{"gene":"BECN1","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2007,"finding":"Atg6/Beclin 1 (BECN1) is a core component of a lipid kinase complex (class III PI3-kinase/Vps34 complex) required for autophagosome formation; yeast Vps30/Atg6 is required for both autophagy and vacuolar protein sorting","method":"Genetic complementation, fractionation, and physiological studies in yeast and multiple model organisms","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple labs and organisms, foundational review synthesizing extensive experimental work","pmids":["17893711"],"is_preprint":false},{"year":1997,"finding":"Yeast Vps30 (Atg6/BECN1 ortholog) is required for endosome-to-Golgi retrieval of the vacuolar sorting receptor Vps10p; loss of Vps30 causes mislocalization of Vps10p to the vacuole via a Pep12p-dependent endosomal route","method":"Temperature-sensitive allele generation, subcellular fractionation, genetic epistasis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, foundational paper, >350 citations","pmids":["9105038"],"is_preprint":false},{"year":2009,"finding":"NF-κB subunit p65/RelA directly binds a conserved κB site in the BECN1 promoter and upregulates BECN1 transcription, coupling NF-κB signaling to increased autophagy","method":"Promoter reporter assays, EMSA, ChIP, siRNA knockdown, Western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (EMSA, ChIP, promoter assay) in multiple cell systems","pmids":["19289499"],"is_preprint":false},{"year":2016,"finding":"AMPK phosphorylates BECN1 at Thr388, which is required for autophagy induction upon glucose withdrawal; phosphorylation promotes BECN1 interaction with PIK3C3 and ATG14 while reducing BCL2 binding and homodimerization","method":"In vitro kinase assay, phosphorylation-defective/mimic mutants, co-immunoprecipitation, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay plus mutagenesis plus co-IP with defined phenotype","pmids":["27304906"],"is_preprint":false},{"year":2018,"finding":"AMPK-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation, inhibition of system Xc- cystine/glutamate antiporter activity, lipid peroxidation, and ferroptosis","method":"shRNA knockdown, phosphorylation-defective mutants (S90,93,96A), co-immunoprecipitation, in vitro ferroptosis assays, in vivo mouse tumor models","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, phospho-defective mutant rescue, in vivo validation; multiple orthogonal methods","pmids":["30057310"],"is_preprint":false},{"year":2021,"finding":"IL-6 activates JAK2 which directly phosphorylates BECN1 at Y333, and Y333 phosphorylation is required for PI3KC3 complex formation and IL-6-induced autophagy","method":"Co-immunoprecipitation, kinase assays, phospho-mutant constructs, autophagy flux assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct interaction mapping, phospho-mutant phenotype, multiple orthogonal methods","pmids":["34131122"],"is_preprint":false},{"year":2008,"finding":"BECN1 (ATG6) is a caspase substrate; caspase-mediated cleavage of BECN1 links apoptotic and autophagic signaling pathways, and overexpression of BECN1 suppresses cell death","method":"In vitro caspase cleavage assay, pan-caspase inhibitor (zVAD), siRNA knockdown, ectopic expression","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro cleavage assay plus cellular functional follow-up","pmids":["18842334"],"is_preprint":false},{"year":2021,"finding":"CUL3 E3 ubiquitin ligase interacts with BECN1 via the substrate adaptor KLHL38 to promote K48-linked ubiquitination and proteasomal degradation of BECN1, thereby suppressing autophagy","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, cycloheximide chase, CRISPR/shRNA","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, ubiquitination assay with linkage specificity, substrate adaptor identified","pmids":["33977871"],"is_preprint":false},{"year":2014,"finding":"RNF216 E3 ubiquitin ligase interacts with BECN1 and promotes K48-linked ubiquitination of BECN1 via its TRIAD domain, causing BECN1 degradation and autophagy inhibition in macrophages","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, bacterial infection model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction, K48 linkage specificity mapped to TRIAD domain, functional consequence shown","pmids":["25484083"],"is_preprint":false},{"year":2018,"finding":"ULK1 phosphorylates BECN1 at Ser30 specifically within the ATG14-containing PI3KC3 complex (but not the UVRAG complex), and this phosphorylation is required for ATG14-PI3KC3 kinase activation, phagophore formation, and autophagy induction under amino acid starvation","method":"In vitro kinase assay, phospho-site mutants (S30A), co-immunoprecipitation, autophagy flux assays, LC3/phagophore imaging","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay, site-specific mutant rescue, complex-specific phosphorylation confirmed","pmids":["29313410"],"is_preprint":false},{"year":2016,"finding":"CAMK2, activated by TRPM2-mediated Ca2+ influx under oxidative stress, phosphorylates BECN1 at Ser295, which decreases BECN1-PIK3C3 association while increasing BECN1-BCL2 binding, thereby inhibiting autophagy","method":"In vitro kinase assay, co-immunoprecipitation, TRPM2 knockout/knockdown, phospho-mutant constructs","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — direct kinase assay, pathway epistasis, multiple orthogonal methods","pmids":["27245989"],"is_preprint":false},{"year":2015,"finding":"BECN1 is ISGylated by ISG15 at Lys117, Lys263, Lys265, and Lys266 (in competition with K63-linked ubiquitination) in response to type I interferon, and this ISGylation negatively regulates autophagy and EGFR degradation dependent on class III PI3K activity; SENP3 deSUMOylates BECN1 at K380","method":"ISGylation assay, site-directed mutagenesis, USP18 deISGylation assay, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — site mapping by mutagenesis, competition with ubiquitination demonstrated, single-lab study","pmids":["25906440"],"is_preprint":false},{"year":2019,"finding":"BECN1 is SUMO3-conjugated by PIAS3 at K380 and deSUMOylated by SENP3; SUMOylation of BECN1 promotes its interaction with UVRAG, PIK3C3, and ATG14, activates PIK3C3 activity, and enhances autophagosome formation","method":"SUMOylation assay with site-directed mutagenesis, co-immunoprecipitation, PIK3C3 activity assay, liver-specific Senp3 knockout mouse, autophagic flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis, E3 ligase identified, kinase activity assay, in vivo genetic validation","pmids":["31373534"],"is_preprint":false},{"year":2018,"finding":"The BECN1 BARA domain (specifically β-sheet 1) undergoes partial unfolding/membrane insertion to mediate PI3KC3 complex membrane targeting; this mechanism is exploited by BECN1 peptides to activate both PI3KC3-C1 and -C2, inhibited by Rubicon binding to the BARA β-sheet 1, and blocked by HIV-1 Nef which also targets this region","method":"Hydrogen-deuterium exchange, cryo-EM, protein engineering, giant unilamellar vesicle assays, molecular simulations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure, HDX, protein engineering, and reconstitution all in one study","pmids":["30581147"],"is_preprint":false},{"year":2016,"finding":"The BECN1 coiled-coil domain (CCD) forms an antiparallel homodimer; BECN1 CCD interface residues also mediate parallel heterodimer formation with ATG14, and mutations at the heterodimer interface abrogate starvation-induced autophagy without affecting basal autophagy","method":"X-ray crystallography (1.46 Å), SAXS, circular dichroism, co-immunoprecipitation with interface mutants, autophagy flux assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus functional mutagenesis plus SAXS","pmids":["27383850"],"is_preprint":false},{"year":2016,"finding":"BECN1 contains a flexible helical domain (FHD) between the BH3 and coiled-coil domains that is partially disordered and undergoes a disorder-to-helix transition; conserved FHD residues are required for starvation-induced autophagy","method":"X-ray crystallography (2.0 Å SAD), circular dichroism, DEER-EPR, SAXS, MD simulations, cellular autophagy assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus multiple biophysical methods plus functional cellular validation","pmids":["26937551"],"is_preprint":false},{"year":2019,"finding":"STK4/MST1 phosphorylates BECN1 at Thr108 within the BH3 domain, modestly increasing BECN1 affinity for BCL2 and BCL2L1; X-ray crystal structures of BCL2 and BCL2L1 with T108-modified BECN1 BH3 peptides indicate the interaction with a conserved histidine is influenced by membrane-like environments","method":"X-ray crystallography, biophysical binding assays (SPR, MST), molecular dynamics simulations","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biophysical binding measurements plus MD","pmids":["30626284"],"is_preprint":false},{"year":2014,"finding":"ARRB1 (β-arrestin-1) interacts with both BECN1 and PIK3C3 under ischemic stress to form a BECN1 autophagic core complex; loss of ARRB1 impairs BECN1-PIK3C3 interaction, reduces PIK3C3 kinase activity, and suppresses autophagosome formation, leading to neuronal apoptosis/necrosis","method":"Co-immunoprecipitation, PIK3C3 kinase activity assay, Arrb1 knockout mouse model, oxygen-glucose deprivation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, kinase activity assay, genetic KO with defined phenotype","pmids":["24988431"],"is_preprint":false},{"year":2015,"finding":"BCL2-BECN1 binding is disrupted by BH3 mimetic ABT-737 in a BAX/BAK1-independent mechanism to induce autophagy, demonstrating that BCL2 inhibits autophagy directly through BECN1 binding rather than indirectly via proapoptotic BCL2 family members","method":"Genetic BAX/BAK1 double-knockout cell lines, BCL2-BECN1 co-immunoprecipitation, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic genetic system with co-IP and functional autophagy assay","pmids":["25715028"],"is_preprint":false},{"year":2017,"finding":"The Becn1 F121A knock-in mutation disrupts BECN1-BCL2 interaction, leading to constitutively hyperactive autophagy in vivo; this hyperactive autophagy sequesters Aβ oligomers inside autophagosomes and prevents Alzheimer's disease progression","method":"Knock-in mouse generation, co-immunoprecipitation, immunoisolation of autophagosomes, behavioral/cognitive testing, in vivo autophagy flux","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic knock-in with structural basis, multiple functional readouts, in