{"gene":"ATG14","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2008,"finding":"Human ATG14 (mammalian homologue of yeast Atg14) forms a distinct class III PI3-kinase complex with Beclin 1, Vps34, and p150 that is mutually exclusive with UVRAG-containing complexes. ATG14 localizes to autophagic isolation membranes and its coiled-coil region required for binding Vps34 and Beclin 1 is essential for autophagosome formation; silencing ATG14 in HeLa cells suppresses autophagosome formation.","method":"Co-immunoprecipitation, subcellular fractionation/localization by fluorescence microscopy, siRNA knockdown with autophagosome formation readout, computational homology identification","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, live-cell imaging, functional KD phenotype, replicated across multiple subsequent studies","pmids":["18843052"],"is_preprint":false},{"year":2009,"finding":"ATG14L and UVRAG bind to Beclin 1 in a mutually exclusive manner, defining at least three distinct Beclin 1 complexes. GFP-ATG14L localizes to the isolation membrane, autophagosome, and ER. Knockout of ATG14L in mouse ES cells causes a defect in autophagosome formation.","method":"Co-immunoprecipitation, GFP-tagged protein localization by fluorescence microscopy, ATG14L knockout in mouse ES cells with autophagosome formation assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with specific phenotype, live imaging, replicated in independent simultaneous publication (PMID:19270693)","pmids":["19270696"],"is_preprint":false},{"year":2009,"finding":"ATG14L (Atg14L) enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity. ATG14L and Beclin 1 synergistically promote formation of double-membraned organelles associated with Atg5 and Atg12.","method":"In vivo biochemistry (large Beclin 1 complex characterization), PI3-kinase lipid kinase assay, immunofluorescence for double-membrane organelle formation, mouse genetics","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro lipid kinase assay, mouse genetics, orthogonal biochemical and cell biology methods, replicated in parallel publication","pmids":["19270693"],"is_preprint":false},{"year":2010,"finding":"ATG14L recruits the class III PI3-kinase complex to the ER, where it generates PI3P to establish the ER as a platform for autophagosome formation. Knockdown of ATG14L eliminates DFCP1-positive omegasomes, and a point mutation causing defective ER localization also ablates autophagy induction; adding an ER-targeting motif to this mutant fully rescues autophagic defects in ATG14L KO ES cells.","method":"siRNA knockdown, point mutagenesis rescue experiments, ER-targeting domain swap, fluorescence microscopy of DFCP1/omegasome, ATG14L KO ES cell complementation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis, domain-swap rescue, genetic KO complementation, multiple orthogonal methods in one study","pmids":["20713597"],"is_preprint":false},{"year":2011,"finding":"The C-terminal BATS (Barkor/ATG14(L) autophagosome targeting sequence) domain of ATG14L is required for autophagosome targeting. BATS contains an amphipathic alpha helix that binds autophagosome membranes enriched in PtdIns(3)P and PtdIns(4,5)P2 and preferentially senses highly curved membranes; deletion of BATS abolishes PI3KC3 recruitment and autophagy stimulation.","method":"Bioinformatics and mutagenesis of BATS domain, fluorescence microscopy co-localization with Atg16/LC3/DFCP1, in vitro membrane-binding biochemical assay, liposome curvature-sensing assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstituted membrane binding, mutagenesis, cell imaging with functional readout, multiple orthogonal methods","pmids":["21518905"],"is_preprint":false},{"year":2012,"finding":"The Beclin 1 coiled-coil domain forms a metastable antiparallel homodimer rendered unstable by 'imperfect' a-d' pairings; ATG14L (and UVRAG) promote transition of this metastable homodimer to stable Beclin1-ATG14L heterodimer. Beclin 1 mutants with enhanced self-interaction show altered binding to ATG14L.","method":"X-ray crystallography of Beclin 1 CCD, co-immunoprecipitation of mutants, biochemical homodimer/heterodimer formation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutagenesis validation and Co-IP, single lab but multiple orthogonal methods","pmids":["22314358"],"is_preprint":false},{"year":2012,"finding":"ATG14L binds to the fusogenic SNARE effector protein Snapin and co-localizes with it to facilitate endosome maturation. The Snapin-binding activity of ATG14L is distinct from its Beclin 1-binding activity; a Snapin-binding mutant of ATG14L fails to rescue the endocytic trafficking delay caused by ATG14L knockdown, while a Beclin 1-binding mutant does rescue it.","method":"Co-immunoprecipitation, fluorescence co-localization, siRNA knockdown, domain mutant rescue assays measuring receptor degradation kinetics","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutant rescue with defined phenotypic readout, single lab","pmids":["22797916"],"is_preprint":false},{"year":2012,"finding":"ATG14 is critical for an autophagy-dependent phosphorylation of Beclin 1 at serines 90 and 93; phosphorylation at these sites is necessary for maximal autophagy. A unique membrane association domain in Beclin 1 controls autophagosome size and number.","method":"Phosphorylation site mapping, site-directed mutagenesis of Beclin 1 S90/S93, autophagy flux assays, yeast genetic analysis of Atg6 domain","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation sites with functional autophagy readout, single lab","pmids":["23878393"],"is_preprint":false},{"year":2014,"finding":"NRBF2 directly binds ATG14L through its MIT domain and is a component of the specific ATG14L-Beclin1-Vps34-Vps15 complex. NRBF2 binding to ATG14L enhances ATG14L-linked Vps34 kinase activity and autophagy induction; NRBF2-deficient mice show impaired ATG14L-linked Vps34 activity and autophagy with focal liver necrosis.","method":"Co-immunoprecipitation, MIT domain binding assay, Vps34 lipid kinase assay, NRBF2 KO mice with liver phenotype analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, reciprocal Co-IP, genetic KO mouse model with tissue phenotype, multiple orthogonal methods","pmids":["24849286"],"is_preprint":false},{"year":2014,"finding":"NRBF2 (Nrbf2) interacts and co-localizes with ATG14L within the ATG14L-containing Beclin1-Vps34 complex. Nrbf2 deficiency leads to increased PI3P levels and diminished ATG14L-Vps34/Vps15 interactions, suggesting Nrbf2-mediated ATG14L-Vps34/Vps15 interactions inhibit Vps34 activity and suppress autophagosome biogenesis.","method":"Co-immunoprecipitation, siRNA knockdown of Nrbf2, PI3P measurement, fluorescence co-localization with isolation membrane markers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PI3P biochemical measurement, KD functional assay, single lab; partially contradicts PMID:24849286 on directionality of Nrbf2 effect","pmids":["25086043"],"is_preprint":false},{"year":2015,"finding":"ATG14 directly binds the SNARE core domain of STX17 (syntaxin 17) through its coiled-coil domain, stabilizing the STX17-SNAP29 binary t-SNARE complex on autophagosomes. ATG14 homo-oligomerization via cysteine repeats is required for membrane tethering and for enhancing hemifusion and full fusion of proteoliposomes reconstituted with STX17, SNAP29, and VAMP8. ATG14 homo-oligomerization-defective cells form autophagosomes normally but block fusion with endolysosomes.","method":"In vitro reconstituted membrane tethering and fusion assays with protein-free liposomes and proteoliposomes, biochemical SNARE binding assay, homo-oligomerization mutant cell lines, autophagic flux assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of membrane fusion, mutagenesis of oligomerization domain, cell-based functional rescue, multiple orthogonal methods in one study","pmids":["25686604"],"is_preprint":false},{"year":2015,"finding":"ATG14 homo-oligomerization is required for binding the STX17-SNAP29 binary SNARE complex on autophagosomes and for promoting autophagosome-lysosome fusion, but is dispensable for PI3K stimulation and autophagosome biogenesis. This was confirmed using biochemical, cell biology, and genetic approaches showing ATG14 homo-oligomerization mutants lose SNARE binding and fusion-promoting activity while retaining PI3K activity.","method":"Biochemical SNARE complex binding assay, cell biology with homo-oligomerization mutants, genetic complementation, autophagosome-lysosome fusion assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — orthogonal biochemical and cell biology methods, corroborates PMID:25686604 from same group with independent validations","pmids":["25945523"],"is_preprint":false},{"year":2015,"finding":"ATG14L is ubiquitinated and degraded by the ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. A wide range of G-protein-coupled receptor (GPCR) ligands regulate ATG14L protein levels through ZBTB16, providing a mechanism by which GPCR activation suppresses autophagy.","method":"Co-immunoprecipitation of ATG14L with ZBTB16-Cullin3-Roc1 complex, ubiquitination assay, GPCR ligand treatment with ATG14L protein level measurement, pharmacological autophagy modulation in Huntington's disease mouse model","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of E3 complex with substrate, ubiquitination assay, functional GPCR-autophagy link, single lab","pmids":["25821988"],"is_preprint":false},{"year":2016,"finding":"ULK1 phosphorylates ATG14 at serine 29 in an mTOR-dependent manner, and this phosphorylation critically regulates ATG14-Vps34 lipid kinase activity to control autophagy level. ATG14 phosphorylation is decreased in Q175 Huntington's disease mice partly through p62-induced sequestration of ULK1, and phospho-mimetic ATG14 facilitates clearance of polyQ mutant protein.","method":"Anti-phospho-ATG14 (Ser29) antibody generation, ULK1 kinase assay, Vps34 lipid kinase activity assay, HD genetic mouse model analysis, proteasomal inhibition studies","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific phospho-antibody, in vitro kinase assay, in vivo disease model, multiple orthogonal methods","pmids":["27938392"],"is_preprint":false},{"year":2016,"finding":"The ULK1 complex phosphorylates ATG14 at serine 29 via ATG13-mediated interaction of ULK1 with the ATG14-containing PIK3C3/VPS34 complex. ATG14 phosphorylation stimulates class III PI3K complex kinase activity