{"gene":"BECN1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1997,"finding":"VPS30 (yeast BECN1 ortholog) is required for retrograde transport of the vacuolar sorting receptor Vps10p from the prevacuolar endosome back to the Golgi; loss-of-function causes Vps10p to mislocalize to the vacuolar membrane and CPY to be missorted and secreted.","method":"Yeast genetics, subcellular fractionation, temperature-conditional alleles, epistasis with sec1 and pep12 mutations","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple alleles, fractionation, replicated across multiple vps mutants in a rigorous yeast system","pmids":["9105038"],"is_preprint":false},{"year":2005,"finding":"VPS30/ATG6 in yeast is a component of two distinct PI3-kinase complexes: PI3K complex I (required for autophagy) and complex II (required for the CPY-to-vacuole sorting pathway). Excess soluble A1PiZ uses the CPY pathway, while aggregated A1PiZ uses the autophagy pathway for vacuolar delivery.","method":"Yeast complementation, genetic epistasis, characterization of A1PiZ degradation-deficient mutants","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementation, epistasis, and distinct substrate sorting confirmed with multiple assays in a dedicated mechanistic study","pmids":["16267277"],"is_preprint":false},{"year":2009,"finding":"The NF-κB family member p65/RelA directly binds a conserved κB site in the BECN1 promoter and transcriptionally upregulates BECN1 mRNA and protein, leading to increased autophagy; this was demonstrated in Jurkat cells upon PMA-ionomycin stimulation and in primary T cells.","method":"Promoter analysis, EMSA, ChIP, siRNA knockdown, western blot, autophagy flux assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, EMSA, and in vivo promoter studies with pharmacological inhibition across multiple cell types in one rigorous study","pmids":["19289499"],"is_preprint":false},{"year":2016,"finding":"AMPK phosphorylates BECN1 at Thr388, which is required for autophagy upon glucose withdrawal. The T388A phosphorylation-defective mutant has higher BCL2 affinity, reduced interaction with PIK3C3 and ATG14, and decreased autophagy; the phosphomimetic T388D shows stronger PIK3C3/ATG14 binding and higher autophagy.","method":"In vitro kinase assay, phosphorylation-defective and phosphomimetic mutants, co-immunoprecipitation, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and multiple orthogonal methods (Co-IP, flux) in a single focused study","pmids":["27304906"],"is_preprint":false},{"year":2016,"finding":"BECN1 BARA domain β-sheet 1 can partially unfold and insert into membranes to enable PI3KC3 complex binding to membranes. Rubicon inhibits and HIV-1 Nef inhibits PI3KC3 complex II via this BARA domain; a BECN1 β-sheet-1 derived peptide activates both PI3KC3 complexes I and II.","method":"Cryo-EM, hydrogen-deuterium exchange, protein engineering, giant unilamellar vesicle assays, molecular dynamics simulations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with HDX, GUV assays, and MD simulations; multiple orthogonal methods confirming membrane-insertion mechanism","pmids":["30581147"],"is_preprint":false},{"year":2016,"finding":"The X-ray crystal structure of the antiparallel BECN1 CCD homodimer was determined at 1.46 Å. BECN1 forms a parallel heterodimer with ATG14 via their CCDs; mutations of interface residues impair BECN1:ATG14 heterodimerization, reduce co-immunoprecipitation of the partner, and abrogate starvation-induced but not basal autophagy.","method":"X-ray crystallography, circular dichroism, SAXS, co-immunoprecipitation, mutagenesis, autophagy flux assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SAXS, CD, and mutagenesis with functional validation of interface residues","pmids":["27383850"],"is_preprint":false},{"year":2018,"finding":"AMPK-mediated phosphorylation of BECN1 at Ser90/93/96 is required for the formation of a BECN1-SLC7A11 complex that directly blocks system Xc- activity, induces lipid peroxidation, and promotes ferroptosis. A phosphorylation-defective S90,93,96A mutant reverses BECN1-induced ferroptosis, distinct from autophagy-dependent BECN1 function.","method":"shRNA knockdown, siRNA, phosphorylation-defective mutants, co-immunoprecipitation, lipid peroxidation assays, in vivo tumor models","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, and in vivo validation across multiple ferroptosis inducers and cell lines","pmids":["30057310"],"is_preprint":false},{"year":2018,"finding":"ULK1 phosphorylates BECN1 at Ser30 specifically in the ATG14-containing (but not UVRAG-containing) complex, requiring ATG13 and RB1CC1. Ser30 phosphorylation activates the ATG14-containing PIK3C3 complex and stimulates autophagosome formation in response to amino acid starvation, hypoxia, and MTORC1 inhibition; the S30A mutation suppresses all these responses.","method":"In vitro kinase assay, phospho-specific antibodies, co-immunoprecipitation, CRISPR knockouts, autophagy flux assays, phagophore imaging","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus multiple mutants and genetic knockouts with orthogonal readouts in one study","pmids":["29313410"],"is_preprint":false},{"year":2019,"finding":"STK4/MST1 phosphorylates BECN1 at T108 within its BH3 domain, increasing BECN1 affinity (modestly, <2-fold) for anti-apoptotic BCL2 and BCL2L1. Crystal structures of BCL2 and BCL2L1 with T108-modified BECN1 BH3 peptides showed no persistent electrostatic interaction with the conserved histidine; the interaction can be stabilized by local environmental factors such as detergent/membranes.","method":"X-ray crystallography, surface plasmon resonance, microscale thermophoresis, molecular dynamics, biophysical binding studies","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with multiple biophysical methods in one rigorous study; conclusion is nuanced (modest affinity change)","pmids":["30626284"],"is_preprint":false},{"year":2016,"finding":"BECN1 N-terminal domain (residues 1–150) is intrinsically disordered as determined by NMR spectroscopy. The BH3 subdomain forms an α-helix upon interaction with BCL2L1 but reverts to disordered state upon competitive inhibitor-mediated dissociation. No significant interdomain contacts between N- and C-terminal domains were detected.","method":"NMR spectroscopy, biophysical characterization (CD, size-exclusion chromatography), competitive inhibitor dissociation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution NMR with multiple biophysical methods in a single dedicated structural study","pmids":["27046249"],"is_preprint":false},{"year":2014,"finding":"BECN1 interacts with PARK2 (Parkin) in the cytosol. Loss of BECN1 inhibits CCCP- or PINK1 overexpression-induced PARK2 translocation to mitochondria, prevents MFN2 ubiquitination by PARK2, and rescues MFN2-loss-induced suppression of mitochondrial fusion, placing BECN1 upstream of PARK2 in mitophagy initiation.","method":"Co-immunoprecipitation, siRNA knockdown, fluorescence imaging of PARK2 translocation, MFN2 ubiquitination assay, mitochondrial fusion assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional rescue experiments with multiple orthogonal readouts in a single lab study","pmids":["24879156"],"is_preprint":false},{"year":2017,"finding":"Following mitophagic stimuli, endogenous PINK1 and BECN1 relocalize to mitochondria-associated membranes (MAM), where they promote enhancement of ER-mitochondria contact sites and formation of omegasomes (autophagosome precursors). PINK1 silencing impairs BECN1 enrichment at MAM independently of PARK2.","method":"Subcellular fractionation, immunofluorescence, proximity ligation assay, siRNA knockdown, live imaging of omegasome formation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — fractionation, proximity ligation, and epistasis (PINK1→BECN1 at MAM) with functional consequence (omegasome formation)","pmids":["28368777"],"is_preprint":false},{"year":2017,"finding":"Knock-in of F121A mutation in mouse Becn1 reduces interaction of BECN1 with its inhibitor BCL2, leading to constitutively active autophagy. This hyperactivated autophagy sequestrates amyloid-β oligomers inside autophagosomes and prevents cognitive decline in AD mouse models; disrupting BECN1-BCL2 binding is sufficient to hyperactivate autophagy in vivo.","method":"Knock-in mouse model, co-immunoprecipitation, autophagy flux assays, immunoisolation of autophagosomes, behavioral testing","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knock-in model with Co-IP, biochemical autophagosome isolation, and in vivo behavioral phenotype confirmed across multiple autophagy inducers","pmids":["28806762"],"is_preprint":false},{"year":2008,"finding":"ATG6/BECN1 is a caspase substrate; caspases directly cleave BECN1 in a process blocked by pan-caspase inhibitor zVAD. Ectopic BECN1 expression suppresses cell death while BECN1 knockdown sensitizes cells to TRAIL-induced cell death, linking apoptotic and autophagic signaling.","method":"In vitro caspase cleavage assay, zVAD inhibition, siRNA knockdown, ectopic expression, cell death assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro cleavage assay with functional knockdown/OE, but single lab, single study","pmids":["18842334"],"is_preprint":false},{"year":2016,"finding":"CAMK2, activated by TRPM2-mediated Ca2+ influx under oxidative stress, phosphorylates BECN1 at Ser295. This phosphorylation decreases BECN1-PIK3C3 association and increases BECN1-BCL2 binding, resulting in autophagy inhibition. The TRPM2-Ca2+-CAMK2-BECN1 signaling cascade also operates in APAP-induced liver injury.","method":"Co-immunoprecipitation, phospho-specific antibodies, siRNA knockdown, Ca2+ imaging, pharmacological inhibition, in vivo APAP model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, phospho-specific readout, multiple orthogonal methods across in vitro and in vivo models in one study","pmids":["27245989"],"is_preprint":false},{"year":2021,"finding":"IL-6 activates autophagy via a JAK2-BECN1 pathway: IL-6 triggers JAK2-BECN1 interaction, and JAK2 phosphorylates BECN1 at Y333. Y333 phosphorylation is required for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation.","method":"Co-immunoprecipitation, phospho-specific antibodies, in vitro kinase assay (implied), siRNA/mutant analysis, PI3KC3 complex assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, site-specific phosphorylation validation, PI3KC3 complex formation assay, published in high-impact peer-reviewed journal","pmids":["34131122"],"is_preprint":false},{"year":2021,"finding":"CUL3 (cullin 3) E3 ubiquitin ligase interacts with BECN1 and promotes K48-linked ubiquitination and proteasomal degradation of BECN1, with KLHL38 serving as the substrate adaptor for this CUL3 complex. CUL3-mediated BECN1 degradation decreases autophagic activity.