vivo validation","pmids":["28806762"],"is_preprint":false},{"year":2015,"finding":"BECN1 knockout using TALEN in human cells reveals that BECN1 is dispensable for LC3 lipidation but essential for functional autophagosome formation; BECN1-null cells form malformed multi-membrane autophagosome-like structures and have impaired PI3KC3 complex activity and autophagic flux","method":"TALEN-mediated gene knockout, electron microscopy, LC3 lipidation assay, PI3KC3 kinase activity assay, autophagy flux","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — complete genetic KO, ultrastructural EM analysis, kinase activity assay; multiple orthogonal methods","pmids":["25955014"],"is_preprint":false},{"year":2020,"finding":"GLIPR2 binds to BECN1 (amino acids 267-284 region) and directly inhibits the in vitro lipid kinase activity of purified PI3KC3-C1 complex; GLIPR2 knockout increases autophagic flux and PI3P generation in cells and tissues","method":"CRISPR-Cas9 knockout, in vitro lipid kinase assay with purified complex, co-immunoprecipitation, autophagic flux assays, WIPI2 recruitment","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase reconstitution assay with purified complex, genetic KO in cells and mice","pmids":["33222586"],"is_preprint":false},{"year":2011,"finding":"BEC-1 (C. elegans BECN1 ortholog) mediates retrograde endosome-to-Golgi transport in addition to autophagy; bec-1 mutants show reduced RME-8 on endosomal membranes, accumulation of abnormal endosomes, and mislocalization/degradation of MIG-14/Wntless","method":"C. elegans genetics, fluorescence microscopy, RNAi, morphological analysis of endosomes","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model organism with defined trafficking pathway, multiple markers","pmids":["21183797"],"is_preprint":false},{"year":2013,"finding":"Drosophila Atg6 (BECN1 ortholog) is required for autophagy, endocytosis, and protein secretion, but not all these functions overlap with other core autophagy genes; Atg6 mutants show enlarged lymph glands and excess blood cells in a manner not suppressed by p62 or NFκB mutations","method":"Drosophila null mutant generation, genetic epistasis, endocytosis/secretion assays, hematopoietic analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic null mutants with epistasis analysis, multiple cellular pathway readouts","pmids":["23406899"],"is_preprint":false},{"year":2015,"finding":"VDAC2 interacts with both BECN1 and BCL2L1 to stabilize the BECN1-BCL2L1 inhibitory complex in ovarian cells, suppressing autophagy; VDAC2 transgenic pigs show inhibited ovarian autophagy while Vdac2 knockout promotes autophagy","method":"Co-immunoprecipitation, transgenic pig model, Vdac2 knockout, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus genetic gain/loss-of-function in multiple model systems","pmids":["26060891"],"is_preprint":false},{"year":2018,"finding":"TRIM59 regulates BECN1 by two mechanisms: (1) negatively modulating NF-κB pathway to suppress BECN1 transcription, and (2) promoting K48-linked ubiquitination and degradation of TRAF6, thereby reducing TRAF6-induced K63-linked ubiquitination of BECN1 and impairing BECN1-PIK3C3 complex formation","method":"Reporter assays, co-immunoprecipitation, ubiquitination assays, autophagy flux, overexpression/knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — dual mechanism with multiple orthogonal assays, single lab","pmids":["30231667"],"is_preprint":false},{"year":2014,"finding":"TRAF6 promotes K63-linked ubiquitination of BECN1, which is required for BECN1-PI3KC3 complex formation and autophagy induction in response to TLR4 stimulation","method":"Co-immunoprecipitation, ubiquitination assay, knockdown, TLR4 stimulation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay with linkage specificity plus complex formation assay","pmids":["30231667","32384667","31620128"],"is_preprint":false},{"year":2016,"finding":"USP19 deubiquitinase affects BECN1 ubiquitination, promoting autophagosome formation and inhibiting DDX58/RIG-I-mediated type I interferon signaling, revealing a BECN1-USP19 axis linking autophagy and antiviral immunity","method":"Co-immunoprecipitation, ubiquitination assays, interferon signaling assays, knockdown","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 — limited mechanistic detail in abstract, single co-IP approach reported","pmids":["27096686"],"is_preprint":false},{"year":2016,"finding":"HCMV proteins TRS1 and IRS1 contain a BECN1-binding domain (BBD) that is essential for autophagy inhibition; deletion of the BBD from TRS1 abolishes its ability to block autophagy, demonstrating direct binding to BECN1 is required","method":"Domain mapping, BBD deletion mutant viruses, co-immunoprecipitation, autophagy assays in multiple cell lines","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with deletion mutants and functional rescue in viral context","pmids":["26654401"],"is_preprint":false},{"year":2015,"finding":"GADD45A directly interacts with BECN1 (via GADD45A residues 71-81) and disrupts the BECN1-PIK3C3 complex, inhibiting autophagosome initiation; BECN1 knockdown abolishes GADD45A-induced autophagy changes","method":"Co-immunoprecipitation, GST pull-down assay, domain mapping, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — GST pull-down plus co-IP, domain mapping, genetic epistasis with BECN1 KD","pmids":["26636486"],"is_preprint":false},{"year":2017,"finding":"Phosphorylated CAV1 (at Tyr14) interacts with the BECN1/VPS34 complex via CAV1's scaffolding domain under oxidative stress, promoting autophagosome formation and mitochondrial localization of BECN1; PTPN1 phosphatase reverses this by dephosphorylating CAV1","method":"Co-immunoprecipitation, phospho-mutant constructs, Cav1 knockout mouse, LC3 foci imaging, subcellular fractionation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with phospho-mutant, genetic KO mouse, multiple autophagy readouts","pmids":["28542134"],"is_preprint":false},{"year":2016,"finding":"BECN1 directly interacts with plasma membrane-associated APP via the evolutionarily conserved domain (ECD, residues 267-337), and ECD subregion deletion (285-299) impairs APP-BECN1 interaction and APP endocytosis/lysosomal degradation without affecting BECN1-PIK3C3 interaction or autophagy; AKT-mediated phosphorylation of BECN1 Ser295 negatively regulates APP-BECN1 association","method":"Co-immunoprecipitation, domain deletion mutants, surface APP internalization assays, lysosomal degradation assays, APP metabolite secretion","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping, co-IP, functional internalization assay, phospho-mutant effects","pmids":["27715386"],"is_preprint":false},{"year":2021,"finding":"Becn1 promotes adiponectin secretion in adipose tissue by interacting with components of the exocyst complex via its coiled-coil domain; this is a non-degradative, non-cell-autonomous mechanism by which Becn1 improves systemic insulin sensitivity and activates AMPK","method":"Becn1F121A knock-in mice, adipose-specific expression, co-immunoprecipitation with exocyst components, adiponectin secretion assays, AMPK activation measurement","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knock-in mouse, co-IP, domain-specific (CCD) interaction, functional secretion assay","pmids":["34038729"],"is_preprint":false},{"year":2020,"finding":"PKD2 forms a protein complex with BECN1 via PKD2's CC1 coiled-coil domain, and this complex formation requires Ca2+ channel activity; PKD2 overexpression induces autophagy through increased BECN1 interaction, while a Ca2+-channel-deficient mutant (D509V) shows diminished BECN1 binding and fails to induce autophagy","method":"Co-immunoprecipitation, domain deletion mutants, Ca2+ chelation (BAPTA-AM), PKD2 mutant expression, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping, Ca2+-dependence assay, loss-of-function mutant with phenotypic readout","pmids":["32543276"],"is_preprint":false},{"year":2024,"finding":"VCP/p97 is UFMylated at K109 by E3 ligase UFL1; this modification promotes BECN1 stabilization through ATXN3-mediated deubiquitination of BECN1, thereby facilitating PI3KC3 complex assembly and autophagy initiation","method":"UFMylation site mapping, ATXN3 deubiquitination assay, co-immunoprecipitation of PI3KC3 complex, VCP knockdown/rescue with UFMylation-defective mutant","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — modification site identified, deubiquitinase identified, complex assembly assayed, rescue with mutant","pmids":["38762759"],"is_preprint":false},{"year":2019,"finding":"HSPB6 wild-type protein interacts with BECN1, preventing BECN1 ubiquitination and proteasomal degradation, and competitively suppresses BECN1-BCL2 binding to stimulate autophagy; the DCM-associated mutant HSPB6S10F shows reduced BECN1 interaction, leading to BECN1 ubiquitination, degradation, and autophagy inhibition","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, autophagy flux assays, transgenic mouse hearts","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — disease mutant vs. WT comparison, multiple biochemical assays, in vivo cardiac model","pmids":["29157081"],"is_preprint":false},{"year":2020,"finding":"HIV-1 Nef enhances the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner to block autophagy initiation, in addition to previously known effects on autophagy maturation","method":"Co-immunoprecipitation, PRKN knockout/knockdown, autophagy flux assays, viral replication assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP of BECN1-BCL2 complex modulated by Nef, PRKN dependency shown genetically","pmids":["32097085"],"is_preprint":false},{"year":2022,"finding":"USP15 deubiquitinase interacts with BECN1 (not TRAF6) and induces deubiquitination of BECN1, thereby attenuating autophagy induction and lung cancer migration downstream of the TLR4-TRAF6-BECN1 axis","method":"CRISPR-Cas9 USP15 knockout, co-immunoprecipitation, deubiquitination assay, cancer migration/invasion assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO, direct interaction co-IP, deubiquitination assay, functional cancer phenotype","pmids":["35422093"],"is_preprint":false},{"year":2019,"finding":"BECN1 interacts with the tight junction protein occludin at the intestinal epithelial membrane; Tat-beclin 1 peptide activates BECN1 and promotes occludin endocytosis and reduction in total occludin levels, increasing TJ permeability in an autophagy-independent manner","method":"Co-immunoprecipitation, immunofluorescence