and facilitates phagophore and autophagosome formation. ULK1-mediated ATG14 phosphorylation requires BECN1 but not PE-conjugation machinery or PIK3C3 kinase activity. ATG9A is required to suppress ULK1 activity under nutrient-enriched conditions.","method":"Co-immunoprecipitation (ATG13-ULK1-ATG14 interaction), ULK1 kinase assay for ATG14 Ser29 phosphorylation, PI3K activity assay, starvation/MTORC1 inhibition conditions, ATG9A epistasis experiment","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, reciprocal Co-IP, epistasis with ATG9A, multiple orthogonal methods, corroborated by PMID:27938392","pmids":["27046250"],"is_preprint":false},{"year":2016,"finding":"PAQR3 functions as a scaffold protein that preferentially facilitates formation of the ATG14L-linked Vps34 complex (not UVRAG-linked), enhancing PI3P generation. AMPK phosphorylates PAQR3 at threonine 32, which is required for activation of ATG14L-associated PI3K upon glucose starvation.","method":"Co-immunoprecipitation of PAQR3 with ATG14L-Beclin1-Vps34 complex, PI3P generation assay, AMPK phosphorylation site mutagenesis (T32A), PAQR3 deletion mice with exercise-induced autophagy assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, Co-IP, genetic KO mice, multiple orthogonal methods","pmids":["26834238"],"is_preprint":false},{"year":2016,"finding":"ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme generating PtdIns(4,5)P2. The BATS domain of ATG14 binds PtdIns(4,5)P2, regulating ATG14 interaction with VPS34 and Beclin 1 and ATG14 complex assembly. Loss of PIPKIγi5 results in loss of ATG14, UVRAG, and Beclin 1 and autophagy block.","method":"Co-immunoprecipitation of ATG14 with PIPKIγi5, BATS domain lipid-binding assay for PtdIns(4,5)P2, PIPKIγi5 knockdown with ATG14/Beclin1 protein level and autophagy assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, lipid binding assay, KD phenotype, single lab","pmids":["27621469"],"is_preprint":false},{"year":2016,"finding":"ATG14 crystal structure (BECN1:ATG14 CCD heterodimer) determined by SAXS shows the heterodimer is more curved than other BECN1-containing dimers. ATG14 CCD is disordered alone but becomes more helical upon heterodimerization with BECN1 CCD. Point mutations at the BECN1:ATG14 interface abrogate starvation-induced but not basal autophagy.","method":"X-ray crystallography of BECN1 CCD homodimer, SAXS of BECN1:ATG14 CCD heterodimer, circular dichroism, co-immunoprecipitation of interface mutants, starvation-induced autophagy assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus SAXS plus mutagenesis with functional readout, single lab but multiple rigorous methods","pmids":["27383850"],"is_preprint":false},{"year":2017,"finding":"BECN2 CCD forms an antiparallel homodimer with weaker self-association than BECN1 but binds ATG14 CCD more tightly than BECN1 does. Crystal structure shows BECN2:ATG14 CCD forms a parallel, curved heterodimer stabilized by conserved polar interactions; mutation of nonideal BECN2 interface residues improves homodimerization but weakens ATG14 binding.","method":"X-ray crystallography of BECN2 CCD homodimer and BECN2:ATG14 CCD heterodimer, site-directed mutagenesis, thermal stability assay, binding affinity measurements","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis and binding measurements, single lab but rigorous structural study","pmids":["28218432"],"is_preprint":false},{"year":2018,"finding":"ULK1 phosphorylates BECN1 at Ser30 specifically in association with ATG14-containing (not UVRAG-containing) PIK3C3 complex. This phosphorylation is induced by amino acid starvation, hypoxia, and MTORC1 inhibition, and requires ATG13 and RB1CC1. Blocking Ser30 phosphorylation (S30A mutant) suppresses ATG14-containing PIK3C3 kinase activity and reduces autophagy flux and autophagosome formation without affecting ATG14 Ser29 phosphorylation.","method":"In vitro ULK1 kinase assay for BECN1 Ser30, site-directed mutagenesis (S30A), co-immunoprecipitation, PIK3C3 lipid kinase activity assay, autophagy flux measurement","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, mutagenesis, kinase activity assay, Co-IP, multiple conditions tested","pmids":["29313410"],"is_preprint":false},{"year":2018,"finding":"ULK1 is O-GlcNAcylated at threonine 754 by OGT upon glucose starvation (after mTOR-dependent Ser757 dephosphorylation by PP1 and AMPK-mediated phosphorylation). ULK1 O-GlcNAcylation is required for binding and phosphorylation of ATG14L, enabling VPS34 lipid kinase activation, PI3P production, and phagophore formation.","method":"O-GlcNAc modification identification (mass spectrometry), OGT/PP1 inhibitor studies, co-immunoprecipitation of ULK1-ATG14L, VPS34 lipid kinase assay, phagophore formation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical PTM identification, Co-IP, kinase assay, functional phagophore readout, single lab","pmids":["30517873"],"is_preprint":false},{"year":2019,"finding":"Intestinal epithelium-specific ATG14 knockout mice develop spontaneous villus loss and epithelial cell death (apoptosis) in the small intestine. ATG14-deficient intestinal epithelial cells are sensitive to TNF-triggered apoptosis; TNF-blocking antibody and genetic deletion of TNFR1 rescue the phenotype. Similarly, FIP200 intestinal-specific deletion causes the same villus atrophy phenotype.","method":"Conditional KO (Atg14-Cre/VillinCre) mice, caspase cleavage markers, TNF-blocking antibody rescue, TNFR1 genetic deletion epistasis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic conditional KO mouse, antibody rescue, genetic epistasis with TNFR1 and FIP200, defined apoptosis phenotype","pmids":["30894050"],"is_preprint":false},{"year":2020,"finding":"GLIPR2 (a Golgi-associated protein) binds to the BECN1-ATG14-containing PtdIns3K-C1 complex and directly inhibits its in vitro lipid kinase activity. CRISPR-Cas9 depletion of GLIPR2 increases autophagic flux and PI3P generation in cells and in mice.","method":"In vitro lipid kinase assay with purified PtdIns3K-C1 plus recombinant GLIPR2, CRISPR-Cas9 KO in cells and mice, PI3P measurement, autophagic flux assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay with purified complex, genetic KO in cells and animals, PI3P biochemical measurement","pmids":["33222586"],"is_preprint":false},{"year":2021,"finding":"ATG14 muscle-specific conditional KO (atg14-cKO) mice develop hypertrophic cardiomyopathy with abnormal accumulation of autophagic cargoes in the heart and early mortality; skeletal muscles show autophagic vacuolar myopathy with ubiquitin+/SQSTM1+ deposits. Unlike rb1cc1-cKO mice, atg14-cKO mice do not show TARDBP/TDP-43+ pathology, indicating distinct roles for ATG14 vs. RB1CC1 in muscle autophagy.","method":"Muscle-specific conditional KO mice (Ckm-Cre), histopathology, immunohistochemistry for autophagy cargo markers, cardiac function assessment","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with tissue-specific phenotype, comparison to parallel KO models establishing epistatic distinctions","pmids":["33794726"],"is_preprint":false},{"year":2022,"finding":"SETD2 promotes expression of the long ATG14 isoform (ATG14L) containing the N-terminal cysteine repeats domain required for efficient autophagosome-lysosome fusion. Loss of SETD2 decreases ATG14L expression and autophagic flux, and impairs degradation of aggregation-prone mutant HTT.","method":"SETD2 loss-of-function, isoform expression analysis, autophagic flux measurement, mutant HTT clearance assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with isoform-specific and functional readout, single lab, no in vitro reconstitution","pmids":["36371383"],"is_preprint":false},{"year":2022,"finding":"PI4K2A generates a pool of PI4P on mature autophagosomes that facilitates ATG14 recruitment. PI4K2A binds ATG14, suggesting in situ PI4P synthesis near ATG14. Impaired ATG14 targeting to autophagosomes in PI4K2A-depleted cells is rescued by exogenous PI4P but not PI(4,5)P2.","method":"PI4K2A knockdown with ATG14 localization assay by fluorescence microscopy, PI4K2A-ATG14 co-immunoprecipitation, PI4P and PI(4,5)P2 rescue experiments","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD with localization readout, lipid rescue experiment, single lab","pmids":["35380781"],"is_preprint":false},{"year":2022,"finding":"Drosophila Miga (ER-mitochondrial contact protein) binds Atg14 and Uvrag; Miga overexpression recruits Atg14 and Uvrag to mitochondria. Miga-mediated stabilization of Syx17 (STX17) is dependent on Atg14, while PI3K activity enhancement by Miga requires Uvrag.","method":"Co-immunoprecipitation of Miga with Atg14/Uvrag, gain-of-function overexpression localization assay, genetic loss-of-function in Drosophila, PI3P measurement, Syx17 stability assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic epistasis in Drosophila model, functional PI3P and fusion readouts, single lab","pmids":["36323251"],"is_preprint":false},{"year":2023,"finding":"MARCH7 (MARCHF7), an E3 ubiquitin ligase, ubiquitinates ATG14 with K6-, K11-, and K63-linked mixed polyubiquitin chains, causing ATG14 aggregation and reduced solubility. Ubiquitinated ATG14 has fewer interactions with STX17, inhibiting autophagy flux. MARCH7 depletion decreases aggresome-like induced structures.","method":"E3 ligase identification by Co-IP, in vitro/in cell ubiquitination assay with chain-type mapping, ATG14 solubility fractionation, STX17 binding assay for ubiquitinated vs. unmodified ATG14, MARCH7 KO cell analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ubiquitination assay with chain-type specificity, solubility assay, interaction assay with downstream SNARE, genetic KO, multiple orthogonal methods","pmids":["37632749"],"is_preprint":false},{"year":2023,"finding":"RUNDC1 interacts with ATG14 and negatively regulates autophagy by blocking autophagosome-lysosome fusion. RUNDC1 clasps the ATG14-STX17-SNAP29 complex by stimulating ATG14 homo-oligomerization, preventing ATG14 dissociation and VAMP8 binding to STX17-SNAP29. Phosphorylation of RUNDC1 Ser379 is crucial for this inhibitory mechanism in human cells and zebrafish.","method":"Co-immunoprecipitation, gain/loss-of-function in human cells and zebrafish, STX17-SNAP29-VAMP8 complex assembly assay, ATG14 homo-oligomerization assay, phosphorylation site mutagenesis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, SNARE assembly assay, phospho-site mutagenesis, zebrafish