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, cycloheximide chase, KLHL38 adaptor validation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS identification, ubiquitination assay, adaptor validation with multiple methods in one study","pmids":["33977871"],"is_preprint":false},{"year":2019,"finding":"BECN1 is SUMOylated by PIAS3 predominantly at K380 (SUMO3-conjugated) and deSUMOylated by SENP3. Starvation-induced SUMOylation of BECN1 enhances its interaction with UVRAG, PIK3C3, and ATG14, promoting PIK3C3 activity and autophagosome formation; SENP3-mediated deSUMOylation impairs BECN1-PIK3C3 complex formation and fine-tunes autophagy.","method":"SUMO pull-down, co-immunoprecipitation, conditional knockout mice, PI3KC3 activity assay, mutagenesis (K380)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout model plus Co-IP, enzyme assay, and site-specific mutant in one dedicated study","pmids":["31373534"],"is_preprint":false},{"year":2015,"finding":"GADD45A directly interacts with BECN1 (binding mapped to GADD45A residues 71–81) and dissociates the BECN1-PIK3C3 complex, thereby inhibiting autophagosome initiation. BECN1 knockdown abolishes autophagy alterations induced by GADD45A.","method":"Co-immunoprecipitation, GST affinity pull-down, domain mapping, western blot, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP and GST pull-down with domain mapping, single lab, single study","pmids":["26636486"],"is_preprint":false},{"year":2015,"finding":"Complete TALEN-mediated knockout of BECN1 in human cells does not abolish LC3B lipidation but leads to malformed autophagosome-like structures with multiple membrane layers and disrupted PIK3C3 complex activity and autophagy flux, demonstrating that BECN1 is essential for functional autophagosome formation but not LC3B lipidation per se.","method":"TALEN-mediated knockout, electron microscopy, fluorescence microscopy, autophagy flux assay, PI3KC3 kinase activity assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — complete genetic knockout with EM ultrastructural analysis and biochemical PI3KC3 activity assay, multiple orthogonal methods","pmids":["25955014"],"is_preprint":false},{"year":2014,"finding":"ARRB1 interacts with BECN1 and PIK3C3 under ischemic conditions, and Arrb1 deletion disrupts the BECN1-PIK3C3 interaction and markedly reduces PIK3C3 kinase activity, impairing autophagosome formation and promoting neuronal death during cerebral ischemia.","method":"Co-immunoprecipitation, Arrb1 knockout mice, in vivo ischemia model, PIK3C3 kinase activity assay, cell death assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo KO model, and biochemical kinase activity measurement across in vitro and in vivo settings","pmids":["24988431"],"is_preprint":false},{"year":2018,"finding":"TRIM59 regulates BECN1 through two mechanisms: (1) negatively modulating NF-κB pathway to suppress BECN1 transcription, and (2) promoting K48-linked ubiquitination of TRAF6, leading to TRAF6 proteasomal degradation and reduced TRAF6-induced K63-linked ubiquitination of BECN1, thereby impairing BECN1-PIK3C3 complex formation.","method":"Co-immunoprecipitation, ubiquitination assays, luciferase reporter (NF-κB), western blot, siRNA knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assays but single lab, mechanistic chain inferred from multiple steps","pmids":["30231667"],"is_preprint":false},{"year":2017,"finding":"Phosphorylation of CAV1 at tyrosine-14 is required for interaction of CAV1 (via its scaffolding domain) with the BECN1/VPS34 complex under oxidative stress, facilitating autophagosome formation and localization of BECN1 to mitochondria. PTPN1 phosphatase reduces CAV1 phosphorylation and inhibits this autophagy activation.","method":"Co-immunoprecipitation, phospho-specific antibodies, CAV1 knockout cells, Cav1 KO mice, in vivo ischemia model, fluorescence imaging","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with phospho-mutant, KO mice, in vivo validation, single lab study","pmids":["28542134"],"is_preprint":false},{"year":2016,"finding":"ABHD5 directly competes with CASP3 for binding to BECN1 cleavage sites, preventing BECN1 from being cleaved and inactivated by CASP3, thereby preserving autophagic flux. ABHD5 deficiency allows CASP3 to cleave BECN1, impairing autophagy and augmenting genomic instability.","method":"Co-immunoprecipitation, competitive binding assays, caspase cleavage assays, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — competitive binding/cleavage assays with Co-IP, single lab, single study","pmids":["27559856"],"is_preprint":false},{"year":2020,"finding":"GLIPR2 binds to BECN1 (at residues 267–284) and directly inhibits purified PtdIns3K-C1 lipid kinase activity in vitro. GLIPR2 knockout in cells and mice increases autophagic flux and PtdIns3P generation, confirming GLIPR2 as a negative regulator of PtdIns3K-C1.","method":"CRISPR-Cas9 knockout (cells and mice), in vitro PI3K activity assay with purified complex, autophagy flux assays, PtdIns3P WIPI2 recruitment assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted kinase assay with purified complex, combined with in vivo KO mice and multiple flux assays","pmids":["33222586"],"is_preprint":false},{"year":2018,"finding":"HSPB6 wild-type interacts with BECN1 to protect it from ubiquitination and proteasomal degradation, and competitively suppresses BECN1-BCL2 binding to stimulate autophagy. The DCM-associated HSPB6S10F mutant has reduced interaction with BECN1, leading to BECN1 ubiquitination, proteasomal degradation, impaired autophagy flux, and increased apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, transgenic mouse model, autophagy flux assay, cardiac functional analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay with in vivo mouse model, single lab study","pmids":["29157081"],"is_preprint":false},{"year":2016,"finding":"BECN1 interacts with plasma membrane-associated APP via its evolutionarily conserved domain (ECD, residues 267–337), and recruits PIK3C3 and UVRAG. BECN1 promotes surface APP internalization, sorting to endolysosomes, lysosomal degradation of APP, and reduction of secreted APP metabolites. AKT-mediated phosphorylation of BECN1 Ser295 inhibits APP-BECN1 interaction and APP degradation.","method":"Co-immunoprecipitation, BECN1 domain-deletion mutants, surface APP internalization assay, lysosomal degradation assay, sAPP secretion measurement, AKT inhibitors/phosphomimetics","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with domain mapping and functional trafficking assays, single lab, multiple methods but not replicated","pmids":["27715386"],"is_preprint":false},{"year":2021,"finding":"Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via its coiled-coil domain. Adipose-specific Becn1F121A (autophagy-hyperactive) expression is sufficient to increase adiponectin secretion, activate systemic AMPK, and improve insulin sensitivity through a non-cell-autonomous, non-degradative mechanism.","method":"Adipose-specific knock-in mouse model, co-immunoprecipitation with exocyst components, adiponectin secretion assay, AMPK activation measurement in distal tissues","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific knock-in mouse, Co-IP with domain validation, in vivo metabolic phenotype, multiple orthogonal methods","pmids":["34038729"],"is_preprint":false},{"year":2019,"finding":"Beclin 1 co-immunoprecipitates with the tight junction protein occludin, and BECN1 activation promotes occludin endocytosis and reduces total occludin levels, increasing intestinal TJ permeability in an autophagy-independent manner. Induction of autophagy terminates this constitutive BECN1 function and enhances TJ barrier.","method":"Co-immunoprecipitation, BECN1 siRNA knockdown, Tat-beclin 1 peptide, autophagy induction, TEER measurement, mouse colon perfusion","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and functional permeability assays in vitro and in vivo, single lab study","pmids":["30892937"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, Atg6 (the BECN1 ortholog) is