbations, single lab\",\n      \"pmids\": [\"36148140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERK1/2 associates with ATG13 and FIP200 upon glucose starvation; ATG13 and FIP200 contain ERK consensus phosphorylation sites. Phospho-defective ATG13 mutants block glucose starvation-induced autophagy and sensitize renal cells to hypoglycemia-induced death, while phospho-mimetic ATG13 mutants induce autophagy and protect cells.\",\n      \"method\": \"Co-immunoprecipitation (ERK1/2-ATG13 interaction), phospho-defective/mimetic mutant reconstitution, autophagy flux assays, cell viability assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus phospho-mutant reconstitution, single lab, limited orthogonal methods\",\n      \"pmids\": [\"33682133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSBP1 (a small coiled-coil protein) physically interacts with FIP200 and ATG13 (binding via FIP200). HSBP1 depletion reduces stability of ULK kinase complex subunits and impairs autophagy induction. The FIP200-ATG13 subcomplex negatively regulates HSBP1's pro-picornaviral function during infections.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/CRISPR knockdown/knockout, autophagy induction assays, viral replication assays\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus KD/KO with autophagy and viral replication phenotypes, single lab\",\n      \"pmids\": [\"34869056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Live imaging and mathematical modeling of ATG13 translocation reveal that in nonselective autophagy ATG13 recruitment follows a normal distribution of intensity/duration, while mitophagy involves multiple, oscillatory ATG13 translocations whose number is directly proportional to the diameter of targeted mitochondrial fragments, consistent with successive phagophore nucleation events.\",\n      \"method\": \"Live fluorescence imaging, mathematical modeling, wortmannin perturbation, ivermectin-induced mitophagy model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — live imaging with mathematical modeling validated by chemical perturbation, single lab\",\n      \"pmids\": [\"32320309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AlphaFold-based structure prediction and in vitro validation establish that the intrinsically disordered region of ATG13 engages the bases of two UBL domains in the FIP200 dimer via two phenylalanines, and also binds the tandem MIT domain of ULK1, yielding a 1:1:2 stoichiometry for the ULK1-ATG13-FIP200 core complex. Each pairwise interaction (ULK1-ATG13, ATG13-FIP200) additively contributes to autophagic flux.\",\n      \"method\": \"AlphaFold structure prediction, in vitro binding assays with point mutants, co-immunoprecipitation in cells, autophagy flux assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structure-guided mutagenesis, direct in vitro binding validation, and cell-based functional assays with additive mutant analysis\",\n      \"pmids\": [\"40552710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The RNA-binding protein YBX3 interacts with and stabilizes ATG13 mRNA via its 3' UTR, increasing ATG13 protein expression. YBX3 depletion reduces ATG13 mRNA and protein levels in multiple human cell lines, identifying posttranscriptional mRNA stabilization as a regulatory mechanism for ATG13 abundance.\",\n      \"method\": \"RNA immunoprecipitation (RIP), mRNA stability assays, 3' UTR reporter assays, YBX3 depletion with western blot/qPCR readouts\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus 3' UTR functional assay plus protein/mRNA measurement across multiple cell lines, single lab\",\n      \"pmids\": [\"39414370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATG13:ATG101 HORMA dimer forms a tight complex with WIPI3 (and WIPI2). Bound to WIPIs, ATG13:ATG101 aligns with membranes and inserts the ATG101 WF finger into the membrane. A PVP motif within the ULK1 IDR docks onto the ATG13:ATG101 HORMA surface, bringing the ULK1 kinase domain near the membrane for substrate phosphorylation. WIPI3:ATG13 engagement is required for ATG16L1 phosphorylation by ULK1, ATG13 puncta formation, and bulk autophagic flux.\",\n      \"method\": \"Biochemical reconstitution, molecular dynamics simulations, cell-based autophagy and phosphorylation assays, pulldown assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution plus MD simulations plus multiple cell-based functional assays; preprint but mechanistically novel\",\n      \"pmids\": [\"bio_10.1101_2025.11.07.687251\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ULK1 phosphorylates ATG101, triggering ATG101 homo-dimerization that dramatically accelerates ATG101 association with ATG13 and ATG9A to form the ATG9A-ATG13-ATG101 initiation complex. ATG101 dimers create a positive autocatalytic feedback propagating activation independently of further ULK1 activity, and this memory of activation persists for hours after dephosphorylation.