model, single lab","pmids":["37684417"],"is_preprint":false},{"year":2023,"finding":"USP1 interacts with ATG14, deubiquitinates it, and enhances ATG14 protein stability by reducing ubiquitin binding. USP1 inhibition promotes proteasome-dependent ATG14 degradation, reducing autophagy initiation and flux.","method":"Co-immunoprecipitation of USP1 with ATG14, ubiquitination level assay with USP1 overexpression/inhibition, proteasomal inhibition rescue, autophagy flux measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome rescue experiment, single lab","pmids":["39814232"],"is_preprint":false},{"year":2023,"finding":"S. pneumoniae CbpC interacts with ATG14 via ATG14's coiled-coil domain and CbpC residue Y83 (dp3 domain), activating autophagy. However, CbpC also acts as a decoy by recruiting ATG14 to p62/SQSTM1-dependent autophagic degradation, depleting ATG14 and impairing ATG14-STX17 complex formation, thereby suppressing bactericidal autophagy and promoting pneumococcal intracellular survival.","method":"Co-immunoprecipitation of CbpC with ATG14, domain mutagenesis (Y83), ATG14 protein level measurement in infected cells, ATG14-STX17 complex formation assay, bacterial survival assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain mutagenesis, complex formation assay, bacterial survival readout, single lab","pmids":["32239622"],"is_preprint":false},{"year":2023,"finding":"ATG14 and ATG7 are both required to restrict Mycobacterium tuberculosis replication in human iPSC-derived macrophages. ATG14 deletion specifically impairs phagosome-lysosome fusion in phagosomes containing Mtb, enabling both cytosolic and phagosomal bacterial restriction, while ATG7 primarily controls canonical autophagy of cytosolic Mtb.","method":"CRISPR-Cas9 deletion of ATG14 and ATG7 in iPSDM, single-cell high-content imaging with Mtb replication reporters, phagosome-lysosome fusion quantitative imaging with Mtb mutant panel","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO in human iPSC-derived primary cells, quantitative single-cell imaging, Mtb mutant epistasis, multiple bacterial strains","pmids":["36959508"],"is_preprint":false},{"year":2024,"finding":"ATG14 targets lipid droplets (LDs) via its BATS domain and acts as an autophagic receptor for lipophagy by interacting with ATG8 family proteins. STX18 (syntaxin 18) binds ATG14, disrupting ATG14-ATG8 interactions and PI3KC3-C1 complex formation. Coronavirus M protein binds STX18 to subvert the STX18-ATG14 interaction and induce lipophagy to degrade the anti-viral protein Viperin.","method":"BATS domain mutagenesis for LD targeting, Co-immunoprecipitation of ATG14 with ATG8 family members and STX18, STX18 knockdown-dependent lipophagy assay, Viperin degradation assay with coronavirus M protein","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mutagenesis, reciprocal Co-IP, functional lipophagy assay, viral protein epistasis, multiple orthogonal methods","pmids":["38245527"],"is_preprint":false},{"year":2024,"finding":"ATG14 localizes to lipid droplets via its BATS domain and directly interacts with adipose triglyceride lipase (ATGL) and its coactivator CGI-58. ATG14 enhances the ATGL-CGI58 interaction; ATG14 deficiency markedly decreases triglyceride hydrolysis in hepatocytes.","method":"Fluorescence imaging of ATG14 on lipid droplets, BATS domain deletion/mutagenesis, co-immunoprecipitation of ATG14 with ATGL and CGI-58, in vitro lipolysis assay in ATG14-deficient hepatocytes and mouse livers","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro lipolysis reconstitution, domain mutagenesis, Co-IP of endogenous proteins, both cell and in vivo KO validation","pmids":["37741434"],"is_preprint":false},{"year":2024,"finding":"GULP1 (engulfment adaptor GULP1) interacts with ATG14 and potentiates its stimulatory effect on PI3KC3-C1 activity. GULP1 facilitates targeting of ATG14 to the ER. A GULP1 mutation disrupting the GULP1-ATG14 interaction abolishes these effects. GULP1-APP complex (via GULP1-ATG14 axis) further enhances PI3KC3-C1 activity and promotes APP processing by directing APP into autophagic vacuoles.","method":"Co-immunoprecipitation of GULP1 with ATG14, PI3KC3-C1 kinase activity assay, GULP1 mutant (disrupted ATG14 binding) rescue assay, ER targeting assay by fluorescence microscopy, autophagic vacuole fractionation for APP/ATG14 co-localization","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, kinase activity assay, mutant rescue, single lab","pmids":["39080084"],"is_preprint":false},{"year":2012,"finding":"ATG14 is regulated transcriptionally by FoxO transcription factors and circadian clock machinery (Clock/Bmal1) in mouse liver. Knockdown of ATG14 in mouse liver leads to elevated triglycerides in liver and serum; overexpression of ATG14 improves hypertriglyceridemia in high-fat diet and FoxO1/3/4 liver KO mice.","method":"Luciferase reporter assays, chromatin immunoprecipitation (ChIP) for FoxOs and Clock/Bmal1 at ATG14 promoter, liver-specific ATG14 knockdown and overexpression in mice, liver triglyceride and serum lipid measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter for transcriptional regulation, in vivo KD/OE with metabolic phenotype, single lab","pmids":["22992773"],"is_preprint":false},{"year":2025,"finding":"ATG14 safeguards oviduct cellular integrity by suppressing pyroptosis. Conditional depletion of Atg14 in oviduct causes severe structural abnormalities and abnormal embryo retention. Mechanistically, Atg14 loss triggers unscheduled pyroptosis via altered mitochondrial integrity in non-ciliary oviduct cells; pharmacological pyroptosis activation phenocopies the genetic defect.","method":"Conditional oviduct-specific Atg14 KO mice, histopathology for structural defects, embryo tracking assay, pyroptosis marker analysis, mitochondrial integrity assay, pharmacological pyroptosis induction","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse, pharmacological phenocopy, mitochondrial integrity assay, single lab","pmids":["40100261"],"is_preprint":false},{"year":2013,"finding":"CCCP-induced LC3 lipidation is independent of Beclin 1 and ATG14; FIP200 and ATG13 (ULK complex components) are only partially required, while ATG9 is required for CCCP-induced LC3 lipidation. This establishes that CCCP/mitophagy-induced autophagy can bypass the Beclin 1/ATG14 nucleation complex.","method":"Genetic deletion/siRNA knockdown of Beclin 1, ATG14, FIP200, ATG13, ATG9; LC3 lipidation assay (Western blot) under CCCP treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KD/KO of multiple autophagy components with defined biochemical readout (LC3 lipidation); finding is a negative result that is mechanistically informative: Beclin 1/ATG14 complex is dispensable for CCCP-induced LC3 lipidation","pmids":["23402761"],"is_preprint":false},{"year":2014,"finding":"Dapper1 (Dpr1) directly interacts with both Beclin1 and Atg14L, enhances the Beclin1-Vps34 interaction, and increases Vps34 lipid kinase activity, promoting autophagosome formation. Dpr1 ablation in the CNS results in motor coordination defects and accumulation of p62 and ubiquitinated proteins.","method":"Co-immunoprecipitation of Dpr1 with Beclin1 and Atg14L, Vps34 kinase activity assay, Dpr1 CNS-specific KO mice, LC3 puncta formation assay, p62/ubiquitin accumulation","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, kinase assay, genetic KO mice, single lab","pmids":["24980960"],"is_preprint":false}],"current_model":"ATG14 (ATG14L/Barkor/KIAA0831) is a core autophagy-specific subunit of the class III PI3-kinase complex I (PI3KC3-C1: VPS34-VPS15-Beclin1-ATG14) that is mutually exclusive with UVRAG-containing Complex II; it recruits the PI3K complex to the ER via its coiled-coil domain to generate PI3P and initiate autophagosome biogenesis, is targeted to curved PI3P-enriched autophagosomal membranes via its C-terminal BATS domain, and later promotes autophagosome-endolysosome fusion by directly binding the STX17-SNAP29 binary t-SNARE complex through its coiled-coil domain in an oligomerization-dependent manner; ATG14 activity is regulated by ULK1-mediated phosphorylation at Ser29 (stimulatory), ZBTB16-Cullin3 and MARCH7 E3-mediated ubiquitination (inhibitory), and USP1-mediated deubiquitination (stabilizing), and additionally functions as an autophagic receptor on lipid droplets and interfaces with SNARE machinery to regulate lipophagy."},"narrative":{"mechanistic_narrative":"ATG14 (ATG14L/Barkor) is the autophagy-specific subunit that defines a distinct class III PI3-kinase complex with Beclin 1, Vps34, and p150, mutually exclusive with UVRAG-containing complexes and essential for autophagosome formation [PMID:18843052, PMID:19270696]. Through its coiled-coil domain ATG14 binds Vps34 and Beclin 1, converting a metastable Beclin 1 homodimer into a stable, curved Beclin1–ATG14 heterodimer [PMID:22314358, PMID:27383850], and it enhances Vps34 lipid kinase activity to drive PI3P generation [PMID:19270693]. ATG14 recruits this complex to the ER to establish the omegasome platform for autophagosome biogenesis; ER localization is required for autophagy, and its C-terminal BATS domain bears an amphipathic helix that senses highly curved PI3P/PI(4,5)P2-enriched autophagosomal membranes to target the complex [PMID:20713597, PMID:21518905]. In a separable late-stage function, ATG14 directly binds the SNARE core of STX17 through its coiled-coil domain and, via cysteine-repeat-mediated homo-oligomerization, stabilizes the STX17–SNAP29 t-SNARE complex and tethers membranes to promote autophagosome–endolysosome fusion; oligomerization is dispensable for PI3K stimulation but required for fusion [PMID:25686604, PMID:25945523]. ATG14 levels and activity are tightly regulated: ULK1 phosphorylates ATG14 at Ser29 to stimulate Vps34 activity [PMID:27938392, PMID:27046250], while turnover is controlled by ZBTB16-Cullin3 and MARCH7 E3 ubiquitination (inhibitory) [PMID:25821988, PMID:37632749] and USP1 deubiquitination (stabilizing) [PMID:39814232]. Beyond degradative autophagy, ATG14 targets lipid droplets via its BATS domain, acting as an ATG8-binding autophagic receptor for lipophagy and as a direct enhancer of ATGL–CGI-58-mediated triglyceride hydrolysis [PMID:38245527, PMID:37741434]. Tissue-specific loss of ATG14 produces intestinal epithelial apoptosis, hypertrophic cardiomyopathy and vacuolar myopathy, reflecting its requirement for basal autophagy in vivo [PMID:30894050, PMID:33794726].","teleology":[{"year":2008,"claim":"Established that ATG14 nucleates a dedicated autophagy PI3-kinase complex, answering whether mammals have a discrete Vps34 complex committed to autophagosome formation.","evidence":"Co-IP, fluorescence localization, and siRNA knockdown with autophagosome readout in HeLa cells","pmids":["18843052"],"confidence":"High","gaps":["Did not resolve how the complex is targeted to membranes","Structural basis of subunit assembly unknown"]},{"year":2009,"claim":"Confirmed mutually exclusive ATG14- vs UVRAG-Beclin1 complexes and demonstrated ATG14 stimulates Vps34 lipid kinase activity, defining ATG14 as a positive regulator of autophagic PI3P output.","evidence":"Reciprocal Co-IP, GFP localization, lipid kinase assay, and ATG14L knockout in mouse ES cells","pmids":["19270696","19270693"],"confidence":"High","gaps":["Mechanism of Vps34 activation not defined","Membrane targeting determinant not identified"]},{"year":2010,"claim":"Showed ATG14 recruits the PI3K complex to the ER to generate PI3P and form omegasomes, identifying the ER as the autophagosome assembly platform.","evidence":"siRNA, point-mutagenesis rescue, ER-targeting domain swap, and KO ES cell complementation with omegasome imaging","pmids":["20713597"],"confidence":"High","gaps":["Did not define the lipid/curvature signal sensed by ATG14"]},{"year":2011,"claim":"Identified the BATS domain as a curvature-sensing amphipathic helix that targets ATG14 to PI3P/PI(4,5)P2-enriched autophagosomal membranes, explaining membrane localization.","evidence":"Bioinformatics/mutagenesis, in vitro membrane binding and liposome curvature-sensing assays, cell imaging","pmids":["21518905"],"confidence":"High","gaps":["Relative contribution of distinct phosphoinositides in vivo unresolved"]},{"year":2012,"claim":"Structural and biochemical work showed ATG14 stabilizes Beclin 1 from a metastable homodimer into a curved heterodimer, providing the assembly logic of the complex.","evidence":"X-ray crystallography of Beclin 1 CCD with Co-IP and dimerization assays","pmids":["22314358"],"confidence":"High","gaps":["Full-complex architecture with Vps34/Vps15 not solved"]},{"year":2012,"claim":"Linked ATG14 to additional functions: a Beclin 1-independent Snapin interaction in endosome maturation and a role in transcriptional/metabolic control of hepatic lipid homeostasis.","evidence":"Co-IP, domain-mutant rescue (Snapin); ChIP, reporter assays, and liver KD/OE with lipid measurements (FoxO/Clock)","pmids":["22797916","22992773"],"confidence":"Medium","gaps":["Snapin interaction validated in a single lab","Direct transcriptional regulation vs indirect metabolic effect not fully separated"]},{"year":2015,"claim":"Demonstrated a separable late-autophagy function: ATG14 directly binds STX17 and, via homo-oligomerization, stabilizes the STX17-SNAP29 t-SNARE and promotes autophagosome-lysosome fusion.","evidence":"In vitro reconstituted membrane tethering/fusion with proteoliposomes, SNARE binding assays, oligomerization mutant cell lines","pmids":["25686604","25945523"],"confidence":"High","gaps":["How biogenesis and fusion functions are temporally switched not defined"]},{"year":2016,"claim":"Established ULK1-mediated Ser29 phosphorylation of ATG14 as a stimulatory input coupling nutrient/mTOR status to Vps34 activation.","evidence":"Phospho-specific antibody, in vitro ULK1 and Vps34 kinase assays, ATG13-dependent Co-IP, HD mouse model","pmids":["27938392","27046250"],"confidence":"High","gaps":["Phosphatase reversing Ser29 not identified"]},{"year":2016,"claim":"Identified multiple positive regulators (NRBF2, PAQR3, PIPKIγ i5) feeding into ATG14-Vps34 activity and complex assembly, integrating metabolic and lipid cues.","evidence":"Co-IP, MIT/BATS binding assays, Vps34/PI3P kinase assays, KO mice (NRBF2, PAQR3); KD phenotypes","pmids":["24849286","25086043","26834238","27621469"],"confidence":"Medium","gaps":["NRBF2 directionality on Vps34 activity conflicts between studies","PIPKIγ i5 and PAQR3 effects validated in single labs"]},{"year":2018,"claim":"Refined the ULK1 input by showing ATG14-complex-specific BECN1 Ser30 phosphorylation and an O-GlcNAcylation switch on ULK1 controlling ATG14 binding.","evidence":"In vitro ULK1 kinase assays, S30A mutagenesis, PIK3C3 activity assays; mass spec PTM mapping with OGT inhibitor studies","pmids":["29313410","30517873"],"confidence":"Medium","gaps":["O-GlcNAc/ULK1 mechanism from single lab","Integration of Ser29 and Ser30 phosphorylation events not fully ordered"]},{"year":2020,"claim":"Identified GLIPR2 as a direct negative regulator of the ATG14-Beclin1 lipid kinase complex, expanding the network controlling PI3P output.","evidence":"In vitro lipid kinase assay with purified complex plus recombinant GLIPR2, CRISPR KO in cells and mice","pmids":["33222586"],"confidence":"High","gaps":["Physiological context selecting GLIPR2 inhibition unclear"]},{"year":2021,"claim":"In vivo conditional KO studies defined ATG14's tissue-essential roles, showing intestinal epithelial TNF-sensitive apoptosis and muscle vacuolar myopathy/cardiomyopathy.","evidence":"Tissue-specific conditional KO mice, histopathology, caspase markers, TNFR1 epistasis; comparison to RB1CC1 KO","pmids":["30894050","33794726"],"confidence":"High","gaps":["Whether phenotypes reflect canonical autophagy loss or non-canonical ATG14 functions not fully separated"]},{"year":2023,"claim":"Defined opposing ubiquitin-dependent control of ATG14 abundance/activity and a clasp-based fusion brake, establishing ATG14 as a tightly regulated node.","evidence":"MARCH7 ubiquitination/solubility/STX17-binding assays; USP1 deubiquitination and proteasome rescue; RUNDC1 SNARE-assembly and oligomerization assays","pmids":["37632749","39814232","37684417"],"confidence":"Medium","gaps":["RUNDC1 and USP1 mechanisms from single labs","Coordination among MARCH7, ZBTB16-Cul3, and USP1 unresolved"]},{"year":2023,"claim":"Showed ATG14 is targeted by pathogens and required for anti-bacterial autophagy, linking its STX17-fusion function to host defense.","evidence":"CRISPR KO in iPSC-derived macrophages with single-cell Mtb imaging; pneumococcal CbpC Co-IP and ATG14-STX17 complex/survival assays","pmids":["36959508","32239622"],"confidence":"Medium","gaps":["CbpC decoy mechanism from single lab","Generality across other intracellular pathogens unknown"]},{"year":2024,"claim":"Revealed a degradation-independent metabolic role: ATG14 acts as a lipid-droplet autophagic receptor for lipophagy and directly potentiates ATGL-CGI58 lipolysis.","evidence":"BATS-domain LD-targeting mutagenesis, ATG8/STX18 Co-IP and lipophagy assays; ATGL-CGI58 Co-IP and in vitro lipolysis in ATG14-deficient hepatocytes/livers","pmids":["38245527","37741434"],"confidence":"High","gaps":["Relationship between ATG14's receptor and lipase-activating roles not integrated","Switch between degradative and lipolytic functions undefined"]},{"year":null,"claim":"How ATG14 switches between its early PI3P-generating biogenesis role and its late STX17-dependent fusion role, and how its many regulators are integrated in time, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No temporal model coordinating biogenesis vs fusion functions","Full-length complex structure with membrane not solved","Hierarchy among phosphorylation, ubiquitination, and lipid cues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,16,32,33]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,11,0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,3,34]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[32,33]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,3,10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[33,35]}],"complexes":["PI3KC3 complex I (VPS34-VPS15-Beclin1-ATG14)","STX17-SNAP29 t-SNARE complex (binding partner)"],"partners":["BECN1","PIK3C3/VPS34","STX17","SNAP29","NRBF2","ULK1","MARCHF7","ATGL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZNE5","full_name":"Beclin 1-associated autophagy-related key regulator","aliases":["Autophagy-related protein 14-like protein","Atg14L"],"length_aa":492,"mass_kda":55.3,"function":"Required for both basal and inducible autophagy. Determines the localization of the autophagy-specific PI3-kinase complex PI3KC3-C1 (PubMed:18843052, PubMed:19050071). Plays a role in autophagosome formation and MAP1LC3/LC3 conjugation to phosphatidylethanolamine (PubMed:19270696, PubMed:20713597). Promotes BECN1 translocation from the trans-Golgi network to autophagosomes (PubMed:20713597). Enhances PIK3C3 activity in a BECN1-dependent manner. Essential for the autophagy-dependent phosphorylation of BECN1 (PubMed:23878393). Stimulates the phosphorylation of BECN1, but suppresses the phosphorylation PIK3C3 by AMPK (PubMed:23878393). Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion (PubMed:25686604, PubMed:37632749). Modulates the hepatic lipid metabolism (By similarity)","subcellular_location":"Cytoplasm; Endoplasmic reticulum membrane; Preautophagosomal structure membrane; Cytoplasmic vesicle, autophagosome membrane","url":"https://www.uniprot.org/uniprotkb/Q6ZNE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATG14","classification":"Not Classified","n_dependent_lines":29,"n_total_lines":1208,"dependency_fraction":0.024006622516556293},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000126775","cell_line_id":"CID001817","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PIK3C3","stoichiometry":10.0},{"gene":"PIK3R4","stoichiometry":10.0},{"gene":"NRBF2","stoichiometry":10.0},{"gene":"BECN1","stoichiometry":10.0},{"gene":"PSME4","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001817","total_profiled":1310},"omim":[{"mim_id":"616477","title":"NUCLEAR RECEPTOR-BINDING FACTOR 2; NRBF2","url":"https://www.omim.org/entry/616477"},{"mim_id":"615687","title":"BECLIN 2; BECN2","url":"https://www.omim.org/entry/615687"},{"mim_id":"613516","title":"RUN DOMAIN- AND CYSTEINE-RICH DOMAIN-CONTAINING BECLIN-1-INTERACTING PROTEIN; RUBCN","url":"https://www.omim.org/entry/613516"},{"mim_id":"613515","title":"AUTOPHAGY-RELATED 14; ATG14","url":"https://www.omim.org/entry/613515"},{"mim_id":"604378","title":"BECLIN 1; BECN1","url":"https://www.omim.org/entry/604378"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATG14"},"hgnc":{"alias_symbol":["ATG14L"],"prev_symbol":["KIAA0831"]},"alphafold":{"accession":"Q6ZNE5","domains":[{"cath_id":"-","chopping":"208-214_235-287_298-407","consensus_level":"high","plddt":84.8407,"start":208,"end":407}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZNE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZNE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZNE5-F1-predicted_aligned_error_v6.png","plddt_mean":73.