essential not only for autophagy but also for endocytosis and protein secretion, and is required for normal hematopoiesis. Atg6 mutant flies show enlarged lymph glands, elevated blood cell numbers, and melanotic masses, phenotypes not suppressed by p62 or NFκB mutations, implying these arise from non-autophagy trafficking defects.","method":"Drosophila Atg6 null mutant generation, fluorescence and electron microscopy, genetic epistasis with p62 and NFκB mutants","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mutant in vivo with rigorous genetic epistasis and multiple assays (endocytosis, secretion, autophagy, hematopoiesis) in one study","pmids":["23406899"],"is_preprint":false},{"year":2011,"finding":"BEC-1 (C. elegans BECN1 ortholog) is required for retrograde transport from endosomes to the Golgi: bec-1 mutants show mislocalization and degradation of MIG-14/Wntless, reduced RME-8 on endosomal membranes, and accumulation of morphologically abnormal endosomes. BEC-1 also functions in phagosome maturation for apoptotic corpse clearance.","method":"C. elegans genetics, GFP reporter trafficking assays, immunofluorescence of endosomal markers, RNAi, corpse clearance assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic mutant analysis with multiple trafficking reporters and orthogonal assays in a model organism","pmids":["21183797"],"is_preprint":false},{"year":2015,"finding":"BH3 mimetic ABT-737 induces autophagy in parallel with disruption of BCL2-BECN1 binding in BAX/BAK1-double-deficient cells, demonstrating that BCL2 inhibits autophagy by directly binding BECN1 through a BAX/BAK1-independent mechanism.","method":"ABT-737 treatment of BAX/BAK1 double-knockout MEFs and HCT116 cells, BCL2-BECN1 Co-IP, autophagy flux assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function model with Co-IP and flux assay, single study, single lab","pmids":["25715028"],"is_preprint":false},{"year":2020,"finding":"PKD2 forms a protein complex with BECN1 via its coiled-coil domain 1 (CC1). PKD2 overexpression triggers autophagy through increased BECN1 interaction; a Ca2+-channel-deficient PKD2D509V mutant does not induce autophagy and shows diminished BECN1 interaction. Intracellular Ca2+ depletion with BAPTA-AM blunts starvation-induced autophagy and disrupts the PKD2-BECN1 complex.","method":"Co-immunoprecipitation, GST pulldown, PKD2 domain mutants, Ca2+ chelation (BAPTA-AM), autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and GST pulldown with domain mutants and Ca2+ manipulation, single lab study","pmids":["32543276"],"is_preprint":false},{"year":2024,"finding":"VCP/p97 is UFMylated on K109 by E3 ligase UFL1; this modification stabilizes BECN1 through ATXN3-mediated deubiquitination and facilitates assembly of the PtdIns3K complex. Expression of UFMylation-defective VCP K109 mutant fails to rescue VCP-depletion-induced autophagy defects.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination/UFMylation assays, mutagenesis, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, MS, and biochemical assays with defined mutants, single lab study","pmids":["38762759"],"is_preprint":false},{"year":2020,"finding":"BECN1 knockdown in colorectal cancer cells promotes STAT3 phosphorylation and activates the STAT3 signaling pathway by regulating the interaction between STAT3 and JAK2, an autophagy-independent mechanism that promotes CRC cell motility and invasion.","method":"siRNA knockdown, phospho-STAT3 western blot, co-immunoprecipitation of STAT3-JAK2, cell migration/invasion assays, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and KD with functional assays, autophagy-independence established by parallel autophagy markers, single lab study","pmids":["32358527"],"is_preprint":false},{"year":2020,"finding":"BECN1 interacts with USP14 (a deubiquitinase) and Vimentin, and regulates USP14-mediated de-ubiquitination of Vimentin. BECN1 overexpression increases NSCLC cell migration; BECN1 knockdown reduces migration, mediated through K48-linked ubiquitination of Vimentin.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, cell migration assays","journal":"Cell adhesion & migration","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, functional link to migration is correlative","pmids":["31272261"],"is_preprint":false},{"year":2015,"finding":"A conserved autophagy-specific domain (ECD/BARA-like) of BECN1 is required for its interaction with APP; deletion of BECN1 residues 285–299 does not impair PIK3C3 interaction or macroautophagy but specifically abolishes APP-BECN1 interaction and BECN1-dependent APP internalization and degradation.","method":"BECN1 deletion mutants, co-immunoprecipitation, surface APP internalization assays, lysosomal degradation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain-deletion mutagenesis with Co-IP and functional trafficking assays, single lab","pmids":["27715386"],"is_preprint":false},{"year":2014,"finding":"GABP transcription factor binds to conserved GABP sites in the BECN1 promoter and activates transcription of BECN1 and other BECN1-PIK3C3 complex genes. Nutrient starvation increases GABP-dependent transcriptional activity and GABP recruitment to the BECN1 promoter; GABP knockdown reduces BECN1-PIK3C3 complex protein levels and autophagy.","method":"Promoter luciferase assays, ChIP, siRNA knockdown, qPCR, western blot, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and promoter assays with functional knockdown, single lab, focused on transcriptional regulation","pmids":["25046113"],"is_preprint":false},{"year":2020,"finding":"BECN1 translocates to the nucleus in response to ionizing radiation. Nuclear BECN1 interacts with CDC25C (via residues 89–155) and CHK2 (via residues 151–224), facilitating CHK2-CDC25C interaction and CDC25C phosphorylation, which leads to CDK1 inactivation and G2/M checkpoint arrest.","method":"Nuclear fractionation, co-immunoprecipitation with domain mapping, western blot for phospho-CDC25C/CDK1, BECN1 knockdown, irradiation assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — nuclear fractionation with Co-IP and domain mapping, single lab; autophagy-independence of this function not fully resolved","pmids":["32802407"],"is_preprint":false},{"year":2019,"finding":"SENP3 deSUMOylates BECN1, impairing BECN1-PIK3C3 complex formation and suppressing autophagy. PIAS3 is the SUMO3 E3 ligase that conjugates SUMO3 to BECN1 predominantly at K380; K380 SUMOylation enhances interactions with UVRAG, PIK3C3, and ATG14.","method":"SUMO pull-down, Co-IP, Senp3 knockout mice (liver-specific), site-directed mutagenesis of K380, PI3KC3 complex activity assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout model plus site-specific mutagenesis and biochemical complex assays in one dedicated mechanistic study","pmids":["31373534"],"is_preprint":false}],"current_model":"BECN1/Beclin 1 is an intrinsically disordered scaffold protein that serves as the core organizer of the class III PI3-kinase (PIK3C3/VPS34) complexes; it forms parallel coiled-coil heterodimers with ATG14 (complex I, autophagy) or UVRAG (complex II, endosomal trafficking), and its BARA domain undergoes conditional partial unfolding to insert into membranes and activate PI3KC3. BECN1 activity is regulated by an array of post-translational modifications—phosphorylation by AMPK (Thr388, Ser90/93/96), ULK1 (Ser30), JAK2 (Tyr333), CAMK2 (Ser295), and STK4/MST1 (Thr108); SUMOylation at K380 by PIAS3 (reversed by SENP3); K48-linked ubiquitination and degradation by CUL3-KLHL38 and RNF216; and stabilization by HSPB6, SLC9A3R1, and VCP UFMylation via ATXN3—all converging to tune PI3KC3 complex assembly and autophagosome nucleation. Beyond canonical autophagy, BECN1 directly blocks system Xc- (SLC7A11) activity after AMPK-dependent phosphorylation to promote ferroptosis, facilitates mitophagy by enabling PARK2 translocation to mitochondria at MAM, promotes adiponectin secretion via exocyst binding, regulates intestinal tight junction permeability through occludin endocytosis, and mediates G2/M checkpoint control by scaffolding CHK2-CDC25C interactions in the nucleus."