\",\n      \"method\": \"Interaction kinetics measurements, biochemical reconstitution, ULK1 in vitro phosphorylation assay, homo-dimerization analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biochemical reconstitution and kinetics in a preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.27.661946\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In C. elegans, the divergent ATG13 homolog EPG-1 (encoded by epg-1) directly interacts with the C. elegans Atg1 homolog UNC-51 and is required for autophagy-regulated processes including degradation of aggregate-prone proteins and survival under starvation.\",\n      \"method\": \"Genetic loss-of-function, co-immunoprecipitation (EPG-1 with UNC-51), autophagy phenotype assays in C. elegans\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus genetic KO phenotype in C. elegans, single lab\",\n      \"pmids\": [\"19377305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C. elegans, EPG-9 (ATG101 homolog) directly interacts with EPG-1 (ATG13 homolog) and is essential for autophagic degradation of protein aggregates and animal survival under starvation, establishing a conserved ATG101-ATG13 interaction across metazoans.\",\n      \"method\": \"Direct in vitro binding assay, genetic loss-of-function in C. elegans, autophagy phenotype assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro binding plus genetic KO in C. elegans, single lab\",\n      \"pmids\": [\"22885670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Transmembrane mitophagy receptors BNIP3 and NIX can initiate autophagosome biogenesis via a WIPI-ATG13 complex independently of the FIP200/ULK1 complex, establishing that ATG13 participates in a ULK1-independent membrane recruitment pathway for selective mitophagy.\",\n      \"method\": \"Biochemical reconstitution, knockout/rescue experiments, localization assays, autophagy flux measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — reconstitution and cell-based assays in a preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.08.28.609967\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATG13 is a central scaffold of the autophagy initiation machinery that constitutively assembles with ULK1/2, FIP200, and ATG101 into a ~3-MDa complex; mTORC1 (phosphorylating ATG13 at Ser-258) and AMPK (at Ser-224) suppress autophagy by phosphorylating ATG13, while dephosphorylation by PP2A activates autophagy, with PKA and CDK1 providing additional independent phospho-regulatory inputs. Structurally, ATG13 contains an N-terminal HORMA domain (whose conserved Arg residues recruit PI3-kinase subunit Atg14 and whose surface engages ATG101 in a regulated Mad2-like heterodimer) and a large intrinsically disordered C-terminal region that binds ULK1, FIP200, Atg17, Atg8/LC3 via a LIR motif, and negatively charged phospholipid membranes; the ATG13:ATG101 HORMA dimer further binds WIPI2/3 to anchor the complex to PI3P-enriched membranes and position ULK1 for substrate phosphorylation. ATG13 also recruits Atg9 vesicles to the PAS via its HORMA domain and, independently of ULK1, forms an ATG13-ATG101 subcomplex that regulates ATG9A distribution; LUBAC-mediated linear ubiquitination and proteasomal (p38 MAPK-dependent) degradation of ATG13 provide additional post-translational control, while YBX3 stabilizes ATG13 mRNA to maintain protein levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATG13 is a central scaffold of the autophagy initiation machinery, assembling with ULK1/2 and FIP200 into a constitutive ~3-MDa complex whose activity is gated by nutrient signaling and which is essential for autophagosome formation [#0]. ATG13 and FIP200 together stimulate ULK1 kinase activity and direct ULK1 to the pre-autophagosomal structure, and ATG13 also serves as the obligate bridge that incorporates ATG101 into the complex and stabilizes it [#1, #2, #3]. Architecturally the protein is bipartite: an N-terminal HORMA domain whose conserved Arg residues recruit the PI3-kinase subunit Atg14 and which directly binds Atg9 vesicles to deliver them to the PAS, and a large C-terminal intrinsically disordered region that engages ULK1, FIP200, Atg17, LC3 via a LIR motif, and acidic phospholipid membranes [#11, #12, #13, #19, #33]. The ATG13 HORMA domain pairs with ATG101 in a Mad2-like conformational heterodimer that anchors the complex to PI3P-enriched membranes through WIPI3/WIPI2 binding and positions the ULK1 kinase domain for substrate phosphorylation [#14, #35]. ATG13 activity is set by reversible phosphorylation: mTORC1 (Ser-258) and AMPK (Ser-224) phosphorylate ATG13 to inhibit initiation, while dephosphorylation switches autophagy on, with additional kinase inputs from PKA, CDK1/cyclin B during mitosis, and Mec1 coupling autophagy to nutrient and DNA-damage states [#15, #7, #22, #24]. Beyond the canonical complex, an ATG13-ATG101 subcomplex regulates ATG9A distribution independently of ULK1, and ATG13 abundance is further controlled post-translationally by linear ubiquitination and proteasomal degradation and post-transcriptionally by mRNA stabilization [#23, #21, #29, #34]. ATG13 function is broadly conserved from yeast Atg13 through Drosophila and C. elegans EPG-1 [#5, #6, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the mammalian autophagy initiation complex and its nutrient control: whether ATG13 acted within a stable complex and how nutrients controlled it was unknown; the work defined a constitutive ULK1-ATG13-FIP200 assembly directly phosphorylated by mTORC1.