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATG14","jax_strain_url":"https://www.jax.org/strain/search?query=ATG14"},"sequence":{"accession":"Q6ZNE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZNE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZNE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZNE5"}},"corpus_meta":[{"pmid":"19270696","id":"PMC_19270696","title":"Two Beclin 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homologue of yeast Atg14) forms a distinct class III PI3-kinase complex with Beclin 1, Vps34, and p150 that is mutually exclusive with UVRAG-containing complexes. ATG14 localizes to autophagic isolation membranes and its coiled-coil region required for binding Vps34 and Beclin 1 is essential for autophagosome formation; silencing ATG14 in HeLa cells suppresses autophagosome formation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization by fluorescence microscopy, siRNA knockdown with autophagosome formation readout, computational homology identification\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, live-cell imaging, functional KD phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"18843052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATG14L and UVRAG bind to Beclin 1 in a mutually exclusive manner, defining at least three distinct Beclin 1 complexes. GFP-ATG14L localizes to the isolation membrane, autophagosome, and ER. Knockout of ATG14L in mouse ES cells causes a defect in autophagosome formation.\",\n      \"method\": \"Co-immunoprecipitation, GFP-tagged protein localization by fluorescence microscopy, ATG14L knockout in mouse ES cells with autophagosome formation assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with specific phenotype, live imaging, replicated in independent simultaneous publication (PMID:19270693)\",\n      \"pmids\": [\"19270696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATG14L (Atg14L) enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity. ATG14L and Beclin 1 synergistically promote formation of double-membraned organelles associated with Atg5 and Atg12.\",\n      \"method\": \"In vivo biochemistry (large Beclin 1 complex characterization), PI3-kinase lipid kinase assay, immunofluorescence for double-membrane organelle formation, mouse genetics\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro lipid kinase assay, mouse genetics, orthogonal biochemical and cell biology methods, replicated in parallel publication\",\n      \"pmids\": [\"19270693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATG14L recruits the class III PI3-kinase complex to the ER, where it generates PI3P to establish the ER as a platform for autophagosome formation. Knockdown of ATG14L eliminates DFCP1-positive omegasomes, and a point mutation causing defective ER localization also ablates autophagy induction; adding an ER-targeting motif to this mutant fully rescues autophagic defects in ATG14L KO ES cells.\",\n      \"method\": \"siRNA knockdown, point mutagenesis rescue experiments, ER-targeting domain swap, fluorescence microscopy of DFCP1/omegasome, ATG14L KO ES cell complementation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis, domain-swap rescue, genetic KO complementation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20713597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The C-terminal BATS (Barkor/ATG14(L) autophagosome targeting sequence) domain of ATG14L is required for autophagosome targeting. BATS contains an amphipathic alpha helix that binds autophagosome membranes enriched in PtdIns(3)P and PtdIns(4,5)P2 and preferentially senses highly curved membranes; deletion of BATS abolishes PI3KC3 recruitment and autophagy stimulation.\",\n      \"method\": \"Bioinformatics and mutagenesis of BATS domain, fluorescence microscopy co-localization with Atg16/LC3/DFCP1, in vitro membrane-binding biochemical assay, liposome curvature-sensing assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstituted membrane binding, mutagenesis, cell imaging with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"21518905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Beclin 1 coiled-coil domain forms a metastable antiparallel homodimer rendered unstable by 'imperfect' a-d' pairings; ATG14L (and UVRAG) promote transition of this metastable homodimer to stable Beclin1-ATG14L heterodimer. Beclin 1 mutants with enhanced self-interaction show altered binding to ATG14L.\",\n      \"method\": \"X-ray crystallography of Beclin 1 CCD, co-immunoprecipitation of mutants, biochemical homodimer/heterodimer formation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutagenesis validation and Co-IP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22314358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATG14L binds to the fusogenic SNARE effector protein Snapin and co-localizes with it to facilitate endosome maturation. The Snapin-binding activity of ATG14L is distinct from its Beclin 1-binding activity; a Snapin-binding mutant of ATG14L fails to rescue the endocytic trafficking delay caused by ATG14L knockdown, while a Beclin 1-binding mutant does rescue it.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, siRNA knockdown, domain mutant rescue assays measuring receptor degradation kinetics\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutant rescue with defined phenotypic readout, single lab\",\n      \"pmids\": [\"22797916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATG14 is critical for an autophagy-dependent phosphorylation of Beclin 1 at serines 90 and 93; phosphorylation at these sites is necessary for maximal autophagy. A unique membrane association domain in Beclin 1 controls autophagosome size and number.\",\n      \"method\": \"Phosphorylation site mapping, site-directed mutagenesis of Beclin 1 S90/S93, autophagy flux assays, yeast genetic analysis of Atg6 domain\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation sites with functional autophagy readout, single lab\",\n      \"pmids\": [\"23878393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NRBF2 directly binds ATG14L through its MIT domain and is a component of the specific ATG14L-Beclin1-Vps34-Vps15 complex. NRBF2 binding to ATG14L enhances ATG14L-linked Vps34 kinase activity and autophagy induction; NRBF2-deficient mice show impaired ATG14L-linked Vps34 activity and autophagy with focal liver necrosis.\",\n      \"method\": \"Co-immunoprecipitation, MIT domain binding assay, Vps34 lipid kinase assay, NRBF2 KO mice with liver phenotype analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, reciprocal Co-IP, genetic KO mouse model with tissue phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"24849286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NRBF2 (Nrbf2) interacts and co-localizes with ATG14L within the ATG14L-containing Beclin1-Vps34 complex. Nrbf2 deficiency leads to increased PI3P levels and diminished ATG14L-Vps34/Vps15 interactions, suggesting Nrbf2-mediated ATG14L-Vps34/Vps15 interactions inhibit Vps34 activity and suppress autophagosome biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Nrbf2, PI3P measurement, fluorescence co-localization with isolation membrane markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PI3P biochemical measurement, KD functional assay, single lab; partially contradicts PMID:24849286 on directionality of Nrbf2 effect\",\n      \"pmids\": [\"25086043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATG14 directly binds the SNARE core domain of STX17 (syntaxin 17) through its coiled-coil domain, stabilizing the STX17-SNAP29 binary t-SNARE complex on autophagosomes. ATG14 homo-oligomerization via cysteine repeats is required for membrane tethering and for enhancing hemifusion and full fusion of proteoliposomes reconstituted with STX17, SNAP29, and VAMP8. ATG14 homo-oligomerization-defective cells form autophagosomes normally but block fusion with endolysosomes.\",\n      \"method\": \"In vitro reconstituted membrane tethering and fusion assays with protein-free liposomes and proteoliposomes, biochemical SNARE binding assay, homo-oligomerization mutant cell lines, autophagic flux assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of membrane fusion, mutagenesis of oligomerization domain, cell-based functional rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25686604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATG14 homo-oligomerization is required for binding the STX17-SNAP29 binary SNARE complex on autophagosomes and for promoting autophagosome-lysosome fusion, but is dispensable for PI3K stimulation and autophagosome biogenesis. This was confirmed using biochemical, cell biology, and genetic approaches showing ATG14 homo-oligomerization mutants lose SNARE binding and fusion-promoting activity while retaining PI3K activity.\",\n      \"method\": \"Biochemical SNARE complex binding assay, cell biology with homo-oligomerization mutants, genetic complementation, autophagosome-lysosome fusion assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — orthogonal biochemical and cell biology methods, corroborates PMID:25686604 from same group with independent validations\",\n      \"pmids\": [\"25945523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATG14L is ubiquitinated and degraded by the ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. A wide range of G-protein-coupled receptor (GPCR) ligands regulate ATG14L protein levels through ZBTB16, providing a mechanism by which GPCR activation suppresses autophagy.\",\n      \"method\": \"Co-immunoprecipitation of ATG14L with ZBTB16-Cullin3-Roc1 complex, ubiquitination assay, GPCR ligand treatment with ATG14L protein level measurement, pharmacological autophagy modulation in Huntington's disease mouse model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of E3 complex with substrate, ubiquitination assay, functional GPCR-autophagy link, single lab\",\n      \"pmids\": [\"25821988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ULK1 phosphorylates ATG14 at serine 29 in an mTOR-dependent manner, and this phosphorylation critically regulates ATG14-Vps34 lipid kinase activity to control autophagy level. ATG14 phosphorylation is decreased in Q175 Huntington's disease mice partly through p62-induced sequestration of ULK1, and phospho-mimetic ATG14 facilitates clearance of polyQ mutant protein.