},"narrative":{"mechanistic_narrative":"BECN1/Beclin 1 is the core scaffold of class III PI3-kinase (PIK3C3/VPS34) complexes that nucleate autophagosome formation and govern endosomal membrane trafficking [PMID:16267277, PMID:25955014]. It is an intrinsically disordered protein whose N-terminal BH3 subdomain folds into an α-helix only upon binding partners such as BCL2L1, while its C-terminal BARA domain conditionally unfolds its β-sheet-1 to insert into membranes and license PI3KC3 binding and activation [PMID:27046249, PMID:30581147]. BECN1 assembles distinct complexes through coiled-coil heterodimerization with ATG14 (autophagy) or association with UVRAG, and its BARA/evolutionarily conserved domain mediates additional cargo interactions [PMID:27383850, PMID:27715386]. Complete loss of BECN1 yields malformed multilamellar autophagosome-like structures and abolishes functional PIK3C3 activity without preventing LC3B lipidation, defining it as essential for productive autophagosome morphogenesis [PMID:25955014]. Its activity is tuned by an inhibitory interaction with BCL2 that, when disrupted (e.g. F121A), constitutively hyperactivates autophagy in vivo and clears amyloid-β [PMID:28806762, PMID:25715028], and by a dense layer of post-translational modifications: activating phosphorylation by AMPK (Thr388), ULK1 (Ser30 within the ATG14 complex), and JAK2 (Tyr333) all promote PIK3C3 complex formation [PMID:27304906, PMID:29313410, PMID:34131122], whereas CAMK2 (Ser295) phosphorylation inhibits autophagy by displacing PIK3C3 and favoring BCL2 binding [PMID:27245989]. Stability and complex assembly are further controlled by PIAS3/SENP3-reversible SUMOylation at K380 and by CUL3-KLHL38-mediated K48 ubiquitination and degradation [PMID:31373534, PMID:33977871]. Multiple direct binding partners gate PIK3C3 activity, including the inhibitors GLIPR2 and GADD45A and the positive co-factor ARRB1 [PMID:33222586, PMID:26636486, PMID:24988431]. Beyond canonical autophagy, AMPK-dependent phosphorylation at Ser90/93/96 drives a BECN1-SLC7A11 complex that blocks system Xc- and promotes ferroptosis [PMID:30057310]; BECN1 acts upstream of PARK2 in mitophagy and relocalizes with PINK1 to mitochondria-associated membranes to seed omegasomes [PMID:24879156, PMID:28368777]; it promotes exocyst-dependent adiponectin secretion [PMID:34038729]; and nuclear BECN1 scaffolds CHK2-CDC25C to enforce the G2/M checkpoint after irradiation [PMID:32802407]. A deeply conserved trafficking role predates these functions, with orthologs required for retrograde endosome-to-Golgi transport and secretion across yeast, worm, and fly [PMID:9105038, PMID:21183797, PMID:23406899].","teleology":[{"year":1997,"claim":"Established the ancestral function of the BECN1 ortholog before autophagy was attached to it, showing the gene is required for receptor-mediated vacuolar protein sorting.","evidence":"Yeast genetics, subcellular fractionation, and epistasis with sec1/pep12 in VPS30 mutants","pmids":["9105038"],"confidence":"High","gaps":["Did not connect VPS30 to autophagy","No molecular partners or biochemical activity defined"]},{"year":2005,"claim":"Resolved that the ortholog partitions into two functionally distinct PI3-kinase complexes, foreshadowing the autophagy-versus-sorting division of labor later mapped to ATG14 and UVRAG.","evidence":"Yeast complementation and epistasis distinguishing PI3K complex I (autophagy) from complex II (CPY sorting)","pmids":["16267277"],"confidence":"High","gaps":["Complex-specific subunits in metazoans not yet identified","Mechanism of complex switching unknown"]},{"year":2008,"claim":"Linked BECN1 directly to apoptotic signaling by showing it is a caspase substrate and a death modulator, framing autophagy-apoptosis crosstalk.","evidence":"In vitro caspase cleavage with zVAD block, knockdown/overexpression, TRAIL death assays","pmids":["18842334"],"confidence":"Medium","gaps":["Cleavage sites not mapped here","Single-lab study without in vivo validation"]},{"year":2009,"claim":"Identified transcriptional control of BECN1 by NF-κB p65/RelA, explaining how autophagic capacity is set at the gene-expression level.","evidence":"Promoter analysis, EMSA, ChIP, knockdown, and flux assays in T cells","pmids":["19289499"],"confidence":"High","gaps":["Stimulus-specific control of the κB site not fully delineated"]},{"year":2014,"claim":"Placed BECN1 upstream of Parkin in mitophagy and identified ARRB1 as a cofactor for PIK3C3 activity, expanding BECN1 beyond bulk autophagy.","evidence":"Reciprocal Co-IP, knockdown/KO mice, PARK2 translocation imaging, and PIK3C3 kinase assays","pmids":["24879156","24988431"],"confidence":"High","gaps":["How BECN1 enables PARK2 translocation mechanistically unclear","Whether ARRB1 acts only under ischemia not resolved"]},{"year":2016,"claim":"Defined the structural basis of BECN1 function: intrinsic disorder of the N-terminus, conditional folding of the BH3 helix, ATG14 coiled-coil heterodimerization, and BARA β-sheet-1 membrane insertion driving PIK3C3 activation.","evidence":"NMR, X-ray crystallography, SAXS, cryo-EM, HDX, GUV membrane-insertion assays, and mutagenesis","pmids":["27046249","27383850","30581147"],"confidence":"High","gaps":["Full architecture of membrane-engaged complex II not resolved","How modifications change the disordered ensemble unknown"]},{"year":2016,"claim":"Demonstrated that AMPK and CAMK2 phosphorylation act as opposing switches on the BECN1-BCL2/PIK3C3 equilibrium, coupling metabolic and Ca2+/oxidative stress to autophagy decisions.","evidence":"In vitro kinase assays, phospho-mutants, Co-IP, Ca2+ imaging, and in vivo APAP liver injury model","pmids":["27304906","27245989"],"confidence":"High","gaps":["Hierarchy among the many phosphosites not integrated","Crosstalk between Thr388 and Ser295 not tested together"]},{"year":2016,"claim":"Revealed an autophagy-independent trafficking role in which the BECN1 ECD binds APP and routes it to lysosomal degradation, reducing amyloidogenic processing.","evidence":"Domain-deletion mutants, Co-IP, surface internalization and lysosomal degradation assays, AKT phosphomimetics","pmids":["27715386","27559856"],"confidence":"Medium","gaps":["Single-lab evidence for APP route","Relationship to canonical PIK3C3 trafficking unclear"]},{"year":2018,"claim":"Separated a ferroptosis-promoting function from autophagy by showing AMPK-driven Ser90/93/96 phosphorylation builds a BECN1-SLC7A11 complex that blocks system Xc-.","evidence":"Phospho-defective mutants, reciprocal Co-IP, lipid peroxidation assays, and in vivo tumor models","pmids":["30057310"],"confidence":"High","gaps":["Whether membrane insertion is required for SLC7A11 inhibition unknown","Structural basis of the BECN1-SLC7A11 interface undefined"]},{"year":2018,"claim":"Showed ULK1 selectively activates the ATG14-containing complex via Ser30, establishing complex-specific upstream control of PIK3C3 activation.","evidence":"In vitro kinase assays, phospho-specific antibodies, CRISPR knockouts, and phagophore imaging","pmids":["29313410"],"confidence":"High","gaps":["No equivalent activating mark identified for the UVRAG complex"]},{"year":2019,"claim":"Defined SUMOylation (PIAS3/K380) reversed by SENP3 as a regulatory layer that enhances BECN1 binding to UVRAG, ATG14, and PIK3C3, and refined the BH3-T108 BCL2 interaction biophysically.","evidence":"SUMO pull-down, Co-IP, liver-specific Senp3 KO mice, K380 mutants, plus crystallography and SPR/MST of T108 BH3 peptides","pmids":["31373534","30626284","32802407"],"confidence":"High","gaps":["T108 phosphorylation produces only modest affinity changes","Nuclear G2/M scaffolding role (CHK2-CDC25C) shown by single lab"]},{"year":2020,"claim":"Identified GLIPR2 as a direct inhibitor of the purified PtdIns3K-C1 lipid kinase, providing reconstituted evidence for negative regulation at the catalytic step.","evidence":"CRISPR KO in cells and mice, in vitro kinase assay with purified complex, WIPI2/PtdIns3P recruitment assays","pmids":["33222586"],"confidence":"High","gaps":["Physiological signals controlling GLIPR2 binding unknown"]},{"year":2021,"claim":"Extended BECN1 activation to cytokine signaling (JAK2/Y333) and to non-degradative metabolic secretion via exocyst-dependent adiponectin release.","evidence":"Co-IP, phospho-specific analysis, PIK3C3 complex assays, and adipose-specific Becn1 knock-in mice","pmids":["34131122","34038729"],"confidence":"High","gaps":["Mechanistic link between Y333 and membrane insertion unmapped","Exocyst-binding interface not structurally defined"]},{"year":2024,"claim":"Connected VCP UFMylation to BECN1 stabilization through ATXN3-mediated deubiquitination, adding a further proteostatic input to PtdIns3K assembly.","evidence":"Co-IP, MS, UFMylation/ubiquitination assays, and VCP K109 mutant rescue of autophagy","pmids":["38762759"],"confidence":"Medium","gaps":["Single-lab study","Which ubiquitin ligase ATXN3 antagonizes on BECN1 not defined"]},{"year":null,"claim":"How the dozens of post-translational marks, competing binding partners, and conditional structural states are integrated in space and time to set PIK3C3 output across autophagy, trafficking, ferroptosis, and nuclear checkpoint roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating modification hierarchy with complex I/II partitioning","Structural basis of autophagy-independent partner switching (SLC7A11, occludin, CHK2/CDC25C, exocyst) undefined","In vivo contributions of individual marks to each non-canonical function not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,19,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,24,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[10,11,22]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[38]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,30,26]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,7,19]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,30,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[38]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,14,6]}],"complexes":["PI3KC3 complex I (BECN1-ATG14-PIK3C3)","PI3KC3 complex II (BECN1-UVRAG-PIK3C3)"],"partners":["PIK3C3","ATG14","UVRAG","BCL2","SLC7A11","PARK2","ARRB1","GLIPR2"],"other_free_text":[]}},"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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temperature-conditional alleles, epistasis with sec1 and pep12 mutations\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple alleles, fractionation, replicated across multiple vps mutants in a rigorous yeast system\",\n      \"pmids\": [\"9105038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VPS30/ATG6 in yeast is a component of two distinct PI3-kinase complexes: PI3K complex I (required for autophagy) and complex II (required for the CPY-to-vacuole sorting pathway). Excess soluble A1PiZ uses the CPY pathway, while aggregated A1PiZ uses the autophagy pathway for vacuolar delivery.