\",\n      \"evidence\": \"Co-IP, gel filtration, siRNA, rapamycin/starvation and in-cell phosphorylation in mammalian cells\",\n      \"pmids\": [\"19211835\", \"19258318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of subunit contacts\", \"Did not identify the specific mTORC1 phosphosites\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined ATG13/FIP200 as activators of ULK1: it was unclear how the complex tuned kinase output; reconstitution showed both subunits are required for maximal ULK1 activity, localization, and stability.\",\n      \"evidence\": \"In vitro kinase reconstitution plus cellular Co-IP and microscopy\",\n      \"pmids\": [\"19258318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of kinase stimulation not structurally defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed ATG13 as the scaffold for ATG101 incorporation: the metazoan-specific ATG101 lacked a known assembly route; ATG13 was shown to be required for ATG101 to join and stabilize the complex.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA, localization and proteasome-inhibition assays in mammalian cells\",\n      \"pmids\": [\"19597335\", \"19287211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ATG13-ATG101 interface not yet defined\", \"How ATG101 reciprocally stabilizes ATG13 mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated Atg13 dephosphorylation as the molecular switch for autophagy: it was unclear whether TORC1 phosphorylation directly gated Atg1 complex assembly; an unphosphorylatable mutant bypassed TORC1 to induce autophagy.\",\n      \"evidence\": \"In vitro TORC1 kinase assay and 8SA-mutant bypass in yeast\",\n      \"pmids\": [\"20383061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase responsible for dephosphorylation not identified here\", \"Direct mammalian sites not yet mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed the HORMA fold as a distinct functional module: domain assignment for ATG13's N-terminus was unknown; crystallography defined a HORMA domain with conserved Arg residues required for Atg14 recruitment but not Atg1 binding.\",\n      \"evidence\": \"X-ray crystallography (2.3 Å) plus yeast mutant and localization assays\",\n      \"pmids\": [\"23509291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Arg residues bind phosphate directly was not demonstrated\", \"HORMA conformational dynamics not characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified ATG13 as a direct LC3-family interactor: it was unknown whether ATG13 itself binds Atg8-family proteins; structures showed LIR-mediated binding to LC3A/B/C gated by an LC3 Lys49 gatekeeper.\",\n      \"evidence\": \"Crystal structures of LC3-ATG13 LIR complexes and cell-based puncta assays\",\n      \"pmids\": [\"24290141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the LIR in autophagosome formation not fully dissected\", \"Isoform selectivity in vivo not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Assigned the HORMA domain a vesicle-recruitment role: how Atg9 vesicles reach the PAS was unclear; the Atg13 HORMA domain was shown to directly bind Atg9 and deliver vesicles, distinct from C-terminal scaffolding.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, localization and HORMA point-mutant autophagy assays\",\n      \"pmids\": [\"25737544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atg9 binding surface on HORMA not structurally mapped\", \"Coordination with ATG101 in vesicle recruitment not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the ATG13-ATG101 HORMA heterodimer architecture: how the two HORMA proteins assemble was unknown; the structure revealed a Mad2-like dimer with a sequestered WF finger suggesting regulated exposure.\",\n      \"evidence\": \"X-ray crystallography of the human ATG13-ATG101 HORMA heterodimer\",\n      \"pmids\": [\"26299944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for WF finger exposure not identified\", \"Functional partners docking on the hydrophobic pockets not yet found\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the inhibitory mammalian phosphosites: the direct mTOR/AMPK targets on ATG13 were undefined; Ser-258 (mTOR) and Ser-224 (AMPK) were shown to suppress autophagy via ULK1 activity.\",\n      \"evidence\": \"In vitro mTOR kinase assay and ATG13-KO reconstitution with phospho-mutants\",\n      \"pmids\": [\"26801615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing these sites in mammals not identified here\", \"Full mammalian phosphosite map incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the IDR drives supramolecular complex self-assembly: how Atg1 complexes oligomerize at the PAS was unclear; the Atg13 IDR was found to carry two Atg17 sites linking subcomplexes and promoting Atg1 autophosphorylation and Atg9 recruitment.