\",\n      \"method\": \"Anti-phospho-ATG14 (Ser29) antibody generation, ULK1 kinase assay, Vps34 lipid kinase activity assay, HD genetic mouse model analysis, proteasomal inhibition studies\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific phospho-antibody, in vitro kinase assay, in vivo disease model, multiple orthogonal methods\",\n      \"pmids\": [\"27938392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The ULK1 complex phosphorylates ATG14 at serine 29 via ATG13-mediated interaction of ULK1 with the ATG14-containing PIK3C3/VPS34 complex. ATG14 phosphorylation stimulates class III PI3K complex kinase activity and facilitates phagophore and autophagosome formation. ULK1-mediated ATG14 phosphorylation requires BECN1 but not PE-conjugation machinery or PIK3C3 kinase activity. ATG9A is required to suppress ULK1 activity under nutrient-enriched conditions.\",\n      \"method\": \"Co-immunoprecipitation (ATG13-ULK1-ATG14 interaction), ULK1 kinase assay for ATG14 Ser29 phosphorylation, PI3K activity assay, starvation/MTORC1 inhibition conditions, ATG9A epistasis experiment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, reciprocal Co-IP, epistasis with ATG9A, multiple orthogonal methods, corroborated by PMID:27938392\",\n      \"pmids\": [\"27046250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PAQR3 functions as a scaffold protein that preferentially facilitates formation of the ATG14L-linked Vps34 complex (not UVRAG-linked), enhancing PI3P generation. AMPK phosphorylates PAQR3 at threonine 32, which is required for activation of ATG14L-associated PI3K upon glucose starvation.\",\n      \"method\": \"Co-immunoprecipitation of PAQR3 with ATG14L-Beclin1-Vps34 complex, PI3P generation assay, AMPK phosphorylation site mutagenesis (T32A), PAQR3 deletion mice with exercise-induced autophagy assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, Co-IP, genetic KO mice, multiple orthogonal methods\",\n      \"pmids\": [\"26834238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme generating PtdIns(4,5)P2. The BATS domain of ATG14 binds PtdIns(4,5)P2, regulating ATG14 interaction with VPS34 and Beclin 1 and ATG14 complex assembly. Loss of PIPKIγi5 results in loss of ATG14, UVRAG, and Beclin 1 and autophagy block.\",\n      \"method\": \"Co-immunoprecipitation of ATG14 with PIPKIγi5, BATS domain lipid-binding assay for PtdIns(4,5)P2, PIPKIγi5 knockdown with ATG14/Beclin1 protein level and autophagy assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, lipid binding assay, KD phenotype, single lab\",\n      \"pmids\": [\"27621469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATG14 crystal structure (BECN1:ATG14 CCD heterodimer) determined by SAXS shows the heterodimer is more curved than other BECN1-containing dimers. ATG14 CCD is disordered alone but becomes more helical upon heterodimerization with BECN1 CCD. Point mutations at the BECN1:ATG14 interface abrogate starvation-induced but not basal autophagy.\",\n      \"method\": \"X-ray crystallography of BECN1 CCD homodimer, SAXS of BECN1:ATG14 CCD heterodimer, circular dichroism, co-immunoprecipitation of interface mutants, starvation-induced autophagy assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus SAXS plus mutagenesis with functional readout, single lab but multiple rigorous methods\",\n      \"pmids\": [\"27383850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BECN2 CCD forms an antiparallel homodimer with weaker self-association than BECN1 but binds ATG14 CCD more tightly than BECN1 does. Crystal structure shows BECN2:ATG14 CCD forms a parallel, curved heterodimer stabilized by conserved polar interactions; mutation of nonideal BECN2 interface residues improves homodimerization but weakens ATG14 binding.\",\n      \"method\": \"X-ray crystallography of BECN2 CCD homodimer and BECN2:ATG14 CCD heterodimer, site-directed mutagenesis, thermal stability assay, binding affinity measurements\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis and binding measurements, single lab but rigorous structural study\",\n      \"pmids\": [\"28218432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ULK1 phosphorylates BECN1 at Ser30 specifically in association with ATG14-containing (not UVRAG-containing) PIK3C3 complex. This phosphorylation is induced by amino acid starvation, hypoxia, and MTORC1 inhibition, and requires ATG13 and RB1CC1. Blocking Ser30 phosphorylation (S30A mutant) suppresses ATG14-containing PIK3C3 kinase activity and reduces autophagy flux and autophagosome formation without affecting ATG14 Ser29 phosphorylation.\",\n      \"method\": \"In vitro ULK1 kinase assay for BECN1 Ser30, site-directed mutagenesis (S30A), co-immunoprecipitation, PIK3C3 lipid kinase activity assay, autophagy flux measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, mutagenesis, kinase activity assay, Co-IP, multiple conditions tested\",\n      \"pmids\": [\"29313410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ULK1 is O-GlcNAcylated at threonine 754 by OGT upon glucose starvation (after mTOR-dependent Ser757 dephosphorylation by PP1 and AMPK-mediated phosphorylation). ULK1 O-GlcNAcylation is required for binding and phosphorylation of ATG14L, enabling VPS34 lipid kinase activation, PI3P production, and phagophore formation.\",\n      \"method\": \"O-GlcNAc modification identification (mass spectrometry), OGT/PP1 inhibitor studies, co-immunoprecipitation of ULK1-ATG14L, VPS34 lipid kinase assay, phagophore formation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical PTM identification, Co-IP, kinase assay, functional phagophore readout, single lab\",\n      \"pmids\": [\"30517873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Intestinal epithelium-specific ATG14 knockout mice develop spontaneous villus loss and epithelial cell death (apoptosis) in the small intestine. ATG14-deficient intestinal epithelial cells are sensitive to TNF-triggered apoptosis; TNF-blocking antibody and genetic deletion of TNFR1 rescue the phenotype. Similarly, FIP200 intestinal-specific deletion causes the same villus atrophy phenotype.\",\n      \"method\": \"Conditional KO (Atg14-Cre/VillinCre) mice, caspase cleavage markers, TNF-blocking antibody rescue, TNFR1 genetic deletion epistasis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic conditional KO mouse, antibody rescue, genetic epistasis with TNFR1 and FIP200, defined apoptosis phenotype\",\n      \"pmids\": [\"30894050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GLIPR2 (a Golgi-associated protein) binds to the BECN1-ATG14-containing PtdIns3K-C1 complex and directly inhibits its in vitro lipid kinase activity. CRISPR-Cas9 depletion of GLIPR2 increases autophagic flux and PI3P generation in cells and in mice.\",\n      \"method\": \"In vitro lipid kinase assay with purified PtdIns3K-C1 plus recombinant GLIPR2, CRISPR-Cas9 KO in cells and mice, PI3P measurement, autophagic flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay with purified complex, genetic KO in cells and animals, PI3P biochemical measurement\",\n      \"pmids\": [\"33222586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG14 muscle-specific conditional KO (atg14-cKO) mice develop hypertrophic cardiomyopathy with abnormal accumulation of autophagic cargoes in the heart and early mortality; skeletal muscles show autophagic vacuolar myopathy with ubiquitin+/SQSTM1+ deposits. Unlike rb1cc1-cKO mice, atg14-cKO mice do not show TARDBP/TDP-43+ pathology, indicating distinct roles for ATG14 vs. RB1CC1 in muscle autophagy.\",\n      \"method\": \"Muscle-specific conditional KO mice (Ckm-Cre), histopathology, immunohistochemistry for autophagy cargo markers, cardiac function assessment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with tissue-specific phenotype, comparison to parallel KO models establishing epistatic distinctions\",\n      \"pmids\": [\"33794726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SETD2 promotes expression of the long ATG14 isoform (ATG14L) containing the N-terminal cysteine repeats domain required for efficient autophagosome-lysosome fusion. Loss of SETD2 decreases ATG14L expression and autophagic flux, and impairs degradation of aggregation-prone mutant HTT.\",\n      \"method\": \"SETD2 loss-of-function, isoform expression analysis, autophagic flux measurement, mutant HTT clearance assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with isoform-specific and functional readout, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"36371383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PI4K2A generates a pool of PI4P on mature autophagosomes that facilitates ATG14 recruitment. PI4K2A binds ATG14, suggesting in situ PI4P synthesis near ATG14. Impaired ATG14 targeting to autophagosomes in PI4K2A-depleted cells is rescued by exogenous PI4P but not PI(4,5)P2.\",\n      \"method\": \"PI4K2A knockdown with ATG14 localization assay by fluorescence microscopy, PI4K2A-ATG14 co-immunoprecipitation, PI4P and PI(4,5)P2 rescue experiments\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD with localization readout, lipid rescue experiment, single lab\",\n      \"pmids\": [\"35380781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Drosophila Miga (ER-mitochondrial contact protein) binds Atg14 and Uvrag; Miga overexpression recruits Atg14 and Uvrag to mitochondria. Miga-mediated stabilization of Syx17 (STX17) is dependent on Atg14, while PI3K activity enhancement by Miga requires Uvrag.\",\n      \"method\": \"Co-immunoprecipitation of Miga with Atg14/Uvrag, gain-of-function overexpression localization assay, genetic loss-of-function in Drosophila, PI3P measurement, Syx17 stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic epistasis in Drosophila model, functional PI3P and fusion readouts, single lab\",\n      \"pmids\": [\"36323251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MARCH7 (MARCHF7), an E3 ubiquitin ligase, ubiquitinates ATG14 with K6-, K11-, and K63-linked mixed polyubiquitin chains, causing ATG14 aggregation and reduced solubility. Ubiquitinated ATG14 has fewer interactions with STX17, inhibiting autophagy flux. MARCH7 depletion decreases aggresome-like induced structures.