\",\n      \"method\": \"Yeast complementation, genetic epistasis, characterization of A1PiZ degradation-deficient mutants\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementation, epistasis, and distinct substrate sorting confirmed with multiple assays in a dedicated mechanistic study\",\n      \"pmids\": [\"16267277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The NF-κB family member p65/RelA directly binds a conserved κB site in the BECN1 promoter and transcriptionally upregulates BECN1 mRNA and protein, leading to increased autophagy; this was demonstrated in Jurkat cells upon PMA-ionomycin stimulation and in primary T cells.\",\n      \"method\": \"Promoter analysis, EMSA, ChIP, siRNA knockdown, western blot, autophagy flux assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, EMSA, and in vivo promoter studies with pharmacological inhibition across multiple cell types in one rigorous study\",\n      \"pmids\": [\"19289499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AMPK phosphorylates BECN1 at Thr388, which is required for autophagy upon glucose withdrawal. The T388A phosphorylation-defective mutant has higher BCL2 affinity, reduced interaction with PIK3C3 and ATG14, and decreased autophagy; the phosphomimetic T388D shows stronger PIK3C3/ATG14 binding and higher autophagy.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-defective and phosphomimetic mutants, co-immunoprecipitation, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and multiple orthogonal methods (Co-IP, flux) in a single focused study\",\n      \"pmids\": [\"27304906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BECN1 BARA domain β-sheet 1 can partially unfold and insert into membranes to enable PI3KC3 complex binding to membranes. Rubicon inhibits and HIV-1 Nef inhibits PI3KC3 complex II via this BARA domain; a BECN1 β-sheet-1 derived peptide activates both PI3KC3 complexes I and II.\",\n      \"method\": \"Cryo-EM, hydrogen-deuterium exchange, protein engineering, giant unilamellar vesicle assays, molecular dynamics simulations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with HDX, GUV assays, and MD simulations; multiple orthogonal methods confirming membrane-insertion mechanism\",\n      \"pmids\": [\"30581147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The X-ray crystal structure of the antiparallel BECN1 CCD homodimer was determined at 1.46 Å. BECN1 forms a parallel heterodimer with ATG14 via their CCDs; mutations of interface residues impair BECN1:ATG14 heterodimerization, reduce co-immunoprecipitation of the partner, and abrogate starvation-induced but not basal autophagy.\",\n      \"method\": \"X-ray crystallography, circular dichroism, SAXS, co-immunoprecipitation, mutagenesis, autophagy flux assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SAXS, CD, and mutagenesis with functional validation of interface residues\",\n      \"pmids\": [\"27383850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AMPK-mediated phosphorylation of BECN1 at Ser90/93/96 is required for the formation of a BECN1-SLC7A11 complex that directly blocks system Xc- activity, induces lipid peroxidation, and promotes ferroptosis. A phosphorylation-defective S90,93,96A mutant reverses BECN1-induced ferroptosis, distinct from autophagy-dependent BECN1 function.\",\n      \"method\": \"shRNA knockdown, siRNA, phosphorylation-defective mutants, co-immunoprecipitation, lipid peroxidation assays, in vivo tumor models\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, and in vivo validation across multiple ferroptosis inducers and cell lines\",\n      \"pmids\": [\"30057310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ULK1 phosphorylates BECN1 at Ser30 specifically in the ATG14-containing (but not UVRAG-containing) complex, requiring ATG13 and RB1CC1. Ser30 phosphorylation activates the ATG14-containing PIK3C3 complex and stimulates autophagosome formation in response to amino acid starvation, hypoxia, and MTORC1 inhibition; the S30A mutation suppresses all these responses.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, co-immunoprecipitation, CRISPR knockouts, autophagy flux assays, phagophore imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus multiple mutants and genetic knockouts with orthogonal readouts in one study\",\n      \"pmids\": [\"29313410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STK4/MST1 phosphorylates BECN1 at T108 within its BH3 domain, increasing BECN1 affinity (modestly, <2-fold) for anti-apoptotic BCL2 and BCL2L1. Crystal structures of BCL2 and BCL2L1 with T108-modified BECN1 BH3 peptides showed no persistent electrostatic interaction with the conserved histidine; the interaction can be stabilized by local environmental factors such as detergent/membranes.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance, microscale thermophoresis, molecular dynamics, biophysical binding studies\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with multiple biophysical methods in one rigorous study; conclusion is nuanced (modest affinity change)\",\n      \"pmids\": [\"30626284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BECN1 N-terminal domain (residues 1–150) is intrinsically disordered as determined by NMR spectroscopy. The BH3 subdomain forms an α-helix upon interaction with BCL2L1 but reverts to disordered state upon competitive inhibitor-mediated dissociation. No significant interdomain contacts between N- and C-terminal domains were detected.\",\n      \"method\": \"NMR spectroscopy, biophysical characterization (CD, size-exclusion chromatography), competitive inhibitor dissociation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution NMR with multiple biophysical methods in a single dedicated structural study\",\n      \"pmids\": [\"27046249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BECN1 interacts with PARK2 (Parkin) in the cytosol. Loss of BECN1 inhibits CCCP- or PINK1 overexpression-induced PARK2 translocation to mitochondria, prevents MFN2 ubiquitination by PARK2, and rescues MFN2-loss-induced suppression of mitochondrial fusion, placing BECN1 upstream of PARK2 in mitophagy initiation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, fluorescence imaging of PARK2 translocation, MFN2 ubiquitination assay, mitochondrial fusion assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional rescue experiments with multiple orthogonal readouts in a single lab study\",\n      \"pmids\": [\"24879156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Following mitophagic stimuli, endogenous PINK1 and BECN1 relocalize to mitochondria-associated membranes (MAM), where they promote enhancement of ER-mitochondria contact sites and formation of omegasomes (autophagosome precursors). PINK1 silencing impairs BECN1 enrichment at MAM independently of PARK2.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, proximity ligation assay, siRNA knockdown, live imaging of omegasome formation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation, proximity ligation, and epistasis (PINK1→BECN1 at MAM) with functional consequence (omegasome formation)\",\n      \"pmids\": [\"28368777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knock-in of F121A mutation in mouse Becn1 reduces interaction of BECN1 with its inhibitor BCL2, leading to constitutively active autophagy. This hyperactivated autophagy sequestrates amyloid-β oligomers inside autophagosomes and prevents cognitive decline in AD mouse models; disrupting BECN1-BCL2 binding is sufficient to hyperactivate autophagy in vivo.\",\n      \"method\": \"Knock-in mouse model, co-immunoprecipitation, autophagy flux assays, immunoisolation of autophagosomes, behavioral testing\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knock-in model with Co-IP, biochemical autophagosome isolation, and in vivo behavioral phenotype confirmed across multiple autophagy inducers\",\n      \"pmids\": [\"28806762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATG6/BECN1 is a caspase substrate; caspases directly cleave BECN1 in a process blocked by pan-caspase inhibitor zVAD. Ectopic BECN1 expression suppresses cell death while BECN1 knockdown sensitizes cells to TRAIL-induced cell death, linking apoptotic and autophagic signaling.\",\n      \"method\": \"In vitro caspase cleavage assay, zVAD inhibition, siRNA knockdown, ectopic expression, cell death assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro cleavage assay with functional knockdown/OE, but single lab, single study\",\n      \"pmids\": [\"18842334\"],\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. This phosphorylation decreases BECN1-PIK3C3 association and increases BECN1-BCL2 binding, resulting in autophagy inhibition. The TRPM2-Ca2+-CAMK2-BECN1 signaling cascade also operates in APAP-induced liver injury.