colocalization, permeability assays, BECN1 siRNA, mouse colon perfusion","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP, functional permeability assay, siRNA rescue, in vivo confirmation","pmids":["30892937"],"is_preprint":false},{"year":2016,"finding":"ASPP2 binds directly to BECN1 and inhibits autophagy by (1) repressing p65/RelA-induced BECN1 transcription via an ASPP2-p65-IκBα complex, and (2) competing with PIK3C3/UVRAG for BECN1 binding while promoting Rubicon-BECN1 interaction, thereby destabilizing the pro-autophagic PI3KC3 complex","method":"Co-immunoprecipitation, reporter assays, ChIP, overexpression/knockdown, autophagic flux assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP, ChIP, dual mechanism shown with multiple orthogonal methods","pmids":["27929538"],"is_preprint":false},{"year":2016,"finding":"SLC9A3R1 binds to BECN1 via its C-terminal domain, blocks ubiquitin-dependent BECN1 degradation, attenuates BECN1-BCL2 interaction, and stimulates autophagy in breast cancer cells","method":"Co-immunoprecipitation, domain deletion mutants, ubiquitination assay, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with domain mapping, ubiquitination assay, functional autophagy phenotype","pmids":["26218645"],"is_preprint":false},{"year":2015,"finding":"ABHD5 directly competes with caspase-3 for binding to the cleavage sites of BECN1, preventing caspase-3-mediated cleavage and inactivation of BECN1, thereby maintaining autophagic flux; ABHD5 deficiency allows caspase-3 to cleave BECN1 and impair autophagy","method":"Co-immunoprecipitation, competitive binding assay, caspase cleavage assay, autophagy flux assays, ABHD5 knockdown/overexpression","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — competitive binding mechanism shown biochemically, caspase cleavage prevented, functional consequence in cells","pmids":["27559856"],"is_preprint":false},{"year":2022,"finding":"Sorafenib activates SHP-1 which dephosphorylates STAT3, downregulates MCL1, and releases BECN1 from MCL1 binding; freed BECN1 then binds SLC7A11 (system Xc-) and inhibits cystine uptake, promoting ferroptosis in hepatocellular carcinoma","method":"Co-immunoprecipitation, siRNA knockdown, SHP-1/STAT3 pathway inhibition, MCL1 ectopic expression rescue","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis via co-IP and siRNA, MCL1 rescue experiment demonstrates mechanism","pmids":["36232407"],"is_preprint":false},{"year":2023,"finding":"BECN1 directly binds SLC7A11 (system Xc-) and the BECN1-SLC7A11 complex formation (promoted by SIRT3/AMPK-mediated autophagy) inhibits system Xc- activity, inducing ferroptosis","method":"Co-immunoprecipitation, siSIRT3/3-MA autophagy inhibition, erastin-induced ferroptosis assays, in vivo tumor model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP confirming complex, pathway inhibitor controls, in vivo validation","pmids":["37196680"],"is_preprint":false},{"year":2015,"finding":"BCL2L10/BCL-B interacts with the BH3 domain of BECN1 and inhibits autophagy; Bcl-B knockdown triggers autophagic cell death dependent on LC3, BECN1, and ATG5","method":"Co-immunoprecipitation, Bcl-B overexpression/knockdown, autophagy assays with multiple stimuli, genetic epistasis with ATG5/BECN1","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with BH3 domain specificity, genetic epistasis, functional autophagy readout","pmids":["22498477"],"is_preprint":false}],"current_model":"BECN1 (Beclin 1) functions as a central scaffold of the class III PI3-kinase (PI3KC3/VPS34) complexes that nucleate autophagosome formation by generating PI3P; its activity is controlled by a web of post-translational modifications (phosphorylation at multiple sites by AMPK, ULK1, JAK2, CAMK2, STK4; ubiquitination by CUL3/KLHL38, RNF216, and TRAF6; ISGylation by ISG15; SUMOylation by PIAS3/SENP3; UFMylation-dependent stabilization via VCP/p97-ATXN3) and protein–protein interactions that either promote autophagy (e.g., ATG14, UVRAG, PIK3C3, ARRB1, CAV1-pY14, PKD2, HSPB6) or inhibit it (e.g., BCL2/BCL2L1 binding to the BH3 domain, Rubicon and GLIPR2 binding to the BARA domain), while its BARA domain mediates membrane targeting through partial unfolding of β-sheet 1; beyond autophagy, phosphorylated BECN1 directly binds and blocks the SLC7A11 subunit of system Xc- to promote ferroptosis, interacts with the exocyst complex to facilitate adiponectin secretion, and regulates endocytic/retrograde trafficking in a PI3KC3-dependent manner."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that the BECN1 ortholog Vps30 functions in endosomal sorting revealed its primordial role beyond autophagy — it is required for endosome-to-Golgi retrieval of the vacuolar sorting receptor Vps10p.","evidence":"Temperature-sensitive alleles, subcellular fractionation, and genetic epistasis in S. cerevisiae","pmids":["9105038"],"confidence":"High","gaps":["Mammalian trafficking function not yet demonstrated","Whether sorting and autophagy functions are separable was unknown"]},{"year":2007,"claim":"Consolidation of BECN1 as a core subunit of the VPS34/PI3KC3 lipid-kinase complex resolved how it mechanistically contributes to autophagosome nucleation via PI3P generation.","evidence":"Genetic complementation, fractionation, and functional studies across yeast, worms, flies, and mammals","pmids":["17893711"],"confidence":"High","gaps":["Structural basis of BECN1 within the complex unresolved","Which post-translational modifications regulate complex assembly unknown"]},{"year":2008,"claim":"Discovery that BECN1 is a caspase substrate provided the first evidence for direct crosstalk between apoptotic and autophagic machineries at the level of BECN1 proteolysis.","evidence":"In vitro caspase cleavage assay and pan-caspase inhibitor treatment in human cells","pmids":["18842334"],"confidence":"Medium","gaps":["Cleavage sites not mapped at residue resolution in this study","Physiological relevance of cleavage fragments unclear"]},{"year":2009,"claim":"Identification of NF-κB/p65 as a direct transcriptional activator of the BECN1 promoter established a signaling input linking inflammatory pathways to autophagy gene expression.","evidence":"EMSA, ChIP, promoter reporter assays, and siRNA knockdown in multiple human cell lines","pmids":["19289499"],"confidence":"High","gaps":["Other transcription factors regulating BECN1 not systematically catalogued","In vivo relevance not tested"]},{"year":2011,"claim":"Demonstration that C. elegans BEC-1 controls retrograde endosome-to-Golgi transport of Wntless/MIG-14 confirmed that BECN1's trafficking role is conserved beyond yeast.","evidence":"Genetic analysis, RNAi, and fluorescence microscopy of endosomal markers in C. elegans","pmids":["21183797"],"confidence":"Medium","gaps":["Whether mammalian BECN1 similarly controls Wntless trafficking not shown","Dependence on PI3KC3 activity versus other BECN1 interactions not dissected"]},{"year":2014,"claim":"Mapping of TRAF6-mediated K63-linked ubiquitination and ARRB1 scaffolding as positive regulators of BECN1–PI3KC3 complex formation revealed that ubiquitin signaling and stress-specific adaptors control autophagy initiation at the BECN1 level.","evidence":"Co-IP, ubiquitination assays with linkage specificity, PI3KC3 kinase activity assays, Arrb1 knockout mice","pmids":["24988431","30231667"],"confidence":"Medium","gaps":["K63-ubiquitination sites on BECN1 not mapped","Relative contributions of ARRB1 and TRAF6 in different tissues unclear"]},{"year":2015,"claim":"Multiple studies converged to define the BCL2 family (BCL2, BCL2L1, BCL2L10/BCL-B) as direct BH3-domain-dependent inhibitors of BECN1 autophagy function, operating independently of BAX/BAK1 proapoptotic signaling.","evidence":"BH3 mimetic ABT-737 in BAX/BAK1 DKO cells, BCL2L10 co-IP/knockdown epistasis, VDAC2 stabilization of BECN1–BCL2L1 complex","pmids":["25715028","22498477","26060891"],"confidence":"Medium","gaps":["Quantitative affinities of different BCL2 family members for BECN1 BH3 not compared","In vivo relevance of BCL-B and VDAC2 regulation not fully characterized"]},{"year":2015,"claim":"BECN1 knockout in human cells showed it is dispensable for LC3 lipidation but essential for proper autophagosome morphology and autophagic flux, redefining its role as a quality-control scaffold rather than an absolute upstream requirement for LC3 conjugation.","evidence":"TALEN-mediated BECN1 KO, electron microscopy, PI3KC3 kinase activity assay","pmids":["25955014"],"confidence":"High","gaps":["Whether compensatory PI3K pathways explain residual LC3 lipidation unknown","Long-term cellular consequences of BECN1 loss not fully explored"]},{"year":2016,"claim":"High-resolution structures of the BECN1 coiled-coil domain (homodimer and ATG14 heterodimer interface) and the flexible helical domain (FHD) defined the structural logic by which BECN1 switches between inactive homodimer and active ATG14-bound heterodimer states during starvation-induced autophagy.","evidence":"X-ray crystallography (1.46 Å CCD; 2.0 Å FHD), SAXS, DEER-EPR, interface mutagenesis, autophagy flux assays","pmids":["27383850","26937551"],"confidence":"High","gaps":["Full-length BECN1 structure not yet solved","How FHD conformational change is triggered in cells unclear"]},{"year":2016,"claim":"Identification of multiple kinases (AMPK at Thr388, CAMK2 at Ser295) that phosphorylate BECN1 with opposing effects on PI3KC3 complex assembly versus BCL2 binding established phosphorylation as a bidirectional regulatory switch for autophagy.","evidence":"In vitro kinase assays, phospho-defective/mimic mutants, co-IP for PI3KC3/BCL2 binding, TRPM2-Ca²⁺ pathway epistasis","pmids":["27304906","27245989"],"confidence":"High","gaps":["Cross-talk between phosphorylation sites not systematically mapped","Phosphatases that reverse these modifications largely unknown"]},{"year":2017,"claim":"The Becn1-F121A knock-in mouse, which constitutively disrupts BECN1–BCL2 binding and hyperactivates autophagy, demonstrated that modulating BECN1 activity can prevent amyloid-β accumulation and Alzheimer's-like pathology in vivo.","evidence":"Knock-in mouse crossed with AD model, immunoisolation of autophagosomes, behavioral testing","pmids":["28806762"],"confidence":"High","gaps":["Whether this protection extends to tau pathology unknown","Mechanism of Aβ capture by autophagosomes not molecularly defined"]},{"year":2018,"claim":"AMPK-mediated phosphorylation of BECN1 at Ser90/93/96 was shown to promote direct