\",\n      \"method\": \"E3 ligase identification by Co-IP, in vitro/in cell ubiquitination assay with chain-type mapping, ATG14 solubility fractionation, STX17 binding assay for ubiquitinated vs. unmodified ATG14, MARCH7 KO cell analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ubiquitination assay with chain-type specificity, solubility assay, interaction assay with downstream SNARE, genetic KO, multiple orthogonal methods\",\n      \"pmids\": [\"37632749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RUNDC1 interacts with ATG14 and negatively regulates autophagy by blocking autophagosome-lysosome fusion. RUNDC1 clasps the ATG14-STX17-SNAP29 complex by stimulating ATG14 homo-oligomerization, preventing ATG14 dissociation and VAMP8 binding to STX17-SNAP29. Phosphorylation of RUNDC1 Ser379 is crucial for this inhibitory mechanism in human cells and zebrafish.\",\n      \"method\": \"Co-immunoprecipitation, gain/loss-of-function in human cells and zebrafish, STX17-SNAP29-VAMP8 complex assembly assay, ATG14 homo-oligomerization assay, phosphorylation site mutagenesis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, SNARE assembly assay, phospho-site mutagenesis, zebrafish model, single lab\",\n      \"pmids\": [\"37684417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP1 interacts with ATG14, deubiquitinates it, and enhances ATG14 protein stability by reducing ubiquitin binding. USP1 inhibition promotes proteasome-dependent ATG14 degradation, reducing autophagy initiation and flux.\",\n      \"method\": \"Co-immunoprecipitation of USP1 with ATG14, ubiquitination level assay with USP1 overexpression/inhibition, proteasomal inhibition rescue, autophagy flux measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome rescue experiment, single lab\",\n      \"pmids\": [\"39814232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"S. pneumoniae CbpC interacts with ATG14 via ATG14's coiled-coil domain and CbpC residue Y83 (dp3 domain), activating autophagy. However, CbpC also acts as a decoy by recruiting ATG14 to p62/SQSTM1-dependent autophagic degradation, depleting ATG14 and impairing ATG14-STX17 complex formation, thereby suppressing bactericidal autophagy and promoting pneumococcal intracellular survival.\",\n      \"method\": \"Co-immunoprecipitation of CbpC with ATG14, domain mutagenesis (Y83), ATG14 protein level measurement in infected cells, ATG14-STX17 complex formation assay, bacterial survival assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain mutagenesis, complex formation assay, bacterial survival readout, single lab\",\n      \"pmids\": [\"32239622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATG14 and ATG7 are both required to restrict Mycobacterium tuberculosis replication in human iPSC-derived macrophages. ATG14 deletion specifically impairs phagosome-lysosome fusion in phagosomes containing Mtb, enabling both cytosolic and phagosomal bacterial restriction, while ATG7 primarily controls canonical autophagy of cytosolic Mtb.\",\n      \"method\": \"CRISPR-Cas9 deletion of ATG14 and ATG7 in iPSDM, single-cell high-content imaging with Mtb replication reporters, phagosome-lysosome fusion quantitative imaging with Mtb mutant panel\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO in human iPSC-derived primary cells, quantitative single-cell imaging, Mtb mutant epistasis, multiple bacterial strains\",\n      \"pmids\": [\"36959508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATG14 targets lipid droplets (LDs) via its BATS domain and acts as an autophagic receptor for lipophagy by interacting with ATG8 family proteins. STX18 (syntaxin 18) binds ATG14, disrupting ATG14-ATG8 interactions and PI3KC3-C1 complex formation. Coronavirus M protein binds STX18 to subvert the STX18-ATG14 interaction and induce lipophagy to degrade the anti-viral protein Viperin.\",\n      \"method\": \"BATS domain mutagenesis for LD targeting, Co-immunoprecipitation of ATG14 with ATG8 family members and STX18, STX18 knockdown-dependent lipophagy assay, Viperin degradation assay with coronavirus M protein\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mutagenesis, reciprocal Co-IP, functional lipophagy assay, viral protein epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"38245527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATG14 localizes to lipid droplets via its BATS domain and directly interacts with adipose triglyceride lipase (ATGL) and its coactivator CGI-58. ATG14 enhances the ATGL-CGI58 interaction; ATG14 deficiency markedly decreases triglyceride hydrolysis in hepatocytes.\",\n      \"method\": \"Fluorescence imaging of ATG14 on lipid droplets, BATS domain deletion/mutagenesis, co-immunoprecipitation of ATG14 with ATGL and CGI-58, in vitro lipolysis assay in ATG14-deficient hepatocytes and mouse livers\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro lipolysis reconstitution, domain mutagenesis, Co-IP of endogenous proteins, both cell and in vivo KO validation\",\n      \"pmids\": [\"37741434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GULP1 (engulfment adaptor GULP1) interacts with ATG14 and potentiates its stimulatory effect on PI3KC3-C1 activity. GULP1 facilitates targeting of ATG14 to the ER. A GULP1 mutation disrupting the GULP1-ATG14 interaction abolishes these effects. GULP1-APP complex (via GULP1-ATG14 axis) further enhances PI3KC3-C1 activity and promotes APP processing by directing APP into autophagic vacuoles.\",\n      \"method\": \"Co-immunoprecipitation of GULP1 with ATG14, PI3KC3-C1 kinase activity assay, GULP1 mutant (disrupted ATG14 binding) rescue assay, ER targeting assay by fluorescence microscopy, autophagic vacuole fractionation for APP/ATG14 co-localization\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, kinase activity assay, mutant rescue, single lab\",\n      \"pmids\": [\"39080084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATG14 is regulated transcriptionally by FoxO transcription factors and circadian clock machinery (Clock/Bmal1) in mouse liver. Knockdown of ATG14 in mouse liver leads to elevated triglycerides in liver and serum; overexpression of ATG14 improves hypertriglyceridemia in high-fat diet and FoxO1/3/4 liver KO mice.\",\n      \"method\": \"Luciferase reporter assays, chromatin immunoprecipitation (ChIP) for FoxOs and Clock/Bmal1 at ATG14 promoter, liver-specific ATG14 knockdown and overexpression in mice, liver triglyceride and serum lipid measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter for transcriptional regulation, in vivo KD/OE with metabolic phenotype, single lab\",\n      \"pmids\": [\"22992773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATG14 safeguards oviduct cellular integrity by suppressing pyroptosis. Conditional depletion of Atg14 in oviduct causes severe structural abnormalities and abnormal embryo retention. Mechanistically, Atg14 loss triggers unscheduled pyroptosis via altered mitochondrial integrity in non-ciliary oviduct cells; pharmacological pyroptosis activation phenocopies the genetic defect.\",\n      \"method\": \"Conditional oviduct-specific Atg14 KO mice, histopathology for structural defects, embryo tracking assay, pyroptosis marker analysis, mitochondrial integrity assay, pharmacological pyroptosis induction\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse, pharmacological phenocopy, mitochondrial integrity assay, single lab\",\n      \"pmids\": [\"40100261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCCP-induced LC3 lipidation is independent of Beclin 1 and ATG14; FIP200 and ATG13 (ULK complex components) are only partially required, while ATG9 is required for CCCP-induced LC3 lipidation. This establishes that CCCP/mitophagy-induced autophagy can bypass the Beclin 1/ATG14 nucleation complex.\",\n      \"method\": \"Genetic deletion/siRNA knockdown of Beclin 1, ATG14, FIP200, ATG13, ATG9; LC3 lipidation assay (Western blot) under CCCP treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KD/KO of multiple autophagy components with defined biochemical readout (LC3 lipidation); finding is a negative result that is mechanistically informative: Beclin 1/ATG14 complex is dispensable for CCCP-induced LC3 lipidation\",\n      \"pmids\": [\"23402761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dapper1 (Dpr1) directly interacts with both Beclin1 and Atg14L, enhances the Beclin1-Vps34 interaction, and increases Vps34 lipid kinase activity, promoting autophagosome formation. Dpr1 ablation in the CNS results in motor coordination defects and accumulation of p62 and ubiquitinated proteins.\",\n      \"method\": \"Co-immunoprecipitation of Dpr1 with Beclin1 and Atg14L, Vps34 kinase activity assay, Dpr1 CNS-specific KO mice, LC3 puncta formation assay, p62/ubiquitin accumulation\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, kinase assay, genetic KO mice, single lab\",\n      \"pmids\": [\"24980960\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATG14 (ATG14L/Barkor/KIAA0831) is a core autophagy-specific subunit of the class III PI3-kinase complex I (PI3KC3-C1: VPS34-VPS15-Beclin1-ATG14) that is mutually exclusive with UVRAG-containing Complex II; it recruits the PI3K complex to the ER via its coiled-coil domain to generate PI3P and initiate autophagosome biogenesis, is targeted to curved PI3P-enriched autophagosomal membranes via its C-terminal BATS domain, and later promotes autophagosome-endolysosome fusion by directly binding the STX17-SNAP29 binary t-SNARE complex through its coiled-coil domain in an oligomerization-dependent manner; ATG14 activity is regulated by ULK1-mediated phosphorylation at Ser29 (stimulatory), ZBTB16-Cullin3 and MARCH7 E3-mediated ubiquitination (inhibitory), and USP1-mediated deubiquitination (stabilizing), and additionally functions as an autophagic receptor on lipid droplets and interfaces with SNARE machinery to regulate lipophagy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATG14 (ATG14L/Barkor) is the autophagy-specific subunit that defines a distinct class III PI3-kinase complex with Beclin 1, Vps34, and p150, mutually exclusive with UVRAG-containing complexes and essential for autophagosome formation [#0, #1]. Through its coiled-coil domain ATG14 binds Vps34 and Beclin 1, converting a metastable Beclin 1 homodimer into a stable, curved Beclin1–ATG14 heterodimer [#5, #17], and it enhances Vps34 lipid kinase activity to drive PI3P generation [#2]. ATG14 recruits this complex to the ER to establish the omegasome platform for autophagosome biogenesis; ER localization is required for autophagy, and its C-terminal BATS domain bears an amphipathic helix that senses highly curved PI3P/PI(4,5)P2-enriched autophagosomal membranes to target the complex [#3, #4]. In a separable late-stage function, ATG14 directly binds the SNARE core of STX17 through its coiled-coil domain and, via cysteine-repeat-mediated homo-oligomerization, stabilizes the STX17–SNAP29 t-SNARE complex and tethers membranes to promote autophagosome–endolysosome fusion; oligomerization is dispensable for PI3K stimulation but required for fusion [#10, #11]. ATG14 levels and activity are tightly regulated: ULK1 phosphorylates ATG14 at Ser29 to stimulate Vps34 activity [#13, #14], while turnover is controlled by ZBTB16-Cullin3 and MARCH7 E3 ubiquitination (inhibitory) [#12, #27] and USP1 deubiquitination (stabilizing) [#29]. Beyond degradative autophagy, ATG14 targets lipid droplets via its BATS domain, acting as an ATG8-binding autophagic receptor for lipophagy and as a direct enhancer of ATGL–CGI-58-mediated triglyceride hydrolysis [#32, #33]. Tissue-specific loss of ATG14 produces intestinal epithelial apoptosis, hypertrophic cardiomyopathy and vacuolar myopathy, reflecting its requirement for basal autophagy in vivo [#21, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that ATG14 nucleates a dedicated autophagy PI3-kinase complex, answering whether mammals have a discrete Vps34 complex committed to autophagosome formation.\",\n      \"evidence\": \"Co-IP, fluorescence localization, and siRNA knockdown with autophagosome readout in HeLa cells\",\n      \"pmids\": [\"18843052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the complex is targeted to membranes\", \"Structural basis of subunit assembly unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed mutually exclusive ATG14- vs UVRAG-Beclin1 complexes and demonstrated ATG14 stimulates Vps34 lipid kinase activity, defining ATG14 as a positive regulator of autophagic PI3P output.\",\n      \"evidence\": \"Reciprocal Co-IP, GFP localization, lipid kinase assay, and ATG14L knockout in mouse ES cells\",\n      \"pmids\": [\"19270696\", \"19270693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Vps34 activation not defined\", \"Membrane targeting determinant not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed ATG14 recruits the PI3K complex to the ER to generate PI3P and form omegasomes, identifying the ER as the autophagosome assembly platform.\",\n      \"evidence\": \"siRNA, point-mutagenesis rescue, ER-targeting domain swap, and KO ES cell complementation with omegasome imaging\",\n      \"pmids\": [\"20713597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the lipid/curvature signal sensed by ATG14\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the BATS domain as a curvature-sensing amphipathic helix that targets ATG14 to PI3P/PI(4,5)P2-enriched autophagosomal membranes, explaining membrane localization.\",\n      \"evidence\": \"Bioinformatics/mutagenesis, in vitro membrane binding and liposome curvature-sensing assays, cell imaging\",\n      \"pmids\": [\"21518905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of distinct phosphoinositides in vivo unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Structural and biochemical work showed ATG14 stabilizes Beclin 1 from a metastable homodimer into a curved heterodimer, providing the assembly logic of the complex.\",\n      \"evidence\": \"X-ray crystallography of Beclin 1 CCD with Co-IP and dimerization assays\",\n      \"pmids\": [\"22314358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-complex architecture with Vps34/Vps15 not solved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ATG14 to additional functions: a Beclin 1-independent Snapin interaction in endosome maturation and a role in transcriptional/metabolic control of hepatic lipid homeostasis.\",\n      \"evidence\": \"Co-IP, domain-mutant rescue (Snapin); ChIP, reporter assays, and liver KD/OE with lipid measurements (FoxO/Clock)\",\n      \"pmids\": [\"22797916\", \"22992773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Snapin interaction validated in a single lab\", \"Direct transcriptional regulation vs indirect metabolic effect not fully separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a separable late-autophagy function: ATG14 directly binds STX17 and, via homo-oligomerization, stabilizes the STX17-SNAP29 t-SNARE and promotes autophagosome-lysosome fusion.\",\n      \"evidence\": \"In vitro reconstituted membrane tethering/fusion with proteoliposomes, SNARE binding assays, oligomerization mutant cell lines\",\n      \"pmids\": [\"25686604\", \"25945523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How biogenesis and fusion functions are temporally switched not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ULK1-mediated Ser29 phosphorylation of ATG14 as a stimulatory input coupling nutrient/mTOR status to Vps34 activation.\",\n      \"evidence\": \"Phospho-specific antibody, in vitro ULK1 and Vps34 kinase assays, ATG13-dependent Co-IP, HD mouse model\",\n      \"pmids\": [\"27938392\", \"27046250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing Ser29 not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified multiple positive regulators (NRBF2, PAQR3, PIPKIγ i5) feeding into ATG14-Vps34 activity and complex assembly, integrating metabolic and lipid cues.\",\n      \"evidence\": \"Co-IP, MIT/BATS binding assays, Vps34/PI3P kinase assays, KO mice (NRBF2, PAQR3); KD phenotypes\",\n      \"pmids\": [\"24849286\", \"25086043\", \"26834238\", \"27621469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NRBF2 directionality on Vps34 activity conflicts between studies\", \"PIPKIγ i5 and PAQR3 effects validated in single labs\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined the ULK1 input by showing ATG14-complex-specific BECN1 Ser30 phosphorylation and an O-GlcNAcylation switch on ULK1 controlling ATG14 binding.\",\n      \"evidence\": \"In vitro ULK1 kinase assays, S30A mutagenesis, PIK3C3 activity assays; mass spec PTM mapping with OGT inhibitor studies\",\n      \"pmids\": [\"29313410\", \"30517873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAc/ULK1 mechanism from single lab\", \"Integration of Ser29 and Ser30 phosphorylation events not fully ordered\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified GLIPR2 as a direct negative regulator of the ATG14-Beclin1 lipid kinase complex, expanding the network controlling PI3P output.\",\n      \"evidence\": \"In vitro lipid kinase assay with purified complex plus recombinant GLIPR2, CRISPR KO in cells and mice\",\n      \"pmids\": [\"33222586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context selecting GLIPR2 inhibition unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In vivo conditional KO studies defined ATG14's tissue-essential roles, showing intestinal epithelial TNF-sensitive apoptosis and muscle vacuolar myopathy/cardiomyopathy.\",\n      \"evidence\": \"Tissue-specific conditional KO mice, histopathology, caspase markers, TNFR1 epistasis; comparison to RB1CC1 KO\",\n      \"pmids\": [\"30894050\", \"33794726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phenotypes reflect canonical autophagy loss or non-canonical ATG14 functions not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined opposing ubiquitin-dependent control of ATG14 abundance/activity and a clasp-based fusion brake, establishing ATG14 as a tightly regulated node.\",\n      \"evidence\": \"MARCH7 ubiquitination/solubility/STX17-binding assays; USP1 deubiquitination and proteasome rescue; RUNDC1 SNARE-assembly and oligomerization assays\",\n      \"pmids\": [\"37632749\", \"39814232\", \"37684417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RUNDC1 and USP1 mechanisms from single labs\", \"Coordination among MARCH7, ZBTB16-Cul3, and USP1 unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ATG14 is targeted by pathogens and required for anti-bacterial autophagy, linking its STX17-fusion function to host defense.\",\n      \"evidence\": \"CRISPR KO in iPSC-derived macrophages with single-cell Mtb imaging; pneumococcal CbpC Co-IP and ATG14-STX17 complex/survival assays\",\n      \"pmids\": [\"36959508\", \"32239622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CbpC decoy mechanism from single lab\", \"Generality across other intracellular pathogens unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a degradation-independent metabolic role: ATG14 acts as a lipid-droplet autophagic receptor for lipophagy and directly potentiates ATGL-CGI58 lipolysis.\",\n      \"evidence\": \"BATS-domain LD-targeting mutagenesis, ATG8/STX18 Co-IP and lipophagy assays; ATGL-CGI58 Co-IP and in vitro lipolysis in ATG14-deficient hepatocytes/livers\",\n      \"pmids\": [\"38245527\", \"37741434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between ATG14's receptor and lipase-activating roles not integrated\", \"Switch between degradative and lipolytic functions undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATG14 switches between its early PI3P-generating biogenesis role and its late STX17-dependent fusion role, and how its many regulators are integrated in time, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No temporal model coordinating biogenesis vs fusion functions\", \"Full-length complex structure with membrane not solved\", \"Hierarchy among phosphorylation, ubiquitination, and lipid cues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 16, 32, 33]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 11, 0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 3, 34]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [32, 33]},\n      {\"term_id\": \"GO:0005776\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 3, 10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [33, 35]}\n    ],\n    \"complexes\": [\n      \"PI3KC3 complex I (VPS34-VPS15-Beclin1-ATG14)\",\n      \"STX17-SNAP29 t-SNARE complex (binding partner)\"\n    ],\n    \"partners\": [\n      \"BECN1\",\n      \"PIK3C3/VPS34\",\n      \"STX17\",\n      \"SNAP29\",\n      \"NRBF2\",\n      \"ULK1\",\n      \"MARCHF7\",\n      \"ATGL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}