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific antibodies, siRNA knockdown, Ca2+ imaging, pharmacological inhibition, in vivo APAP model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phospho-specific readout, multiple orthogonal methods across in vitro and in vivo models in one study\",\n      \"pmids\": [\"27245989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-6 activates autophagy via a JAK2-BECN1 pathway: IL-6 triggers JAK2-BECN1 interaction, and JAK2 phosphorylates BECN1 at Y333. Y333 phosphorylation is required for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific antibodies, in vitro kinase assay (implied), siRNA/mutant analysis, PI3KC3 complex assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, site-specific phosphorylation validation, PI3KC3 complex formation assay, published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"34131122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CUL3 (cullin 3) E3 ubiquitin ligase interacts with BECN1 and promotes K48-linked ubiquitination and proteasomal degradation of BECN1, with KLHL38 serving as the substrate adaptor for this CUL3 complex. CUL3-mediated BECN1 degradation decreases autophagic activity.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, cycloheximide chase, KLHL38 adaptor validation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS identification, ubiquitination assay, adaptor validation with multiple methods in one study\",\n      \"pmids\": [\"33977871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BECN1 is SUMOylated by PIAS3 predominantly at K380 (SUMO3-conjugated) and deSUMOylated by SENP3. Starvation-induced SUMOylation of BECN1 enhances its interaction with UVRAG, PIK3C3, and ATG14, promoting PIK3C3 activity and autophagosome formation; SENP3-mediated deSUMOylation impairs BECN1-PIK3C3 complex formation and fine-tunes autophagy.\",\n      \"method\": \"SUMO pull-down, co-immunoprecipitation, conditional knockout mice, PI3KC3 activity assay, mutagenesis (K380)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout model plus Co-IP, enzyme assay, and site-specific mutant in one dedicated study\",\n      \"pmids\": [\"31373534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GADD45A directly interacts with BECN1 (binding mapped to GADD45A residues 71–81) and dissociates the BECN1-PIK3C3 complex, thereby inhibiting autophagosome initiation. BECN1 knockdown abolishes autophagy alterations induced by GADD45A.\",\n      \"method\": \"Co-immunoprecipitation, GST affinity pull-down, domain mapping, western blot, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP and GST pull-down with domain mapping, single lab, single study\",\n      \"pmids\": [\"26636486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Complete TALEN-mediated knockout of BECN1 in human cells does not abolish LC3B lipidation but leads to malformed autophagosome-like structures with multiple membrane layers and disrupted PIK3C3 complex activity and autophagy flux, demonstrating that BECN1 is essential for functional autophagosome formation but not LC3B lipidation per se.\",\n      \"method\": \"TALEN-mediated knockout, electron microscopy, fluorescence microscopy, autophagy flux assay, PI3KC3 kinase activity assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complete genetic knockout with EM ultrastructural analysis and biochemical PI3KC3 activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"25955014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ARRB1 interacts with BECN1 and PIK3C3 under ischemic conditions, and Arrb1 deletion disrupts the BECN1-PIK3C3 interaction and markedly reduces PIK3C3 kinase activity, impairing autophagosome formation and promoting neuronal death during cerebral ischemia.\",\n      \"method\": \"Co-immunoprecipitation, Arrb1 knockout mice, in vivo ischemia model, PIK3C3 kinase activity assay, cell death assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo KO model, and biochemical kinase activity measurement across in vitro and in vivo settings\",\n      \"pmids\": [\"24988431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM59 regulates BECN1 through two mechanisms: (1) negatively modulating NF-κB pathway to suppress BECN1 transcription, and (2) promoting K48-linked ubiquitination of TRAF6, leading to TRAF6 proteasomal degradation and reduced TRAF6-induced K63-linked ubiquitination of BECN1, thereby impairing BECN1-PIK3C3 complex formation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, luciferase reporter (NF-κB), western blot, siRNA knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assays but single lab, mechanistic chain inferred from multiple steps\",\n      \"pmids\": [\"30231667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylation of CAV1 at tyrosine-14 is required for interaction of CAV1 (via its scaffolding domain) with the BECN1/VPS34 complex under oxidative stress, facilitating autophagosome formation and localization of BECN1 to mitochondria. PTPN1 phosphatase reduces CAV1 phosphorylation and inhibits this autophagy activation.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific antibodies, CAV1 knockout cells, Cav1 KO mice, in vivo ischemia model, fluorescence imaging\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with phospho-mutant, KO mice, in vivo validation, single lab study\",\n      \"pmids\": [\"28542134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ABHD5 directly competes with CASP3 for binding to BECN1 cleavage sites, preventing BECN1 from being cleaved and inactivated by CASP3, thereby preserving autophagic flux. ABHD5 deficiency allows CASP3 to cleave BECN1, impairing autophagy and augmenting genomic instability.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, caspase cleavage assays, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — competitive binding/cleavage assays with Co-IP, single lab, single study\",\n      \"pmids\": [\"27559856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GLIPR2 binds to BECN1 (at residues 267–284) and directly inhibits purified PtdIns3K-C1 lipid kinase activity in vitro. GLIPR2 knockout in cells and mice increases autophagic flux and PtdIns3P generation, confirming GLIPR2 as a negative regulator of PtdIns3K-C1.\",\n      \"method\": \"CRISPR-Cas9 knockout (cells and mice), in vitro PI3K activity assay with purified complex, autophagy flux assays, PtdIns3P WIPI2 recruitment assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted kinase assay with purified complex, combined with in vivo KO mice and multiple flux assays\",\n      \"pmids\": [\"33222586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HSPB6 wild-type interacts with BECN1 to protect it from ubiquitination and proteasomal degradation, and competitively suppresses BECN1-BCL2 binding to stimulate autophagy. The DCM-associated HSPB6S10F mutant has reduced interaction with BECN1, leading to BECN1 ubiquitination, proteasomal degradation, impaired autophagy flux, and increased apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, transgenic mouse model, autophagy flux assay, cardiac functional analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay with in vivo mouse model, single lab study\",\n      \"pmids\": [\"29157081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BECN1 interacts with plasma membrane-associated APP via its evolutionarily conserved domain (ECD, residues 267–337), and recruits PIK3C3 and UVRAG. BECN1 promotes surface APP internalization, sorting to endolysosomes, lysosomal degradation of APP, and reduction of secreted APP metabolites. AKT-mediated phosphorylation of BECN1 Ser295 inhibits APP-BECN1 interaction and APP degradation.\",\n      \"method\": \"Co-immunoprecipitation, BECN1 domain-deletion mutants, surface APP internalization assay, lysosomal degradation assay, sAPP secretion measurement, AKT inhibitors/phosphomimetics\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with domain mapping and functional trafficking assays, single lab, multiple methods but not replicated\",\n      \"pmids\": [\"27715386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via its coiled-coil domain. Adipose-specific Becn1F121A (autophagy-hyperactive) expression is sufficient to increase adiponectin secretion, activate systemic AMPK, and improve insulin sensitivity through a non-cell-autonomous, non-degradative mechanism.\",\n      \"method\": \"Adipose-specific knock-in mouse model, co-immunoprecipitation with exocyst components, adiponectin secretion assay, AMPK activation measurement in distal tissues\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knock-in mouse, Co-IP with domain validation, in vivo metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34038729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Beclin 1 co-immunoprecipitates with the tight junction protein occludin, and BECN1 activation promotes occludin endocytosis and reduces total occludin levels, increasing intestinal TJ permeability in an autophagy-independent manner. Induction of autophagy terminates this constitutive BECN1 function and enhances TJ barrier.\",\n      \"method\": \"Co-immunoprecipitation, BECN1 siRNA knockdown, Tat-beclin 1 peptide, autophagy induction, TEER measurement, mouse colon perfusion\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and functional permeability assays in vitro and in vivo, single lab study\",\n      \"pmids\": [\"30892937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, Atg6 (the BECN1 ortholog) is essential not only for autophagy but also for endocytosis and protein secretion, and is required for normal hematopoiesis. Atg6 mutant flies show enlarged lymph glands, elevated blood cell numbers, and melanotic masses, phenotypes not suppressed by p62 or NFκB mutations, implying these arise from non-autophagy trafficking defects.