Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000423 mitophagy	IBA GO_REF:0000033	MODIFY	Summary: Mitophagy is too cargo-specific for accessible BECN2 evidence; the supported Beclin-family role is autophagosome assembly/autophagy. 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 replacements: autophagosome assembly Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 heterozygous knockout mice have defective autophagy PMID:28218432 ATG14 binding to BECN/Beclin homologs is essential for autophagy file:human/BECN2/BECN2-uniprot.txt GO; GO:0000045; P:autophagosome assembly; IBA:GO_Central
GO:0030674 protein-macromolecule adaptor activity	IBA GO_REF:0000033	ACCEPT	Summary: BECN2 has a supported adaptor/scaffold role in autophagy and GPCR degradation complexes. Reason: Accept as core molecular function. BECN2 links Beclin-family PI3KC3/autophagy components and GASP1-dependent GPCR degradation machinery. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 file:human/BECN2/BECN2-uniprot.txt acts as a regulator of autophagy and as a regulator of G-protein coupled receptors turnover
GO:0043548 phosphatidylinositol 3-kinase binding	IBA GO_REF:0000033	ACCEPT	Summary: Phosphatidylinositol 3-kinase binding is supported by BECN2 interaction with PIK3C3/VPS34 and other PI3KC3 complex components. Reason: Accept as core molecular function/context. BECN2 interacts with class III PI3K complex components and UniProt specifically records PIK3C3/VPS34 interaction. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 file:human/BECN2/BECN2-uniprot.txt Interacts with AMBRA1, UVRAG and PIK3C3/VPS34 file:human/BECN2/BECN2-uniprot.txt GO; GO:0034271; C:phosphatidylinositol 3-kinase complex, class III, type I; IBA:GO_Central file:human/BECN2/BECN2-uniprot.txt GO; GO:0034272; C:phosphatidylinositol 3-kinase complex, class III, type II; IBA:GO_Central
GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I	IBA GO_REF:0000033	ACCEPT	Summary: BECN2 is supportable in ATG14-containing class III PI3K complex I/autophagy-initiation context. 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. Supporting Evidence: file:human/BECN2/BECN2-uniprot.txt GO; GO:0034271; C:phosphatidylinositol 3-kinase complex, class III, type I; IBA:GO_Central file:human/BECN2/BECN2-uniprot.txt Interacts (via coiled-coil domain) with ATG14 file:human/BECN2/BECN2-uniprot.txt Interacts with AMBRA1, UVRAG and PIK3C3/VPS34 PMID:28218432 the BECN2 CCD and ATG14 CCD form a parallel, curved heterodimer
GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II	IBA GO_REF:0000033	ACCEPT	Summary: BECN2 is also supportable in UVRAG-containing class III PI3K complex II/endolysosomal context. Reason: Accept as supported complex membership/context. BECN2 interacts with UVRAG and PIK3C3/VPS34 and has a direct endolysosomal GPCR degradation role. Supporting Evidence: file:human/BECN2/BECN2-uniprot.txt GO; GO:0034272; C:phosphatidylinositol 3-kinase complex, class III, type II; IBA:GO_Central file:human/BECN2/BECN2-uniprot.txt Interacts with AMBRA1, UVRAG and PIK3C3/VPS34 PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 functions in an additional lysosomal degradation pathway
GO:0006995 cellular response to nitrogen starvation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nitrogen-starvation response is plausible autophagy context but is not the most informative BECN2 process annotation. 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. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 heterozygous knockout mice have defective autophagy file:human/BECN2/BECN2-uniprot.txt acts as a regulator of autophagy and as a regulator of G-protein coupled receptors turnover
GO:0045324 late endosome to vacuole transport	IBA GO_REF:0000033	MODIFY	Summary: Late endosome to vacuole transport should be translated to the supported human endosome-to-lysosome/GPCR degradation context. 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 replacements: endosome to lysosome transport Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 functions in an additional lysosomal degradation pathway file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasm is supported as the broad BECN2 cellular location. Reason: Accept as supported location. UniProt places BECN2 in the cytoplasm, consistent with its autophagy and endolysosomal trafficking roles. Supporting Evidence: file:human/BECN2/BECN2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2
GO:0006914 autophagy	IEA GO_REF:0000120	ACCEPT	Summary: Autophagy is a core BECN2 process. Reason: Accept as core process. The primary paper explicitly identifies Beclin 2 as functioning in autophagy and the mouse knockout phenotype includes defective autophagy. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 heterozygous knockout mice have defective autophagy PMID:23954414 converging regulator of autophagy and GPCR turnover PMID:28218432 ATG14 binding to BECN/Beclin homologs is essential for autophagy