\",\n      \"evidence\": \"Crystallography, NMR, in vitro reconstitution, PAS assays, and HS-AFM in yeast\",\n      \"pmids\": [\"27404361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian ATG13 IDR mediates equivalent multimerization not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined direct membrane engagement by the IDR: it was unknown whether Atg13 itself contacts lipid; the C-terminal IDR was shown to bind phospholipids electrostatically and via a Phe insertion, mutually exclusive with Vac8.\",\n      \"evidence\": \"ITC, lipid-binding, CD, and mutagenesis with yeast autophagy assays\",\n      \"pmids\": [\"31352862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo membrane-binding kinetics not resolved\", \"Mammalian conservation of the membrane-binding residues not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established additional independent phospho-inputs: beyond TOR, whether other kinases regulate Atg13 was unknown; PKA was shown to directly phosphorylate Atg13 at distinct sites controlling PAS localization.\",\n      \"evidence\": \"In vitro PKA kinase assay, phospho-site mutants, PAS localization in yeast\",\n      \"pmids\": [\"19805182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of PKA and TOR inputs not quantified\", \"Mammalian PKA control of ATG13 not established here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the activating phosphatase: how dephosphorylation is achieved after TORC1 inactivation was unclear; PP2A-Cdc55/Rts1 were shown to be required for Atg13 dephosphorylation and autophagy induction.\",\n      \"evidence\": \"PP2A deletion-mutant epistasis with non-phosphorylatable Atg13 in yeast\",\n      \"pmids\": [\"27973551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct PP2A action on Atg13 not shown by in vitro phosphatase assay\", \"Mammalian phosphatase counterpart not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked ATG13 phosphorylation to selective mitophagy: how ATG13 contributes to mitochondrial clearance was unknown; Hsp90-Cdc37-stabilized ULK1 phosphorylates ATG13 driving its release and recruitment to damaged mitochondria.\",\n      \"evidence\": \"Co-IP, Hsp90 inhibition, phosphorylation and mitochondrial clearance assays\",\n      \"pmids\": [\"21855797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite mediating release not mapped\", \"Mitochondrial receptor coupling not defined here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected ATG13 to Atg1 homodimerization: the mechanism by which Atg13 activates Atg1 was unclear; Atg13 was shown to promote an Atg1-Atg1 self-interaction required for kinase activity and activation-loop autophosphorylation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, heterologous dimerization rescue in yeast\",\n      \"pmids\": [\"21712380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of the dimer not resolved\", \"Conservation in mammalian ULK1 not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated FIP200- and ULK1-dependent functions: whether ATG13 acts solely through ULK1 was unknown; KO reconstitution showed FIP200 binding is essential while ULK1-binding-deficient ATG13 partially rescues, revealing ULK1-independent roles.\",\n      \"evidence\": \"ATG13-KO cells with domain-mutant reconstitution and flux assays\",\n      \"pmids\": [\"22024743\", \"26213203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the ULK1-independent FIP200 function not defined here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Added cell-cycle phospho-control: whether autophagy initiation is coupled to mitosis was unknown; CDK1/cyclin B was shown to phosphorylate ULK1 and ATG13 to promote mitotic autophagy and proliferation.\",\n      \"evidence\": \"MS phospho-mapping, CDK1 kinase assay, ULK1/ATG13 double-KO cells and xenografts\",\n      \"pmids\": [\"32516310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate consequences of mitotic ATG13 phosphosites not detailed\", \"Relationship to mTOR/AMPK sites unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed ubiquitin control at the phagophore: how ATG13 is modified during maturation was unknown; LUBAC linear-ubiquitinates ATG13 (countered by OTULIN) to balance initiation versus maturation.\",\n      \"evidence\": \"siRNA, Co-IP, co-localization and ubiquitination assays\",\n      \"pmids\": [\"32543267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Ubiquitinated lysines not mapped\", \"Mechanism linking ubiquitination to maturation block unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a ULK1-independent ATG13-ATG101-ATG9A axis: whether the HORMA dimer functions outside the ULK1 complex was unknown; the dimer was shown to bind ATG9A independently of ULK1 and regulate its distribution.\",\n      \"evidence\": \"BioID, split-mVenus, KO/reconstitution with ULK1-binding-deficient mutant rescue\",\n      \"pmids\": [\"34369648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of altered ATG9A distribution incompletely defined\", \"Direct ATG9A-HORMA contact not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Coupled DNA-damage sensing to PAS assembly: whether Mec1 acts directly on Atg13 was unknown; a direct Mec1-Atg13 interaction via defined MBR/ABR regions was shown to be required for PAS recruitment and starvation autophagy.