binding to SLC7A11 and inhibition of system Xc⁻, establishing a non-autophagic ferroptosis-promoting function for BECN1.","evidence":"Phospho-defective mutant (S90,93,96A), reciprocal co-IP, ferroptosis assays, in vivo tumor models","pmids":["30057310"],"confidence":"High","gaps":["Whether BECN1-SLC7A11 interaction occurs at a specific membrane compartment unknown","Stoichiometry and structural basis of BECN1-SLC7A11 binding unresolved"]},{"year":2018,"claim":"Cryo-EM and hydrogen-deuterium exchange revealed that the BECN1 BARA domain β-sheet 1 undergoes partial unfolding to insert into membranes, providing a structural mechanism for PI3KC3 complex membrane targeting — exploited by Rubicon and HIV-1 Nef as an inhibitory binding site.","evidence":"Cryo-EM, HDX-MS, protein engineering, giant unilamellar vesicle reconstitution, molecular simulations","pmids":["30581147"],"confidence":"High","gaps":["Lipid specificity of BARA membrane insertion not fully defined","How partial unfolding is regulated in vivo unclear"]},{"year":2018,"claim":"ULK1 phosphorylation of BECN1 at Ser30 was shown to selectively activate the ATG14-containing PI3KC3-C1 complex (not the UVRAG complex), demonstrating subcomplex-specific kinase regulation.","evidence":"In vitro kinase assay, S30A mutant, complex-specific co-IP, phagophore imaging","pmids":["29313410"],"confidence":"High","gaps":["Whether other ULK1 phosphorylation sites exist on BECN1 not excluded","How Ser30 phosphorylation structurally favors ATG14 binding unknown"]},{"year":2019,"claim":"SUMO3 conjugation of BECN1 at K380 by PIAS3 (reversed by SENP3) was shown to promote interactions with UVRAG, PIK3C3, and ATG14 and enhance PI3KC3 kinase activity, adding SUMOylation to the post-translational code governing BECN1 complex assembly.","evidence":"SUMOylation site mutagenesis, PI3KC3 activity assay, liver-specific Senp3 KO mice","pmids":["31373534"],"confidence":"High","gaps":["Whether SUMOylation and ISGylation compete at overlapping sites not resolved","Tissue specificity of PIAS3-BECN1 regulation not explored"]},{"year":2019,"claim":"Crystal structures of BCL2/BCL2L1 with Thr108-phosphorylated BECN1 BH3 peptides showed that STK4/MST1-mediated phosphorylation fine-tunes BCL2 family binding affinity, influenced by membrane-like environments.","evidence":"X-ray crystallography, SPR, MST binding assays, molecular dynamics","pmids":["30626284"],"confidence":"High","gaps":["In vivo relevance of T108 phosphorylation for autophagy regulation not demonstrated","Whether STK4 and CAMK2 phosphorylation sites act synergistically unknown"]},{"year":2020,"claim":"GLIPR2 was identified as a direct inhibitor of PI3KC3-C1 kinase activity through binding to BECN1 residues 267–284, demonstrating that the BARA-adjacent region serves as a regulatory hotspot distinct from the BCL2-binding BH3 domain.","evidence":"In vitro lipid kinase assay with purified PI3KC3-C1, CRISPR KO in cells and mice, WIPI2 recruitment assay","pmids":["33222586"],"confidence":"High","gaps":["GLIPR2 regulation itself not characterized","Whether GLIPR2 competes with ASPP2/APP for the same BECN1 region unclear"]},{"year":2021,"claim":"Discovery that CUL3–KLHL38 mediates K48-linked ubiquitination and proteasomal degradation of BECN1 established a dedicated E3 ligase–adaptor pair for BECN1 turnover, complementing earlier identification of RNF216.","evidence":"Mass spectrometry, reciprocal co-IP, K48-linkage-specific ubiquitination assay, cycloheximide chase, CRISPR KO","pmids":["33977871"],"confidence":"High","gaps":["Relative contributions of CUL3/KLHL38 vs. RNF216 in different tissues not compared","BECN1 ubiquitination sites targeted by CUL3/KLHL38 not mapped"]},{"year":2021,"claim":"BECN1 was shown to interact with the exocyst complex via its coiled-coil domain to promote adiponectin secretion, establishing a non-degradative, non-cell-autonomous function for BECN1 in metabolic homeostasis.","evidence":"Becn1-F121A knock-in mice, adipose-specific expression, co-IP with exocyst components, adiponectin secretion and systemic AMPK activation assays","pmids":["34038729"],"confidence":"Medium","gaps":["Which exocyst subunit directly contacts BECN1 not identified","Whether PI3KC3 activity is required for this secretion function not tested"]},{"year":2024,"claim":"The UFMylation–VCP–ATXN3 axis was shown to stabilize BECN1 by promoting its deubiquitination, adding an additional layer of post-translational control over BECN1 protein levels and PI3KC3 complex assembly.","evidence":"UFMylation site mapping on VCP, ATXN3 deubiquitination assay, PI3KC3 co-IP, VCP knockdown/rescue with K109R mutant","pmids":["38762759"],"confidence":"Medium","gaps":["Whether ATXN3 removes K48- or K63-linked ubiquitin chains from BECN1 not specified","In vivo physiological contexts for UFMylation-dependent BECN1 regulation not explored"]},{"year":null,"claim":"A full-length structure of BECN1 within the intact PI3KC3 complex, including conformational dynamics of the FHD and BARA membrane-insertion states, has not been determined; the integration of multiple simultaneous post-translational modifications and their combinatorial effects on BECN1 function remain uncharacterized.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length BECN1 structure in the context of PI3KC3 complex","Combinatorial PTM code (phosphorylation, ubiquitination, SUMOylation, ISGylation, UFMylation) not systematically dissected","Structural basis of BECN1–SLC7A11 interaction in ferroptosis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,9,14,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,42,43]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,20]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,20]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[31,38]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,3,5,9,12,13,14,20,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,42,43]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,22,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,25,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8,34,37]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,28,36]}],"complexes":["PI3KC3-C1 (VPS34-VPS15-BECN1-ATG14)","PI3KC3-C2 (VPS34-VPS15-BECN1-UVRAG)","BECN1-BCL2 inhibitory complex"],"partners":["PIK3C3","ATG14","UVRAG","BCL2","BCL2L1","SLC7A11","TRAF6","RUBCN"],"other_free_text":[]},"mechanistic_narrative":"BECN1 (Beclin 1) is a central scaffold protein of the class III PI3-kinase (PI3KC3/VPS34) complex that orchestrates autophagosome formation, endosomal trafficking, and regulated cell death. Its coiled-coil domain mediates homodimerization and heterodimerization with ATG14 or UVRAG to assemble distinct PI3KC3 subcomplexes, while its BARA domain undergoes partial β-sheet unfolding to anchor the complex on membranes; these activities are positively regulated by ULK1 phosphorylation at Ser30, AMPK phosphorylation at Thr388, JAK2 phosphorylation at Y333, SUMO3 conjugation at K380, and TRAF6-mediated K63-linked ubiquitination, and negatively regulated by BCL2/BCL2L1 binding to its BH3 domain, Rubicon/GLIPR2 binding to the BARA domain, CAMK2 phosphorylation at Ser295, CUL3–KLHL38- and RNF216-mediated K48-linked ubiquitination and degradation, and ISGylation at multiple lysines [PMID:17893711, PMID:27304906, PMID:29313410, PMID:34131122, PMID:30581147, PMID:31373534, PMID:33977871, PMID:27245989, PMID:33222586, PMID:25906440]. Beyond autophagy, AMPK-phosphorylated BECN1 directly binds SLC7A11 to block system Xc⁻ cystine transport and promote ferroptosis, and BECN1 facilitates adiponectin secretion through interaction with the exocyst complex and participates in retrograde endosome-to-Golgi trafficking [PMID:30057310, PMID:34038729, PMID:9105038, PMID:21183797]. Disruption of the BECN1–BCL2 interaction by the F121A knock-in mutation constitutively activates autophagy in vivo, sequestering amyloid-β oligomers and preventing Alzheimer's disease-like pathology in mice [PMID:28806762]."},"prefetch_data":{"uniprot":{"accession":"Q14457","full_name":"Beclin-1","aliases":["Coiled-coil myosin-like BCL2-interacting protein","Protein GT197"],"length_aa":450,"mass_kda":51.9,"function":"Plays a central role in autophagy (PubMed:18570871, PubMed:21358617, PubMed:23184933, PubMed:23974797, PubMed:25484083, PubMed:28445460, PubMed:37776275). Acts as a core subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abscission step in cytokinesis, probably in the context of PI3KC3-C2 (PubMed:20208530, PubMed:20643123, PubMed:23974797, PubMed:26783301). Essential for the formation of PI3KC3-C2 but not PI3KC3-C1 PI3K complex forms. Involved in endocytosis (PubMed:25275521). May play a role in antiviral host defense Beclin-1-C 35 kDa localized to mitochondria can promote apoptosis; it induces the mitochondrial translocation of BAX and the release of proapoptotic factors (Microbial infection) Protects against infection by a neurovirulent strain of Sindbis virus","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q14457/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BECN1","classification":"Not Classified","n_dependent_lines":133,"n_total_lines":1208,"dependency_fraction":0.11009933774834436},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000126581","cell_line_id":"CID001942","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"ATG14","stoichiometry":10.0},{"gene":"UVRAG","stoichiometry":10.0},{"gene":"PIK3R4","stoichiometry":10.0},{"gene":"PIK3C3","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001942","total_profiled":1310},"omim":[{"mim_id":"620261","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 6; EMC6","url":"https://www.omim.org/entry/620261"},{"mim_id":"618990","title":"EVA1 HOMOLOG A, REGULATOR OF PROGRAMMED CELL DEATH; EVA1A","url":"https://www.omim.org/entry/618990"},{"mim_id":"616477","title":"NUCLEAR RECEPTOR-BINDING FACTOR 2; NRBF2","url":"https://www.omim.org/entry/616477"},{"mim_id":"616303","title":"WD REPEAT-CONTAINING PROTEIN 91; WDR91","url":"https://www.omim.org/entry/616303"},{"mim_id":"615687","title":"BECLIN 2; BECN2","url":"https://www.omim.org/entry/615687"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BECN1"},"hgnc":{"alias_symbol":["ATG6","VPS30"],"prev_symbol":[]},"alphafold":{"accession":"Q14457","domains":[{"cath_id":"1.10.418.40","chopping":"274-448","consensus_level":"high","plddt":85.1327,"start":274,"end":448}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14457","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14457-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14457-F1-predicted_aligned_error_v6.png","plddt_mean":76.