\",\n      \"method\": \"Drosophila Atg6 null mutant generation, fluorescence and electron microscopy, genetic epistasis with p62 and NFκB mutants\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mutant in vivo with rigorous genetic epistasis and multiple assays (endocytosis, secretion, autophagy, hematopoiesis) in one study\",\n      \"pmids\": [\"23406899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BEC-1 (C. elegans BECN1 ortholog) is required for retrograde transport from endosomes to the Golgi: bec-1 mutants show mislocalization and degradation of MIG-14/Wntless, reduced RME-8 on endosomal membranes, and accumulation of morphologically abnormal endosomes. BEC-1 also functions in phagosome maturation for apoptotic corpse clearance.\",\n      \"method\": \"C. elegans genetics, GFP reporter trafficking assays, immunofluorescence of endosomal markers, RNAi, corpse clearance assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant analysis with multiple trafficking reporters and orthogonal assays in a model organism\",\n      \"pmids\": [\"21183797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BH3 mimetic ABT-737 induces autophagy in parallel with disruption of BCL2-BECN1 binding in BAX/BAK1-double-deficient cells, demonstrating that BCL2 inhibits autophagy by directly binding BECN1 through a BAX/BAK1-independent mechanism.\",\n      \"method\": \"ABT-737 treatment of BAX/BAK1 double-knockout MEFs and HCT116 cells, BCL2-BECN1 Co-IP, autophagy flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function model with Co-IP and flux assay, single study, single lab\",\n      \"pmids\": [\"25715028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKD2 forms a protein complex with BECN1 via its coiled-coil domain 1 (CC1). PKD2 overexpression triggers autophagy through increased BECN1 interaction; a Ca2+-channel-deficient PKD2D509V mutant does not induce autophagy and shows diminished BECN1 interaction. Intracellular Ca2+ depletion with BAPTA-AM blunts starvation-induced autophagy and disrupts the PKD2-BECN1 complex.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, PKD2 domain mutants, Ca2+ chelation (BAPTA-AM), autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and GST pulldown with domain mutants and Ca2+ manipulation, single lab study\",\n      \"pmids\": [\"32543276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VCP/p97 is UFMylated on K109 by E3 ligase UFL1; this modification stabilizes BECN1 through ATXN3-mediated deubiquitination and facilitates assembly of the PtdIns3K complex. Expression of UFMylation-defective VCP K109 mutant fails to rescue VCP-depletion-induced autophagy defects.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination/UFMylation assays, mutagenesis, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, MS, and biochemical assays with defined mutants, single lab study\",\n      \"pmids\": [\"38762759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BECN1 knockdown in colorectal cancer cells promotes STAT3 phosphorylation and activates the STAT3 signaling pathway by regulating the interaction between STAT3 and JAK2, an autophagy-independent mechanism that promotes CRC cell motility and invasion.\",\n      \"method\": \"siRNA knockdown, phospho-STAT3 western blot, co-immunoprecipitation of STAT3-JAK2, cell migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and KD with functional assays, autophagy-independence established by parallel autophagy markers, single lab study\",\n      \"pmids\": [\"32358527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BECN1 interacts with USP14 (a deubiquitinase) and Vimentin, and regulates USP14-mediated de-ubiquitination of Vimentin. BECN1 overexpression increases NSCLC cell migration; BECN1 knockdown reduces migration, mediated through K48-linked ubiquitination of Vimentin.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, cell migration assays\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, functional link to migration is correlative\",\n      \"pmids\": [\"31272261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A conserved autophagy-specific domain (ECD/BARA-like) of BECN1 is required for its interaction with APP; deletion of BECN1 residues 285–299 does not impair PIK3C3 interaction or macroautophagy but specifically abolishes APP-BECN1 interaction and BECN1-dependent APP internalization and degradation.\",\n      \"method\": \"BECN1 deletion mutants, co-immunoprecipitation, surface APP internalization assays, lysosomal degradation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain-deletion mutagenesis with Co-IP and functional trafficking assays, single lab\",\n      \"pmids\": [\"27715386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GABP transcription factor binds to conserved GABP sites in the BECN1 promoter and activates transcription of BECN1 and other BECN1-PIK3C3 complex genes. Nutrient starvation increases GABP-dependent transcriptional activity and GABP recruitment to the BECN1 promoter; GABP knockdown reduces BECN1-PIK3C3 complex protein levels and autophagy.\",\n      \"method\": \"Promoter luciferase assays, ChIP, siRNA knockdown, qPCR, western blot, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and promoter assays with functional knockdown, single lab, focused on transcriptional regulation\",\n      \"pmids\": [\"25046113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BECN1 translocates to the nucleus in response to ionizing radiation. Nuclear BECN1 interacts with CDC25C (via residues 89–155) and CHK2 (via residues 151–224), facilitating CHK2-CDC25C interaction and CDC25C phosphorylation, which leads to CDK1 inactivation and G2/M checkpoint arrest.\",\n      \"method\": \"Nuclear fractionation, co-immunoprecipitation with domain mapping, western blot for phospho-CDC25C/CDK1, BECN1 knockdown, irradiation assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — nuclear fractionation with Co-IP and domain mapping, single lab; autophagy-independence of this function not fully resolved\",\n      \"pmids\": [\"32802407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SENP3 deSUMOylates BECN1, impairing BECN1-PIK3C3 complex formation and suppressing autophagy. PIAS3 is the SUMO3 E3 ligase that conjugates SUMO3 to BECN1 predominantly at K380; K380 SUMOylation enhances interactions with UVRAG, PIK3C3, and ATG14.\",\n      \"method\": \"SUMO pull-down, Co-IP, Senp3 knockout mice (liver-specific), site-directed mutagenesis of K380, PI3KC3 complex activity assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout model plus site-specific mutagenesis and biochemical complex assays in one dedicated mechanistic study\",\n      \"pmids\": [\"31373534\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BECN1/Beclin 1 is an intrinsically disordered scaffold protein that serves as the core organizer of the class III PI3-kinase (PIK3C3/VPS34) complexes; it forms parallel coiled-coil heterodimers with ATG14 (complex I, autophagy) or UVRAG (complex II, endosomal trafficking), and its BARA domain undergoes conditional partial unfolding to insert into membranes and activate PI3KC3. BECN1 activity is regulated by an array of post-translational modifications—phosphorylation by AMPK (Thr388, Ser90/93/96), ULK1 (Ser30), JAK2 (Tyr333), CAMK2 (Ser295), and STK4/MST1 (Thr108); SUMOylation at K380 by PIAS3 (reversed by SENP3); K48-linked ubiquitination and degradation by CUL3-KLHL38 and RNF216; and stabilization by HSPB6, SLC9A3R1, and VCP UFMylation via ATXN3—all converging to tune PI3KC3 complex assembly and autophagosome nucleation. Beyond canonical autophagy, BECN1 directly blocks system Xc- (SLC7A11) activity after AMPK-dependent phosphorylation to promote ferroptosis, facilitates mitophagy by enabling PARK2 translocation to mitochondria at MAM, promotes adiponectin secretion via exocyst binding, regulates intestinal tight junction permeability through occludin endocytosis, and mediates G2/M checkpoint control by scaffolding CHK2-CDC25C interactions in the nucleus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BECN1/Beclin 1 is the core scaffold of class III PI3-kinase (PIK3C3/VPS34) complexes that nucleate autophagosome formation and govern endosomal membrane trafficking [#1, #19]. It is an intrinsically disordered protein whose N-terminal BH3 subdomain folds into an α-helix only upon binding partners such as BCL2L1, while its C-terminal BARA domain conditionally unfolds its β-sheet-1 to insert into membranes and license PI3KC3 binding and activation [#9, #4]. BECN1 assembles distinct complexes through coiled-coil heterodimerization with ATG14 (autophagy) or association with UVRAG, and its BARA/evolutionarily conserved domain mediates additional cargo interactions [#5, #26]. Complete loss of BECN1 yields malformed multilamellar autophagosome-like structures and abolishes functional PIK3C3 activity without preventing LC3B lipidation, defining it as essential for productive autophagosome morphogenesis [#19]. Its activity is tuned by an inhibitory interaction with BCL2 that, when disrupted (e.g. F121A), constitutively hyperactivates autophagy in vivo and clears amyloid-β [#12, #31], and by a dense layer of post-translational modifications: activating phosphorylation by AMPK (Thr388), ULK1 (Ser30 within the ATG14 complex), and JAK2 (Tyr333) all promote PIK3C3 complex formation [#3, #7, #15], whereas CAMK2 (Ser295) phosphorylation inhibits autophagy by displacing PIK3C3 and favoring BCL2 binding [#14]. Stability and complex assembly are further controlled by PIAS3/SENP3-reversible SUMOylation at K380 and by CUL3-KLHL38-mediated K48 ubiquitination and degradation [#39, #16]. Multiple direct binding partners gate PIK3C3 activity, including the inhibitors GLIPR2 and GADD45A and the positive co-factor ARRB1 [#24, #18, #20]. Beyond canonical autophagy, AMPK-dependent phosphorylation at Ser90/93/96 drives a BECN1-SLC7A11 complex that blocks system Xc- and promotes ferroptosis [#6]; BECN1 acts upstream of PARK2 in mitophagy and relocalizes with PINK1 to mitochondria-associated membranes to seed omegasomes [#10, #11]; it promotes exocyst-dependent adiponectin secretion [#27]; and nuclear BECN1 scaffolds CHK2-CDC25C to enforce the G2/M checkpoint after irradiation [#38]. A deeply conserved trafficking role predates these functions, with orthologs required for retrograde endosome-to-Golgi transport and secretion across yeast, worm, and fly [#0, #30, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the ancestral function of the BECN1 ortholog before autophagy was attached to it, showing the gene is required for receptor-mediated vacuolar protein sorting.