id: A8MW95 gene_symbol: BECN2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- BECN2/Beclin 2 is a mammalian Beclin-family autophagy and endolysosomal trafficking regulator. It interacts with class III PI3K complex components including PIK3C3/VPS34 and ATG14/UVRAG-associated partners to support autophagy/autophagosome assembly, and it also mediates GASP1/GPRASP1-dependent lysosomal degradation of GPCRs. Beclin-family PI3KC3/autophagy-complex participation is a shared core role, while GPCR catabolism is a BECN2-specific functional branch. existing_annotations: - term: id: GO:0000423 label: mitophagy evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Mitophagy is too cargo-specific for accessible BECN2 evidence; the supported Beclin-family role is autophagosome assembly/autophagy. action: MODIFY reason: Modify to autophagosome assembly. BECN2 is directly supported in autophagy and ATG14/PI3KC3 complex context, but neither the cached human paper nor UniProt establishes a BECN2-specific mitophagy role. Quiles et al. 2023 (PMID:36719945) directly show that selective mitophagy is impaired by BECN1 loss but not BECN2 loss, while BECN2 still contributes to general autophagosome formation, independently corroborating this reassignment. proposed_replacement_terms: - &id015 id: GO:0000045 label: autophagosome assembly additional_reference_ids: - PMID:23954414 - PMID:28218432 - PMID:36719945 - file:human/BECN2/BECN2-uniprot.txt supported_by: - &id001 reference_id: PMID:23954414 supporting_text: functions in autophagy and interacts with class III PI3K complex components and Bcl-2 - &id006 reference_id: PMID:23954414 supporting_text: heterozygous knockout mice have defective autophagy - &id009 reference_id: PMID:28218432 supporting_text: ATG14 binding to BECN/Beclin homologs is essential for autophagy - &id017 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: GO; GO:0000045; P:autophagosome assembly; IBA:GO_Central - term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: BECN2 has a supported adaptor/scaffold role in autophagy and GPCR degradation complexes. action: ACCEPT reason: Accept as core molecular function. BECN2 links Beclin-family PI3KC3/autophagy components and GASP1-dependent GPCR degradation machinery. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id001 - &id005 reference_id: PMID:23954414 supporting_text: required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) - &id010 reference_id: PMID:23954414 supporting_text: through its interaction with GASP1 - &id007 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: acts as a regulator of autophagy and as a regulator of G-protein coupled receptors turnover - term: id: GO:0043548 label: phosphatidylinositol 3-kinase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Phosphatidylinositol 3-kinase binding is supported by BECN2 interaction with PIK3C3/VPS34 and other PI3KC3 complex components. action: ACCEPT reason: Accept as core molecular function/context. BECN2 interacts with class III PI3K complex components and UniProt specifically records PIK3C3/VPS34 interaction. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id001 - &id003 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: Interacts with AMBRA1, UVRAG and PIK3C3/VPS34 - &id002 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: GO; GO:0034271; C:phosphatidylinositol 3-kinase complex, class III, type I; IBA:GO_Central - &id004 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: GO; GO:0034272; C:phosphatidylinositol 3-kinase complex, class III, type II; IBA:GO_Central - term: id: GO:0034271 label: phosphatidylinositol 3-kinase complex, class III, type I evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: BECN2 is supportable in ATG14-containing class III PI3K complex I/autophagy-initiation context. action: ACCEPT reason: Accept as PN-relevant complex membership/context. BECN2 interacts with ATG14 and PIK3C3/VPS34 and is annotated by UniProt/GO Central to PI3KC3-C1. additional_reference_ids: - PMID:23954414 - PMID:28218432 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id002 - &id012 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: Interacts (via coiled-coil domain) with ATG14 - *id003 - &id016 reference_id: PMID:28218432 supporting_text: the BECN2 CCD and ATG14 CCD form a parallel, curved heterodimer - term: id: GO:0034272 label: phosphatidylinositol 3-kinase complex, class III, type II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: BECN2 is also supportable in UVRAG-containing class III PI3K complex II/endolysosomal context. action: ACCEPT reason: Accept as supported complex membership/context. BECN2 interacts with UVRAG and PIK3C3/VPS34 and has a direct endolysosomal GPCR degradation role. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id004 - *id003 - *id005 - &id008 reference_id: PMID:23954414 supporting_text: functions in an additional lysosomal degradation pathway - term: id: GO:0006995 label: cellular response to nitrogen starvation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Nitrogen-starvation response is plausible autophagy context but is not the most informative BECN2 process annotation. action: KEEP_AS_NON_CORE reason: Keep as non-core. Starvation is an autophagy context transferred from evolutionary models; the direct human evidence supports autophagy/autophagosome assembly and GPCR turnover. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id001 - *id006 - *id007 - term: id: GO:0045324 label: late endosome to vacuole transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Late endosome to vacuole transport should be translated to the supported human endosome-to-lysosome/GPCR degradation context. action: MODIFY reason: Modify to endosome to lysosome transport. BECN2 is directly required for ligand-induced endolysosomal degradation of GPCRs, while vacuole wording is yeast-specific transfer. proposed_replacement_terms: - &id019 id: GO:0008333 label: endosome to lysosome transport additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id008 - &id011 reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1 - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Cytoplasm is supported as the broad BECN2 cellular location. action: ACCEPT reason: Accept as supported location. UniProt places BECN2 in the cytoplasm, consistent with its autophagy and endolysosomal trafficking roles. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - reference_id: file:human/BECN2/BECN2-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - *id001 - term: id: GO:0006914 label: autophagy evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Autophagy is a core BECN2 process. action: ACCEPT reason: Accept as core process. The primary paper explicitly identifies Beclin 2 as functioning in autophagy and the mouse knockout phenotype includes defective autophagy. additional_reference_ids: - PMID:23954414 - PMID:28218432 supported_by: - *id001 - *id006 - &id013 reference_id: PMID:23954414 supporting_text: converging regulator of autophagy and GPCR turnover - *id009 - term: id: GO:0032801 label: receptor catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Receptor catabolic process is supported by BECN2-dependent GPCR endolysosomal degradation. action: ACCEPT reason: Accept as a supported parent process for the more specific GPCR catabolic role. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - *id011 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23954414 qualifier: enables review: summary: Generic protein binding is not an informative BECN2 molecular-function annotation. action: MARK_AS_OVER_ANNOTATED reason: Mark as over-annotated. The same evidence is better represented as adaptor activity, PI3K binding, ATG14/UVRAG/PIK3C3 complex context, and GASP1-dependent GPCR catabolism. additional_reference_ids: - PMID:23954414 - PMID:28218432 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id010 - *id012 - *id003 - term: id: GO:0008333 label: endosome to lysosome transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Endosome to lysosome transport is a core BECN2 process through GPCR endolysosomal degradation. action: ACCEPT reason: Accept as core process. BECN2 is required for ligand-induced endolysosomal degradation of GPCRs through GASP1/GPRASP1 interaction. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - *id008 - *id011 - term: id: GO:0044877 label: protein-containing complex binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Protein-containing complex binding is broadly true but less informative than adaptor activity for BECN2. action: MODIFY reason: Modify to protein-macromolecule adaptor activity. BECN2 uses interactions with PI3KC3/autophagy components and GASP1 to mediate lysosomal degradation pathways. proposed_replacement_terms: - &id018 id: GO:0030674 label: protein-macromolecule adaptor activity additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id001 - *id005 - *id007 - term: id: GO:1990172 label: G protein-coupled receptor catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: G protein-coupled receptor catabolic process is a core BECN2-specific process. action: ACCEPT reason: 'Accept as core process. This is the distinctive BECN2 branch not shared with BECN1: BECN2 is required for ligand-induced endolysosomal degradation of GPCRs via GASP1.' additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - &id014 reference_id: PMID:23954414 supporting_text: increased levels of brain cannabinoid 1 receptor - *id011 - term: id: GO:0006914 label: autophagy evidence_type: IMP original_reference_id: PMID:23954414 qualifier: acts_upstream_of_or_within review: summary: Autophagy is a core BECN2 process. action: ACCEPT reason: Accept as core process. The primary paper explicitly identifies Beclin 2 as functioning in autophagy and the mouse knockout phenotype includes defective autophagy. additional_reference_ids: - PMID:23954414 - PMID:28218432 supported_by: - *id001 - *id006 - *id013 - *id009 - term: id: GO:0008333 label: endosome to lysosome transport evidence_type: IMP original_reference_id: PMID:23954414 qualifier: acts_upstream_of_or_within review: summary: Endosome to lysosome transport is a core BECN2 process through GPCR endolysosomal degradation. action: ACCEPT reason: Accept as core process. BECN2 is required for ligand-induced endolysosomal degradation of GPCRs through GASP1/GPRASP1 interaction. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - *id008 - *id011 - term: id: GO:1990172 label: G protein-coupled receptor catabolic process evidence_type: IPI original_reference_id: PMID:23954414 qualifier: acts_upstream_of_or_within review: summary: G protein-coupled receptor catabolic process is a core BECN2-specific process. action: ACCEPT reason: 'Accept as core process. This is the distinctive BECN2 branch not shared with BECN1: BECN2 is required for ligand-induced endolysosomal degradation of GPCRs via GASP1.' additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - *id014 - *id011 - term: id: GO:0006914 label: autophagy evidence_type: IMP original_reference_id: PMID:23954414 qualifier: involved_in review: summary: Autophagy is a core BECN2 process. action: ACCEPT reason: Accept as core process. The primary paper explicitly identifies Beclin 2 as functioning in autophagy and the mouse knockout phenotype includes defective autophagy. additional_reference_ids: - PMID:23954414 - PMID:28218432 supported_by: - *id001 - *id006 - *id013 - *id009 - term: id: GO:0008333 label: endosome to lysosome transport evidence_type: IMP original_reference_id: PMID:23954414 qualifier: involved_in review: summary: Endosome to lysosome transport is a core BECN2 process through GPCR endolysosomal degradation. action: ACCEPT reason: Accept as core process. BECN2 is required for ligand-induced endolysosomal degradation of GPCRs through GASP1/GPRASP1 interaction. additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - *id008 - *id011 - term: id: GO:1990172 label: G protein-coupled receptor catabolic process evidence_type: IMP original_reference_id: PMID:23954414 qualifier: involved_in review: summary: G protein-coupled receptor catabolic process is a core BECN2-specific process. action: ACCEPT reason: 'Accept as core process. This is the distinctive BECN2 branch not shared with BECN1: BECN2 is required for ligand-induced endolysosomal degradation of GPCRs via GASP1.' additional_reference_ids: - PMID:23954414 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id005 - *id010 - *id014 - *id011 - term: *id015 evidence_type: IMP original_reference_id: PMID:23954414 qualifier: involved_in review: summary: BECN2 supports autophagosome assembly through ATG14/PI3KC3 autophagy-complex context. action: NEW reason: Add as a new PN-relevant process annotation. BECN2 functions in autophagy, interacts with class III PI3K components, and binds ATG14 through its coiled-coil domain; UniProt/GO Central already lists autophagosome assembly for BECN2. additional_reference_ids: - PMID:23954414 - PMID:28218432 - file:human/BECN2/BECN2-uniprot.txt supported_by: - *id001 - *id006 - *id009 - *id016 - *id017 references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:23954414 title: Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. findings: [] - id: PMID:28218432 title: BECN2 interacts with ATG14 through a metastable coiled-coil to mediate autophagy. findings: [] - id: PMID:37409929 title: The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs. full_text_unavailable: true findings: - statement: The BECN2 coiled-coil domain forms a heterodimer with ATG14, and this BECN2-ATG14 interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs (notably DRD2/D2R), whereas EGFR degradation depends more on BECN1-UVRAG, establishing cargo selectivity distinct from BECN1. - id: PMID:34152938 title: BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy. full_text_unavailable: true findings: - statement: BECN2 negatively regulates NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes by interacting with the sensors and mediating their lysosomal degradation through a ULK1- and ATG9A-dependent, but BECN1/WIPI2/ATG16L1/LC3-independent, non-canonical autophagic pathway involving SNAREs SEC22A, STX5, and STX6. - id: PMID:32865519 title: Beclin 2 negatively regulates innate immune signaling and tumor development. full_text_unavailable: true findings: - statement: BECN2 targets the upstream kinases MEKK3 (MAP3K3) and TAK1 (MAP3K7) for ATG9A-dependent (ATG16L/Beclin 1/LC3-independent) autophagic