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BECN1","jax_strain_url":"https://www.jax.org/strain/search?query=BECN1"},"sequence":{"accession":"Q14457","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14457.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14457/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14457"}},"corpus_meta":[{"pmid":"30057310","id":"PMC_30057310","title":"AMPK-Mediated BECN1 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for both autophagy and vacuolar protein sorting\",\n      \"method\": \"Genetic complementation, fractionation, and physiological studies in yeast and multiple model organisms\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs and organisms, foundational review synthesizing extensive experimental work\",\n      \"pmids\": [\"17893711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Vps30 (Atg6/BECN1 ortholog) is required for endosome-to-Golgi retrieval of the vacuolar sorting receptor Vps10p; loss of Vps30 causes mislocalization of Vps10p to the vacuole via a Pep12p-dependent endosomal route\",\n      \"method\": \"Temperature-sensitive allele generation, subcellular fractionation, genetic epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, foundational paper, >350 citations\",\n      \"pmids\": [\"9105038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NF-κB subunit p65/RelA directly binds a conserved κB site in the BECN1 promoter and upregulates BECN1 transcription, coupling NF-κB signaling to increased autophagy\",\n      \"method\": \"Promoter reporter assays, EMSA, ChIP, siRNA knockdown, Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (EMSA, ChIP, promoter assay) in multiple cell systems\",\n      \"pmids\": [\"19289499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AMPK phosphorylates BECN1 at Thr388, which is required for autophagy induction upon glucose withdrawal; phosphorylation promotes BECN1 interaction with PIK3C3 and ATG14 while reducing BCL2 binding and homodimerization\",\n      \"method\": \"In vitro kinase assay, phosphorylation-defective/mimic mutants, co-immunoprecipitation, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay plus mutagenesis plus co-IP with defined phenotype\",\n      \"pmids\": [\"27304906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AMPK-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation, inhibition of system Xc- cystine/glutamate antiporter activity, lipid peroxidation, and ferroptosis\",\n      \"method\": \"shRNA knockdown, phosphorylation-defective mutants (S90,93,96A), co-immunoprecipitation, in vitro ferroptosis assays, in vivo mouse tumor models\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, phospho-defective mutant rescue, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"30057310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-6 activates JAK2 which directly phosphorylates BECN1 at Y333, and Y333 phosphorylation is required for PI3KC3 complex formation and IL-6-induced autophagy\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, phospho-mutant constructs, autophagy flux assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapping, phospho-mutant phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34131122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BECN1 (ATG6) is a caspase substrate; caspase-mediated cleavage of BECN1 links apoptotic and autophagic signaling pathways, and overexpression of BECN1 suppresses cell death\",\n      \"method\": \"In vitro caspase cleavage assay, pan-caspase inhibitor (zVAD), siRNA knockdown, ectopic expression\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro cleavage assay plus cellular functional follow-up\",\n      \"pmids\": [\"18842334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CUL3 E3 ubiquitin ligase interacts with BECN1 via the substrate adaptor KLHL38 to promote K48-linked ubiquitination and proteasomal degradation of BECN1, thereby suppressing autophagy\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, cycloheximide chase, CRISPR/shRNA\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, ubiquitination assay with linkage specificity, substrate adaptor identified\",\n      \"pmids\": [\"33977871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RNF216 E3 ubiquitin ligase interacts with BECN1 and promotes K48-linked ubiquitination of BECN1 via its TRIAD domain, causing BECN1 degradation and autophagy inhibition in macrophages\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, bacterial infection model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction, K48 linkage specificity mapped to TRIAD domain, functional consequence shown\",\n      \"pmids\": [\"25484083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ULK1 phosphorylates BECN1 at Ser30 specifically within the ATG14-containing PI3KC3 complex (but not the UVRAG complex), and this phosphorylation is required for ATG14-PI3KC3 kinase activation, phagophore formation, and autophagy induction under amino acid starvation\",\n      \"method\": \"In vitro kinase assay, phospho-site mutants (S30A), co-immunoprecipitation, autophagy flux assays, LC3/phagophore imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay, site-specific mutant rescue, complex-specific phosphorylation confirmed\",\n      \"pmids\": [\"29313410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAMK2, activated by TRPM2-mediated Ca2+ influx under oxidative stress, phosphorylates BECN1 at Ser295, which decreases BECN1-PIK3C3 association while increasing BECN1-BCL2 binding, thereby inhibiting autophagy\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, TRPM2 knockout/knockdown, phospho-mutant constructs\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct kinase assay, pathway epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"27245989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BECN1 is ISGylated by ISG15 at Lys117, Lys263, Lys265, and Lys266 (in competition with K63-linked ubiquitination) in response to type I interferon, and this ISGylation negatively regulates autophagy and EGFR degradation dependent on class III PI3K activity; SENP3 deSUMOylates BECN1 at K380\",\n      \"method\": \"ISGylation assay, site-directed mutagenesis, USP18 deISGylation assay, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site mapping by mutagenesis, competition with ubiquitination demonstrated, single-lab study\",\n      \"pmids\": [\"25906440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BECN1 is SUMO3-conjugated by PIAS3 at K380 and deSUMOylated by SENP3; SUMOylation of BECN1 promotes its interaction with UVRAG, PIK3C3, and ATG14, activates PIK3C3 activity, and enhances autophagosome formation\",\n      \"method\": \"SUMOylation assay with site-directed mutagenesis, co-immunoprecipitation, PIK3C3 activity assay, liver-specific Senp3 knockout mouse, autophagic flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis, E3 ligase identified, kinase activity assay, in vivo genetic validation\",\n      \"pmids\": [\"31373534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The BECN1 BARA domain (specifically β-sheet 1) undergoes partial unfolding/membrane insertion to mediate PI3KC3 complex membrane targeting; this mechanism is exploited by BECN1 peptides to activate both PI3KC3-C1 and -C2, inhibited by Rubicon binding to the BARA β-sheet 1, and blocked by HIV-1 Nef which also targets this region\",\n      \"method\": \"Hydrogen-deuterium exchange, cryo-EM, protein engineering, giant unilamellar vesicle assays, molecular simulations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure, HDX, protein engineering, and reconstitution all in one study\",\n      \"pmids\": [\"30581147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The BECN1 coiled-coil domain (CCD) forms an antiparallel homodimer; BECN1 CCD interface residues also mediate parallel heterodimer formation with ATG14, and mutations at the heterodimer interface abrogate starvation-induced autophagy without affecting basal autophagy\",\n      \"method\": \"X-ray crystallography (1.46 Å), SAXS, circular dichroism, co-immunoprecipitation with interface mutants, autophagy flux assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus functional mutagenesis plus SAXS\",\n      \"pmids\": [\"27383850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BECN1 contains a flexible helical domain (FHD) between the BH3 and coiled-coil domains that is partially disordered and undergoes a disorder-to-helix transition; conserved FHD residues are required for starvation-induced autophagy\",\n      \"method\": \"X-ray crystallography (2.0 Å SAD), circular dichroism, DEER-EPR, SAXS, MD simulations, cellular autophagy assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus multiple biophysical methods plus functional cellular validation\",\n      \"pmids\": [\"26937551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STK4/MST1 phosphorylates BECN1 at Thr108 within the BH3 domain, modestly increasing BECN1 affinity for BCL2 and BCL2L1; X-ray crystal structures of BCL2 and BCL2L1 with T108-modified BECN1 BH3 peptides indicate the interaction with a conserved histidine is influenced by membrane-like environments\",\n      \"method\": \"X-ray crystallography, biophysical binding assays (SPR, MST), molecular dynamics simulations\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biophysical binding measurements plus MD\",\n      \"pmids\": [\"30626284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ARRB1 (β-arrestin-1) interacts with both BECN1 and PIK3C3 under ischemic stress to form a BECN1 autophagic core complex; loss of ARRB1 impairs BECN1-PIK3C3 interaction, reduces PIK3C3 kinase activity, and suppresses autophagosome formation, leading to neuronal apoptosis/necrosis\",\n      \"method\": \"Co-immunoprecipitation, PIK3C3 kinase activity assay, Arrb1 knockout mouse model, oxygen-glucose deprivation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, kinase activity assay, genetic KO with defined phenotype\",\n      \"pmids\": [\"24988431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BCL2-BECN1 binding is disrupted by BH3 mimetic ABT-737 in a BAX/BAK1-independent mechanism to induce autophagy, demonstrating that BCL2 inhibits autophagy directly through BECN1 binding rather than indirectly via proapoptotic BCL2 family members\",\n      \"method\": \"Genetic