\",\n      \"evidence\": \"Yeast genetics, subcellular fractionation, and epistasis with sec1/pep12 in VPS30 mutants\",\n      \"pmids\": [\"9105038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect VPS30 to autophagy\", \"No molecular partners or biochemical activity defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved that the ortholog partitions into two functionally distinct PI3-kinase complexes, foreshadowing the autophagy-versus-sorting division of labor later mapped to ATG14 and UVRAG.\",\n      \"evidence\": \"Yeast complementation and epistasis distinguishing PI3K complex I (autophagy) from complex II (CPY sorting)\",\n      \"pmids\": [\"16267277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complex-specific subunits in metazoans not yet identified\", \"Mechanism of complex switching unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked BECN1 directly to apoptotic signaling by showing it is a caspase substrate and a death modulator, framing autophagy-apoptosis crosstalk.\",\n      \"evidence\": \"In vitro caspase cleavage with zVAD block, knockdown/overexpression, TRAIL death assays\",\n      \"pmids\": [\"18842334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage sites not mapped here\", \"Single-lab study without in vivo validation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified transcriptional control of BECN1 by NF-κB p65/RelA, explaining how autophagic capacity is set at the gene-expression level.\",\n      \"evidence\": \"Promoter analysis, EMSA, ChIP, knockdown, and flux assays in T cells\",\n      \"pmids\": [\"19289499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus-specific control of the κB site not fully delineated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed BECN1 upstream of Parkin in mitophagy and identified ARRB1 as a cofactor for PIK3C3 activity, expanding BECN1 beyond bulk autophagy.\",\n      \"evidence\": \"Reciprocal Co-IP, knockdown/KO mice, PARK2 translocation imaging, and PIK3C3 kinase assays\",\n      \"pmids\": [\"24879156\", \"24988431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BECN1 enables PARK2 translocation mechanistically unclear\", \"Whether ARRB1 acts only under ischemia not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the structural basis of BECN1 function: intrinsic disorder of the N-terminus, conditional folding of the BH3 helix, ATG14 coiled-coil heterodimerization, and BARA β-sheet-1 membrane insertion driving PIK3C3 activation.\",\n      \"evidence\": \"NMR, X-ray crystallography, SAXS, cryo-EM, HDX, GUV membrane-insertion assays, and mutagenesis\",\n      \"pmids\": [\"27046249\", \"27383850\", \"30581147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full architecture of membrane-engaged complex II not resolved\", \"How modifications change the disordered ensemble unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that AMPK and CAMK2 phosphorylation act as opposing switches on the BECN1-BCL2/PIK3C3 equilibrium, coupling metabolic and Ca2+/oxidative stress to autophagy decisions.\",\n      \"evidence\": \"In vitro kinase assays, phospho-mutants, Co-IP, Ca2+ imaging, and in vivo APAP liver injury model\",\n      \"pmids\": [\"27304906\", \"27245989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among the many phosphosites not integrated\", \"Crosstalk between Thr388 and Ser295 not tested together\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an autophagy-independent trafficking role in which the BECN1 ECD binds APP and routes it to lysosomal degradation, reducing amyloidogenic processing.\",\n      \"evidence\": \"Domain-deletion mutants, Co-IP, surface internalization and lysosomal degradation assays, AKT phosphomimetics\",\n      \"pmids\": [\"27715386\", \"27559856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence for APP route\", \"Relationship to canonical PIK3C3 trafficking unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Separated a ferroptosis-promoting function from autophagy by showing AMPK-driven Ser90/93/96 phosphorylation builds a BECN1-SLC7A11 complex that blocks system Xc-.\",\n      \"evidence\": \"Phospho-defective mutants, reciprocal Co-IP, lipid peroxidation assays, and in vivo tumor models\",\n      \"pmids\": [\"30057310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether membrane insertion is required for SLC7A11 inhibition unknown\", \"Structural basis of the BECN1-SLC7A11 interface undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed ULK1 selectively activates the ATG14-containing complex via Ser30, establishing complex-specific upstream control of PIK3C3 activation.\",\n      \"evidence\": \"In vitro kinase assays, phospho-specific antibodies, CRISPR knockouts, and phagophore imaging\",\n      \"pmids\": [\"29313410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No equivalent activating mark identified for the UVRAG complex\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SUMOylation (PIAS3/K380) reversed by SENP3 as a regulatory layer that enhances BECN1 binding to UVRAG, ATG14, and PIK3C3, and refined the BH3-T108 BCL2 interaction biophysically.\",\n      \"evidence\": \"SUMO pull-down, Co-IP, liver-specific Senp3 KO mice, K380 mutants, plus crystallography and SPR/MST of T108 BH3 peptides\",\n      \"pmids\": [\"31373534\", \"30626284\", \"32802407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"T108 phosphorylation produces only modest affinity changes\", \"Nuclear G2/M scaffolding role (CHK2-CDC25C) shown by single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified GLIPR2 as a direct inhibitor of the purified PtdIns3K-C1 lipid kinase, providing reconstituted evidence for negative regulation at the catalytic step.\",\n      \"evidence\": \"CRISPR KO in cells and mice, in vitro kinase assay with purified complex, WIPI2/PtdIns3P recruitment assays\",\n      \"pmids\": [\"33222586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling GLIPR2 binding unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended BECN1 activation to cytokine signaling (JAK2/Y333) and to non-degradative metabolic secretion via exocyst-dependent adiponectin release.\",\n      \"evidence\": \"Co-IP, phospho-specific analysis, PIK3C3 complex assays, and adipose-specific Becn1 knock-in mice\",\n      \"pmids\": [\"34131122\", \"34038729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between Y333 and membrane insertion unmapped\", \"Exocyst-binding interface not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected VCP UFMylation to BECN1 stabilization through ATXN3-mediated deubiquitination, adding a further proteostatic input to PtdIns3K assembly.\",\n      \"evidence\": \"Co-IP, MS, UFMylation/ubiquitination assays, and VCP K109 mutant rescue of autophagy\",\n      \"pmids\": [\"38762759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Which ubiquitin ligase ATXN3 antagonizes on BECN1 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dozens of post-translational marks, competing binding partners, and conditional structural states are integrated in space and time to set PIK3C3 output across autophagy, trafficking, ferroptosis, and nuclear checkpoint roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating modification hierarchy with complex I/II partitioning\", \"Structural basis of autophagy-independent partner switching (SLC7A11, occludin, CHK2/CDC25C, exocyst) undefined\", \"In vivo contributions of individual marks to each non-canonical function not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 19, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 24, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [10, 11, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [38]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 30, 26]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 7, 19]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 30, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [38]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 14, 6]}\n    ],\n    \"complexes\": [\n      \"PI3KC3 complex I (BECN1-ATG14-PIK3C3)\",\n      \"PI3KC3 complex II (BECN1-UVRAG-PIK3C3)\"\n    ],\n    \"partners\": [\n      \"PIK3C3\",\n      \"ATG14\",\n      \"UVRAG\",\n      \"BCL2\",\n      \"SLC7A11\",\n      \"PARK2\",\n      \"ARRB1\",\n      \"GLIPR2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}