degradation, thereby negatively regulating ERK1/2 and NF-kB innate immune signaling; Becn2-deficient mice develop increased inflammation and lymphoma, rescued by myeloid MEKK3 ablation. - id: PMID:36719945 title: Deciphering functional roles and interplay between Beclin1 and Beclin2 in autophagosome formation and mitophagy. full_text_unavailable: true findings: - statement: Both Beclin-1 and Beclin-2 contribute to autophagosome formation, but selective mitophagy is compromised only by Beclin-1 loss (requiring ULK1 phosphorylation of Beclin-1 Ser15 and MAM localization); Beclin-2 is not required for mitophagy, supporting reassignment of BECN2 mitophagy annotation to general autophagosome assembly. - id: PMID:26071895 title: 'Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology.' full_text_unavailable: true findings: - statement: Beclin orthologs are integrative hubs for autophagy and membrane trafficking; mammalian-specific Beclin-2 has a unique role in GASP1-dependent lysosomal degradation of certain GPCRs not shared by other class III PI3K complex members. - id: file:human/BECN2/BECN2-uniprot.txt title: UniProtKB record for BECN2 findings: [] - id: file:human/BECN2/BECN2-notes.md title: BECN2 review notes findings: [] core_functions: - molecular_function: id: GO:0043548 label: phosphatidylinositol 3-kinase binding in_complex: id: GO:0034271 label: phosphatidylinositol 3-kinase complex, class III, type I description: BECN2 participates in Beclin-family PI3KC3/autophagy-complex biology through interactions with PIK3C3/VPS34, ATG14, and related class III PI3K components, supporting autophagy/autophagosome assembly. directly_involved_in: - *id015 - id: GO:0006914 label: autophagy locations: - id: GO:0005737 label: cytoplasm supported_by: - *id001 - *id006 - *id003 - *id012 - *id009 - *id016 - molecular_function: *id018 description: BECN2 functions as an adaptor/regulator for GASP1/GPRASP1-dependent endolysosomal degradation of GPCRs, a BECN2-specific lysosomal degradation branch distinct from BECN1. directly_involved_in: - *id019 - id: GO:1990172 label: G protein-coupled receptor catabolic process - id: GO:0032801 label: receptor catabolic process locations: - id: GO:0005737 label: cytoplasm supported_by: - *id005 - *id010 - *id014 - *id008 - *id011 proposed_new_terms: [] suggested_questions: - question: Should BECN2 be curated to PI3KC3-C1 and PI3KC3-C2 complex membership as direct human complex membership or retained primarily as Beclin-family/evolutionary inference? experts: - GO autophagy editors - Reactome autophagy curators - PAINT curators - question: Should BECN2 mitophagy be removed or generalized to autophagosome assembly/autophagy unless direct cargo-specific mitophagy evidence is found? experts: - GO autophagy editors - mitophagy domain experts - question: 'What is the most specific GO molecular function for the BECN2-GASP1 GPCR degradation role: adaptor activity, protein-containing complex binding, or a future GPCR-degradation adaptor term?' experts: - GO molecular function editors - GPCR trafficking curators - question: Should BECN2 acquire process annotations for its ATG9A-dependent (LC3/ATG16L1-independent) non-canonical autophagic degradation of inflammasome sensors and of MAP3K7/MAP3K3, and for negative regulation of NF-kB/innate immune signaling (PMID:34152938, PMID:32865519), given these are not represented in the current GOA-seeded annotations? experts: - GO autophagy editors - GO immunology curators suggested_experiments: - description: Use BECN2 knockout/rescue with ATG14-binding coiled-coil mutants to measure PI3KC3 complex association, WIPI/LC3 recruitment, autophagosome assembly, and autophagic flux. experiment_type: autophagy complex rescue assay hypothesis: BECN2 supports autophagosome assembly through ATG14/PI3KC3 complex recruitment rather than by a generic Beclin-family label alone. - description: Use BECN2 I80S/GASP1-binding mutants and GPCR ligand stimulation to separate GPCR lysosomal degradation from autophagy phenotypes in the same cellular background. experiment_type: separation-of-function GPCR degradation assay hypothesis: BECN2 has separable autophagy and GPCR endolysosomal degradation functions, with GASP1 binding specifically required for GPCR turnover. - description: In BECN2-deficient macrophages, test whether ATG9A or ULK1 ablation (versus ATG16L1/LC3 loss) is required for accumulation of inflammasome sensors (NLRP3/AIM2/NLRP1/NLRC4) and of MAP3K7/MAP3K3, measuring sensor/kinase half-life and downstream IL1B, NF-kB, and ERK1/2 activation. experiment_type: non-canonical autophagic degradation assay hypothesis: BECN2 restrains innate immune signaling by routing inflammasome sensors and MAP3K kinases to ATG9A-dependent, LC3/ATG16L1-independent lysosomal degradation, distinct from canonical BECN1 autophagy.