BAX/BAK1 double-knockout cell lines, BCL2-BECN1 co-immunoprecipitation, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic genetic system with co-IP and functional autophagy assay\",\n      \"pmids\": [\"25715028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Becn1 F121A knock-in mutation disrupts BECN1-BCL2 interaction, leading to constitutively hyperactive autophagy in vivo; this hyperactive autophagy sequesters Aβ oligomers inside autophagosomes and prevents Alzheimer's disease progression\",\n      \"method\": \"Knock-in mouse generation, co-immunoprecipitation, immunoisolation of autophagosomes, behavioral/cognitive testing, in vivo autophagy flux\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knock-in with structural basis, multiple functional readouts, in vivo validation\",\n      \"pmids\": [\"28806762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BECN1 knockout using TALEN in human cells reveals that BECN1 is dispensable for LC3 lipidation but essential for functional autophagosome formation; BECN1-null cells form malformed multi-membrane autophagosome-like structures and have impaired PI3KC3 complex activity and autophagic flux\",\n      \"method\": \"TALEN-mediated gene knockout, electron microscopy, LC3 lipidation assay, PI3KC3 kinase activity assay, autophagy flux\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — complete genetic KO, ultrastructural EM analysis, kinase activity assay; multiple orthogonal methods\",\n      \"pmids\": [\"25955014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GLIPR2 binds to BECN1 (amino acids 267-284 region) and directly inhibits the in vitro lipid kinase activity of purified PI3KC3-C1 complex; GLIPR2 knockout increases autophagic flux and PI3P generation in cells and tissues\",\n      \"method\": \"CRISPR-Cas9 knockout, in vitro lipid kinase assay with purified complex, co-immunoprecipitation, autophagic flux assays, WIPI2 recruitment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase reconstitution assay with purified complex, genetic KO in cells and mice\",\n      \"pmids\": [\"33222586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BEC-1 (C. elegans BECN1 ortholog) mediates retrograde endosome-to-Golgi transport in addition to autophagy; bec-1 mutants show reduced RME-8 on endosomal membranes, accumulation of abnormal endosomes, and mislocalization/degradation of MIG-14/Wntless\",\n      \"method\": \"C. elegans genetics, fluorescence microscopy, RNAi, morphological analysis of endosomes\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model organism with defined trafficking pathway, multiple markers\",\n      \"pmids\": [\"21183797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Atg6 (BECN1 ortholog) is required for autophagy, endocytosis, and protein secretion, but not all these functions overlap with other core autophagy genes; Atg6 mutants show enlarged lymph glands and excess blood cells in a manner not suppressed by p62 or NFκB mutations\",\n      \"method\": \"Drosophila null mutant generation, genetic epistasis, endocytosis/secretion assays, hematopoietic analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic null mutants with epistasis analysis, multiple cellular pathway readouts\",\n      \"pmids\": [\"23406899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VDAC2 interacts with both BECN1 and BCL2L1 to stabilize the BECN1-BCL2L1 inhibitory complex in ovarian cells, suppressing autophagy; VDAC2 transgenic pigs show inhibited ovarian autophagy while Vdac2 knockout promotes autophagy\",\n      \"method\": \"Co-immunoprecipitation, transgenic pig model, Vdac2 knockout, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus genetic gain/loss-of-function in multiple model systems\",\n      \"pmids\": [\"26060891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM59 regulates BECN1 by two mechanisms: (1) negatively modulating NF-κB pathway to suppress BECN1 transcription, and (2) promoting K48-linked ubiquitination and degradation of TRAF6, thereby reducing TRAF6-induced K63-linked ubiquitination of BECN1 and impairing BECN1-PIK3C3 complex formation\",\n      \"method\": \"Reporter assays, co-immunoprecipitation, ubiquitination assays, autophagy flux, overexpression/knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual mechanism with multiple orthogonal assays, single lab\",\n      \"pmids\": [\"30231667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRAF6 promotes K63-linked ubiquitination of BECN1, which is required for BECN1-PI3KC3 complex formation and autophagy induction in response to TLR4 stimulation\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown, TLR4 stimulation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with linkage specificity plus complex formation assay\",\n      \"pmids\": [\"30231667\", \"32384667\", \"31620128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP19 deubiquitinase affects BECN1 ubiquitination, promoting autophagosome formation and inhibiting DDX58/RIG-I-mediated type I interferon signaling, revealing a BECN1-USP19 axis linking autophagy and antiviral immunity\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, interferon signaling assays, knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — limited mechanistic detail in abstract, single co-IP approach reported\",\n      \"pmids\": [\"27096686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HCMV proteins TRS1 and IRS1 contain a BECN1-binding domain (BBD) that is essential for autophagy inhibition; deletion of the BBD from TRS1 abolishes its ability to block autophagy, demonstrating direct binding to BECN1 is required\",\n      \"method\": \"Domain mapping, BBD deletion mutant viruses, co-immunoprecipitation, autophagy assays in multiple cell lines\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with deletion mutants and functional rescue in viral context\",\n      \"pmids\": [\"26654401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GADD45A directly interacts with BECN1 (via GADD45A residues 71-81) and disrupts the BECN1-PIK3C3 complex, inhibiting autophagosome initiation; BECN1 knockdown abolishes GADD45A-induced autophagy changes\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down assay, domain mapping, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GST pull-down plus co-IP, domain mapping, genetic epistasis with BECN1 KD\",\n      \"pmids\": [\"26636486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylated CAV1 (at Tyr14) interacts with the BECN1/VPS34 complex via CAV1's scaffolding domain under oxidative stress, promoting autophagosome formation and mitochondrial localization of BECN1; PTPN1 phosphatase reverses this by dephosphorylating CAV1\",\n      \"method\": \"Co-immunoprecipitation, phospho-mutant constructs, Cav1 knockout mouse, LC3 foci imaging, subcellular fractionation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with phospho-mutant, genetic KO mouse, multiple autophagy readouts\",\n      \"pmids\": [\"28542134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BECN1 directly interacts with plasma membrane-associated APP via the evolutionarily conserved domain (ECD, residues 267-337), and ECD subregion deletion (285-299) impairs APP-BECN1 interaction and APP endocytosis/lysosomal degradation without affecting BECN1-PIK3C3 interaction or autophagy; AKT-mediated phosphorylation of BECN1 Ser295 negatively regulates APP-BECN1 association\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, surface APP internalization assays, lysosomal degradation assays, APP metabolite secretion\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping, co-IP, functional internalization assay, phospho-mutant effects\",\n      \"pmids\": [\"27715386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Becn1 promotes adiponectin secretion in adipose tissue by interacting with components of the exocyst complex via its coiled-coil domain; this is a non-degradative, non-cell-autonomous mechanism by which Becn1 improves systemic insulin sensitivity and activates AMPK\",\n      \"method\": \"Becn1F121A knock-in mice, adipose-specific expression, co-immunoprecipitation with exocyst components, adiponectin secretion assays, AMPK activation measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knock-in mouse, co-IP, domain-specific (CCD) interaction, functional secretion assay\",\n      \"pmids\": [\"34038729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKD2 forms a protein complex with BECN1 via PKD2's CC1 coiled-coil domain, and this complex formation requires Ca2+ channel activity; PKD2 overexpression induces autophagy through increased BECN1 interaction, while a Ca2+-channel-deficient mutant (D509V) shows diminished BECN1 binding and fails to induce autophagy\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, Ca2+ chelation (BAPTA-AM), PKD2 mutant expression, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping, Ca2+-dependence assay, loss-of-function mutant with phenotypic readout\",\n      \"pmids\": [\"32543276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VCP/p97 is UFMylated at K109 by E3 ligase UFL1; this modification promotes BECN1 stabilization through ATXN3-mediated deubiquitination of BECN1, thereby facilitating PI3KC3 complex assembly and autophagy initiation\",\n      \"method\": \"UFMylation site mapping, ATXN3 deubiquitination assay, co-immunoprecipitation of PI3KC3 complex, VCP knockdown/rescue with UFMylation-defective mutant\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — modification site identified, deubiquitinase identified, complex assembly assayed, rescue with mutant\",\n      \"pmids\": [\"38762759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSPB6 wild-type protein interacts with BECN1, preventing BECN1 ubiquitination and proteasomal degradation, and competitively suppresses BECN1-BCL2 binding to stimulate autophagy; the DCM-associated mutant HSPB6S10F shows reduced BECN1 interaction, leading to BECN1 ubiquitination, degradation, and autophagy inhibition\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, autophagy flux assays, transgenic mouse hearts\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — disease mutant vs. WT comparison, multiple biochemical assays, in vivo cardiac model\",\n      \"pmids\": [\"29157081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIV-1 Nef enhances the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner to block autophagy initiation, in addition to previously known effects on autophagy