\",\n      \"evidence\": \"In vitro binding, deletion/point mutants, PAS localization and autophagy assays in yeast\",\n      \"pmids\": [\"36574691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Mec1 phosphorylates Atg13 at the PAS not established\", \"Mammalian conservation unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined autophagy termination via Atg13 re-phosphorylation: how prolonged autophagy is switched off was unknown; Atg1-mediated Atg13 re-phosphorylation (with PP2C and the vacuolar protein Tag1) was shown to disperse the PAS.\",\n      \"evidence\": \"Genetic screen, phosphorylation western blots, PAS microscopy in tag1Δ/kinase-dead mutants\",\n      \"pmids\": [\"33536246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Tag1 mechanism of action on Atg13 unresolved\", \"Mammalian termination pathway not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended phosphatase control to meiosis: developmental regulation of Atg13 was unknown; Cdc14 was shown to dephosphorylate Atg13 in a spatiotemporal manner during meiotic anaphase to stimulate autophagy.\",\n      \"evidence\": \"In vitro Cdc14 phosphatase assay, localization and meiotic autophagy assays in yeast\",\n      \"pmids\": [\"35238874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cdc14 target sites on Atg13 not mapped\", \"Relationship to PP2A control unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a comprehensive phospho-map and a balance principle: the full phospho-regulatory landscape was undefined; 48 Atg13 sites were mapped and reciprocal mutants showed both insufficient and excessive autophagy are detrimental.\",\n      \"evidence\": \"In vivo phosphoproteomics, reciprocal phospho-mutants, PAS assays, Atg11 epistasis in yeast\",\n      \"pmids\": [\"38233718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase assignment for individual sites incomplete\", \"Mammalian equivalence of the 48-site map unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the core complex stoichiometry and interfaces: precise architecture of the ULK1-ATG13-FIP200 core was unknown; structure prediction plus validation established a 1:1:2 complex with ATG13 IDR engaging FIP200 UBL bases and the ULK1 MIT domain.\",\n      \"evidence\": \"AlphaFold prediction, in vitro binding with point mutants, cellular Co-IP and flux assays\",\n      \"pmids\": [\"40552710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length experimental structure not determined\", \"Dynamics of the IDR contacts not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined membrane anchoring and kinase positioning by WIPI binding: how the HORMA dimer couples to PI3P membranes and orients ULK1 was unknown; ATG13:ATG101 was shown to bind WIPI3/WIPI2, insert the ATG101 WF finger into membrane, and dock a ULK1 PVP motif to position the kinase for ATG16L1 phosphorylation.\",\n      \"evidence\": \"Biochemical reconstitution, MD simulations, cell-based phosphorylation and flux assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.07.687251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"In vivo confirmation of WF finger membrane insertion limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established post-transcriptional control of ATG13 abundance: how ATG13 protein levels are set was undefined; YBX3 was shown to bind and stabilize ATG13 mRNA via its 3' UTR.\",\n      \"evidence\": \"RIP, mRNA stability and 3' UTR reporter assays, YBX3 depletion across cell lines\",\n      \"pmids\": [\"39414370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological contexts where this control dominates unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many phospho-, ubiquitin-, and abundance-control inputs are integrated to set a quantitatively correct autophagic response in mammalian cells, and the mechanistic basis of the proposed ATG101-dimerization feedback memory, remain open.\",\n      \"evidence\": \"No single study in the corpus integrates the regulatory layers; the ATG101 autocatalytic feedback model rests on a preprint\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cross-talk between kinase/phosphatase, ubiquitin, and mRNA-stability inputs not reconciled\", \"ATG101-dimerization memory model awaits peer review and in vivo validation\", \"Mammalian phosphosite-specific kinase/phosphatase assignments incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 10, 33]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005776\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 10, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 8, 15]}\n    ],\n    \"complexes\": [\n      \"ULK1-ATG13-FIP200 (ULK initiation complex)\",\n      \"ATG13-ATG101 HORMA heterodimer\",\n      \"Atg1-Atg13-Atg17 complex (yeast)\"\n    ],\n    \"partners\": [\n      \"ULK1\",\n      \"FIP200\",\n      \"ATG101\",\n      \"ATG9A\",\n      \"WIPI3\",\n      \"WIPI2\",\n      \"LC3B\",\n      \"Atg17\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}