maturation\",\n      \"method\": \"Co-immunoprecipitation, PRKN knockout/knockdown, autophagy flux assays, viral replication assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of BECN1-BCL2 complex modulated by Nef, PRKN dependency shown genetically\",\n      \"pmids\": [\"32097085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP15 deubiquitinase interacts with BECN1 (not TRAF6) and induces deubiquitination of BECN1, thereby attenuating autophagy induction and lung cancer migration downstream of the TLR4-TRAF6-BECN1 axis\",\n      \"method\": \"CRISPR-Cas9 USP15 knockout, co-immunoprecipitation, deubiquitination assay, cancer migration/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, direct interaction co-IP, deubiquitination assay, functional cancer phenotype\",\n      \"pmids\": [\"35422093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BECN1 interacts with the tight junction protein occludin at the intestinal epithelial membrane; Tat-beclin 1 peptide activates BECN1 and promotes occludin endocytosis and reduction in total occludin levels, increasing TJ permeability in an autophagy-independent manner\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, permeability assays, BECN1 siRNA, mouse colon perfusion\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, functional permeability assay, siRNA rescue, in vivo confirmation\",\n      \"pmids\": [\"30892937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ASPP2 binds directly to BECN1 and inhibits autophagy by (1) repressing p65/RelA-induced BECN1 transcription via an ASPP2-p65-IκBα complex, and (2) competing with PIK3C3/UVRAG for BECN1 binding while promoting Rubicon-BECN1 interaction, thereby destabilizing the pro-autophagic PI3KC3 complex\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, ChIP, overexpression/knockdown, autophagic flux assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, ChIP, dual mechanism shown with multiple orthogonal methods\",\n      \"pmids\": [\"27929538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLC9A3R1 binds to BECN1 via its C-terminal domain, blocks ubiquitin-dependent BECN1 degradation, attenuates BECN1-BCL2 interaction, and stimulates autophagy in breast cancer cells\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, ubiquitination assay, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping, ubiquitination assay, functional autophagy phenotype\",\n      \"pmids\": [\"26218645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ABHD5 directly competes with caspase-3 for binding to the cleavage sites of BECN1, preventing caspase-3-mediated cleavage and inactivation of BECN1, thereby maintaining autophagic flux; ABHD5 deficiency allows caspase-3 to cleave BECN1 and impair autophagy\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay, caspase cleavage assay, autophagy flux assays, ABHD5 knockdown/overexpression\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — competitive binding mechanism shown biochemically, caspase cleavage prevented, functional consequence in cells\",\n      \"pmids\": [\"27559856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sorafenib activates SHP-1 which dephosphorylates STAT3, downregulates MCL1, and releases BECN1 from MCL1 binding; freed BECN1 then binds SLC7A11 (system Xc-) and inhibits cystine uptake, promoting ferroptosis in hepatocellular carcinoma\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, SHP-1/STAT3 pathway inhibition, MCL1 ectopic expression rescue\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis via co-IP and siRNA, MCL1 rescue experiment demonstrates mechanism\",\n      \"pmids\": [\"36232407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BECN1 directly binds SLC7A11 (system Xc-) and the BECN1-SLC7A11 complex formation (promoted by SIRT3/AMPK-mediated autophagy) inhibits system Xc- activity, inducing ferroptosis\",\n      \"method\": \"Co-immunoprecipitation, siSIRT3/3-MA autophagy inhibition, erastin-induced ferroptosis assays, in vivo tumor model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP confirming complex, pathway inhibitor controls, in vivo validation\",\n      \"pmids\": [\"37196680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BCL2L10/BCL-B interacts with the BH3 domain of BECN1 and inhibits autophagy; Bcl-B knockdown triggers autophagic cell death dependent on LC3, BECN1, and ATG5\",\n      \"method\": \"Co-immunoprecipitation, Bcl-B overexpression/knockdown, autophagy assays with multiple stimuli, genetic epistasis with ATG5/BECN1\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with BH3 domain specificity, genetic epistasis, functional autophagy readout\",\n      \"pmids\": [\"22498477\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BECN1 (Beclin 1) functions as a central scaffold of the class III PI3-kinase (PI3KC3/VPS34) complexes that nucleate autophagosome formation by generating PI3P; its activity is controlled by a web of post-translational modifications (phosphorylation at multiple sites by AMPK, ULK1, JAK2, CAMK2, STK4; ubiquitination by CUL3/KLHL38, RNF216, and TRAF6; ISGylation by ISG15; SUMOylation by PIAS3/SENP3; UFMylation-dependent stabilization via VCP/p97-ATXN3) and protein–protein interactions that either promote autophagy (e.g., ATG14, UVRAG, PIK3C3, ARRB1, CAV1-pY14, PKD2, HSPB6) or inhibit it (e.g., BCL2/BCL2L1 binding to the BH3 domain, Rubicon and GLIPR2 binding to the BARA domain), while its BARA domain mediates membrane targeting through partial unfolding of β-sheet 1; beyond autophagy, phosphorylated BECN1 directly binds and blocks the SLC7A11 subunit of system Xc- to promote ferroptosis, interacts with the exocyst complex to facilitate adiponectin secretion, and regulates endocytic/retrograde trafficking in a PI3KC3-dependent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BECN1 (Beclin 1) is a central scaffold protein of the class III PI3-kinase (PI3KC3/VPS34) complex that orchestrates autophagosome formation, endosomal trafficking, and regulated cell death. Its coiled-coil domain mediates homodimerization and heterodimerization with ATG14 or UVRAG to assemble distinct PI3KC3 subcomplexes, while its BARA domain undergoes partial β-sheet unfolding to anchor the complex on membranes; these activities are positively regulated by ULK1 phosphorylation at Ser30, AMPK phosphorylation at Thr388, JAK2 phosphorylation at Y333, SUMO3 conjugation at K380, and TRAF6-mediated K63-linked ubiquitination, and negatively regulated by BCL2/BCL2L1 binding to its BH3 domain, Rubicon/GLIPR2 binding to the BARA domain, CAMK2 phosphorylation at Ser295, CUL3–KLHL38- and RNF216-mediated K48-linked ubiquitination and degradation, and ISGylation at multiple lysines [PMID:17893711, PMID:27304906, PMID:29313410, PMID:34131122, PMID:30581147, PMID:31373534, PMID:33977871, PMID:27245989, PMID:33222586, PMID:25906440]. Beyond autophagy, AMPK-phosphorylated BECN1 directly binds SLC7A11 to block system Xc⁻ cystine transport and promote ferroptosis, and BECN1 facilitates adiponectin secretion through interaction with the exocyst complex and participates in retrograde endosome-to-Golgi trafficking [PMID:30057310, PMID:34038729, PMID:9105038, PMID:21183797]. Disruption of the BECN1–BCL2 interaction by the F121A knock-in mutation constitutively activates autophagy in vivo, sequestering amyloid-β oligomers and preventing Alzheimer's disease-like pathology in mice [PMID:28806762].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that the BECN1 ortholog Vps30 functions in endosomal sorting revealed its primordial role beyond autophagy — it is required for endosome-to-Golgi retrieval of the vacuolar sorting receptor Vps10p.\",\n      \"evidence\": \"Temperature-sensitive alleles, subcellular fractionation, and genetic epistasis in S. cerevisiae\",\n      \"pmids\": [\"9105038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian trafficking function not yet demonstrated\", \"Whether sorting and autophagy functions are separable was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Consolidation of BECN1 as a core subunit of the VPS34/PI3KC3 lipid-kinase complex resolved how it mechanistically contributes to autophagosome nucleation via PI3P generation.\",\n      \"evidence\": \"Genetic complementation, fractionation, and functional studies across yeast, worms, flies, and mammals\",\n      \"pmids\": [\"17893711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of BECN1 within the complex unresolved\", \"Which post-translational modifications regulate complex assembly unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that BECN1 is a caspase substrate provided the first evidence for direct crosstalk between apoptotic and autophagic machineries at the level of BECN1 proteolysis.\",\n      \"evidence\": \"In vitro caspase cleavage assay and pan-caspase inhibitor treatment in human cells\",\n      \"pmids\": [\"18842334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage sites not mapped at residue resolution in this study\", \"Physiological relevance of cleavage fragments unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of NF-κB/p65 as a direct transcriptional activator of the BECN1 promoter established a signaling input linking inflammatory pathways to autophagy gene expression.\",\n      \"evidence\": \"EMSA, ChIP, promoter reporter assays, and siRNA knockdown in multiple human cell lines\",\n      \"pmids\": [\"19289499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcription factors regulating BECN1 not systematically catalogued\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that C. elegans BEC-1 controls retrograde endosome-to-Golgi transport of Wntless/MIG-14 confirmed that BECN1's trafficking role is conserved beyond yeast.\",\n      \"evidence\": \"Genetic analysis, RNAi, and fluorescence microscopy of endosomal markers in C. elegans\",\n      \"pmids\": [\"21183797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian BECN1 similarly controls Wntless trafficking not shown\", \"Dependence on PI3KC3 activity versus other BECN1 interactions not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping of TRAF6-mediated K63-linked ubiquitination and ARRB1 scaffolding as positive regulators of BECN1–PI3KC3 complex formation revealed that ubiquitin signaling and stress-specific adaptors control autophagy initiation at the BECN1 level.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with linkage specificity, PI3KC3 kinase activity assays, Arrb1 knockout mice\",\n      \"pmids\": [\"24988431\", \"30231667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"K63-ubiquitination sites on BECN1 not mapped\", \"Relative contributions of ARRB1 and TRAF6 in different tissues unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple studies converged to define the BCL2 family (BCL2, BCL2L1, BCL2L10/BCL-B) as direct BH3-domain-dependent inhibitors of BECN1 autophagy function, operating independently of BAX/BAK1 proapoptotic signaling.\",\n      \"evidence\": \"BH3 mimetic ABT-737 in BAX/BAK1 DKO cells, BCL2L10 co-IP/knockdown epistasis, VDAC2 stabilization of BECN1–BCL2L1 complex\",\n      \"pmids\": [\"25715028\", \"22498477\", \"26060891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative affinities of different BCL2 family members for BECN1 BH3 not compared\", \"In vivo relevance of BCL-B and VDAC2 regulation not fully characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"BECN1 knockout in human cells showed it is dispensable for LC3 lipidation but essential for proper autophagosome morphology and autophagic flux, redefining its role as a quality-control scaffold rather than an absolute upstream requirement for LC3 conjugation.\",\n      \"evidence\": \"TALEN-mediated BECN1 KO, electron microscopy, PI3KC3 kinase activity assay\",\n      \"pmids\": [\"25955014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether compensatory PI3K pathways explain residual LC3 lipidation unknown\", \"Long-term cellular consequences of BECN1 loss not fully explored\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"High-resolution structures of the BECN1 coiled-coil domain (homodimer and ATG14 heterodimer interface) and the flexible helical domain (FHD) defined the structural logic by which BECN1 switches between inactive homodimer and active ATG14-bound heterodimer states during starvation-induced autophagy.\",\n      \"evidence\": \"X-ray crystallography (1.46 Å CCD; 2.0 Å FHD), SAXS, DEER-EPR, interface mutagenesis, autophagy flux assays\",\n      \"pmids\": [\"27383850\", \"26937551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length BECN1 structure not yet solved\", \"How FHD conformational change is triggered in cells unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of multiple kinases (AMPK at Thr388, CAMK2 at Ser295) that phosphorylate BECN1 with opposing effects on PI3KC3 complex assembly versus BCL2 binding established phosphorylation as a bidirectional regulatory switch for autophagy.\",\n      \"evidence\": \"In vitro kinase assays, phospho-defective/mimic mutants, co-IP for PI3KC3/BCL2 binding, TRPM2-Ca²⁺ pathway epistasis\",\n      \"pmids\": [\"27304906\", \"27245989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between phosphorylation sites not systematically mapped\", \"Phosphatases that reverse these modifications largely unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The Becn1-F121A knock-in mouse, which constitutively disrupts BECN1–BCL2 binding and hyperactivates autophagy, demonstrated that modulating BECN1 activity can prevent amyloid-β accumulation and Alzheimer's-like pathology in vivo.\",\n      \"evidence\": \"Knock-in mouse crossed with AD model, immunoisolation of autophagosomes, behavioral testing\",\n      \"pmids\": [\"28806762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this protection extends to tau pathology unknown\", \"Mechanism of Aβ capture by autophagosomes not molecularly defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"AMPK-mediated phosphorylation of BECN1 at Ser90/93/96 was shown to promote direct binding to SLC7A11 and inhibition of system Xc⁻, establishing a non-autophagic ferroptosis-promoting function for BECN1.\",\n      \"evidence\": \"Phospho-defective mutant (S90,93,96A), reciprocal co-IP, ferroptosis assays, in vivo tumor models\",\n      \"pmids\": [\"30057310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BECN1-SLC7A11 interaction occurs at a specific membrane compartment unknown\", \"Stoichiometry and structural basis of BECN1-SLC7A11 binding unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM and hydrogen-deuterium exchange revealed that the BECN1 BARA domain β-sheet 1 undergoes partial unfolding to insert into membranes, providing a structural mechanism for PI3KC3 complex membrane targeting — exploited by Rubicon and HIV-1 Nef as an inhibitory binding site.\",\n      \"evidence\": \"Cryo-EM, HDX-MS, protein engineering, giant unilamellar vesicle reconstitution, molecular simulations\",\n      \"pmids\": [\"30581147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid specificity of BARA membrane insertion not fully defined\", \"How partial unfolding is regulated in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ULK1 phosphorylation of BECN1 at Ser30 was shown to selectively activate the ATG14-containing PI3KC3-C1 complex (not the UVRAG complex), demonstrating subcomplex-specific kinase regulation.\",\n      \"evidence\": \"In vitro kinase assay, S30A mutant, complex-specific co-IP, phagophore imaging\",\n      \"pmids\": [\"29313410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other ULK1 phosphorylation sites exist on BECN1 not excluded\", \"How Ser30 phosphorylation structurally favors ATG14 binding unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SUMO3 conjugation of BECN1 at K380 by PIAS3 (reversed by SENP3) was shown to promote interactions with UVRAG, PIK3C3, and ATG14 and enhance PI3KC3 kinase activity, adding SUMOylation to the post-translational code governing BECN1 complex assembly.\",\n      \"evidence\": \"SUMOylation site mutagenesis, PI3KC3 activity assay, liver-specific Senp3 KO mice\",\n      \"pmids\": [\"31373534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUMOylation and ISGylation compete at overlapping sites not resolved\", \"Tissue specificity of PIAS3-BECN1 regulation not explored\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Crystal structures of BCL2/BCL2L1 with Thr108-phosphorylated BECN1 BH3 peptides showed that STK4/MST1-mediated phosphorylation fine-tunes BCL2 family binding affinity, influenced by membrane-like environments.\",\n      \"evidence\": \"X-ray crystallography, SPR, MST binding assays, molecular dynamics\",\n      \"pmids\": [\"30626284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of T108 phosphorylation for autophagy regulation not demonstrated\", \"Whether STK4 and CAMK2 phosphorylation sites act synergistically unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"GLIPR2 was identified as a direct inhibitor of PI3KC3-C1 kinase activity through binding to BECN1 residues 267–284, demonstrating that the BARA-adjacent region serves as a regulatory hotspot distinct from the BCL2-binding BH3 domain.\",\n      \"evidence\": \"In vitro lipid kinase assay with purified PI3KC3-C1, CRISPR KO in cells and mice, WIPI2 recruitment assay\",\n      \"pmids\": [\"33222586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GLIPR2 regulation itself not characterized\", \"Whether GLIPR2 competes with ASPP2/APP for the same BECN1 region unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that CUL3–KLHL38 mediates K48-linked ubiquitination and proteasomal degradation of BECN1 established a dedicated E3 ligase–adaptor pair for BECN1 turnover, complementing earlier identification of RNF216.\",\n      \"evidence\": \"Mass spectrometry, reciprocal co-IP, K48-linkage-specific ubiquitination assay, cycloheximide chase, CRISPR KO\",\n      \"pmids\": [\"33977871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of CUL3/KLHL38 vs. RNF216 in different tissues not compared\", \"BECN1 ubiquitination sites targeted by CUL3/KLHL38 not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"BECN1 was shown to interact with the exocyst complex via its coiled-coil domain to promote adiponectin secretion, establishing a non-degradative, non-cell-autonomous function for BECN1 in metabolic homeostasis.\",\n      \"evidence\": \"Becn1-F121A knock-in mice, adipose-specific expression, co-IP with exocyst components, adiponectin secretion and systemic AMPK activation assays\",\n      \"pmids\": [\"34038729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which exocyst subunit directly contacts BECN1 not identified\", \"Whether PI3KC3 activity is required for this secretion function not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The UFMylation–VCP–ATXN3 axis was shown to stabilize BECN1 by promoting its deubiquitination, adding an additional layer of post-translational control over BECN1 protein levels and PI3KC3 complex assembly.\",\n      \"evidence\": \"UFMylation site mapping on VCP, ATXN3 deubiquitination assay, PI3KC3 co-IP, VCP knockdown/rescue with K109R mutant\",\n      \"pmids\": [\"38762759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATXN3 removes K48- or K63-linked ubiquitin chains from BECN1 not specified\", \"In vivo physiological contexts for UFMylation-dependent BECN1 regulation not explored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structure of BECN1 within the intact PI3KC3 complex, including conformational dynamics of the FHD and BARA membrane-insertion states, has not been determined; the integration of multiple simultaneous post-translational modifications and their combinatorial effects on BECN1 function remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length BECN1 structure in the context of PI3KC3 complex\", \"Combinatorial PTM code (phosphorylation, ubiquitination, SUMOylation, ISGylation, UFMylation) not systematically dissected\", \"Structural basis of BECN1–SLC7A11 interaction in ferroptosis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 9, 14, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 42, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [31, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 3, 5, 9, 12, 13, 14, 20, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 42, 43]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 22, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 25, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8, 34, 37]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 28, 36]}\n    ],\n    \"complexes\": [\n      \"PI3KC3-C1 (VPS34-VPS15-BECN1-ATG14)\",\n      \"PI3KC3-C2 (VPS34-VPS15-BECN1-UVRAG)\",\n      \"BECN1-BCL2 inhibitory complex\"\n    ],\n    \"partners\": [\n      \"PIK3C3\",\n      \"ATG14\",\n      \"UVRAG\",\n      \"BCL2\",\n      \"BCL2L1\",\n      \"SLC7A11\",\n      \"TRAF6\",\n      \"RUBCN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}