GO:0032801 receptor catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: Receptor catabolic process is supported by BECN2-dependent GPCR endolysosomal degradation. Reason: Accept as a supported parent process for the more specific GPCR catabolic role. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:0005515 protein binding	IPI PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is not an informative BECN2 molecular-function annotation. 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. Supporting Evidence: PMID:23954414 through its interaction with GASP1 file:human/BECN2/BECN2-uniprot.txt Interacts (via coiled-coil domain) with ATG14 file:human/BECN2/BECN2-uniprot.txt Interacts with AMBRA1, UVRAG and PIK3C3/VPS34
GO:0008333 endosome to lysosome transport	IEA GO_REF:0000107	ACCEPT	Summary: Endosome to lysosome transport is a core BECN2 process through GPCR endolysosomal degradation. Reason: Accept as core process. BECN2 is required for ligand-induced endolysosomal degradation of GPCRs through GASP1/GPRASP1 interaction. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 PMID:23954414 functions in an additional lysosomal degradation pathway file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:0044877 protein-containing complex binding	IEA GO_REF:0000107	MODIFY	Summary: Protein-containing complex binding is broadly true but less informative than adaptor activity for BECN2. Reason: Modify to protein-macromolecule adaptor activity. BECN2 uses interactions with PI3KC3/autophagy components and GASP1 to mediate lysosomal degradation pathways. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) file:human/BECN2/BECN2-uniprot.txt acts as a regulator of autophagy and as a regulator of G-protein coupled receptors turnover
GO:1990172 G protein-coupled receptor catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: G protein-coupled receptor catabolic process is a core BECN2-specific process. 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. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 PMID:23954414 increased levels of brain cannabinoid 1 receptor file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:0006914 autophagy	IMP PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	ACCEPT	Summary: Autophagy is a core BECN2 process. Reason: Accept as core process. The primary paper explicitly identifies Beclin 2 as functioning in autophagy and the mouse knockout phenotype includes defective autophagy. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 heterozygous knockout mice have defective autophagy PMID:23954414 converging regulator of autophagy and GPCR turnover PMID:28218432 ATG14 binding to BECN/Beclin homologs is essential for autophagy
GO:0008333 endosome to lysosome transport	IMP PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	ACCEPT	Summary: Endosome to lysosome transport is a core BECN2 process through GPCR endolysosomal degradation. Reason: Accept as core process. BECN2 is required for ligand-induced endolysosomal degradation of GPCRs through GASP1/GPRASP1 interaction. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 PMID:23954414 functions in an additional lysosomal degradation pathway file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:1990172 G protein-coupled receptor catabolic process	IPI PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	ACCEPT	Summary: G protein-coupled receptor catabolic process is a core BECN2-specific process. 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. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 PMID:23954414 increased levels of brain cannabinoid 1 receptor file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:0006914 autophagy	IMP PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	ACCEPT	Summary: Autophagy is a core BECN2 process. Reason: Accept as core process. The primary paper explicitly identifies Beclin 2 as functioning in autophagy and the mouse knockout phenotype includes defective autophagy. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 heterozygous knockout mice have defective autophagy PMID:23954414 converging regulator of autophagy and GPCR turnover PMID:28218432 ATG14 binding to BECN/Beclin homologs is essential for autophagy
GO:0008333 endosome to lysosome transport	IMP PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	ACCEPT	Summary: Endosome to lysosome transport is a core BECN2 process through GPCR endolysosomal degradation. Reason: Accept as core process. BECN2 is required for ligand-induced endolysosomal degradation of GPCRs through GASP1/GPRASP1 interaction. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 PMID:23954414 functions in an additional lysosomal degradation pathway file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:1990172 G protein-coupled receptor catabolic process	IMP PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	ACCEPT	Summary: G protein-coupled receptor catabolic process is a core BECN2-specific process. 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. Supporting Evidence: PMID:23954414 required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) PMID:23954414 through its interaction with GASP1 PMID:23954414 increased levels of brain cannabinoid 1 receptor file:human/BECN2/BECN2-uniprot.txt Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1
GO:0000045 autophagosome assembly	IMP PMID:23954414 Beclin 2 functions in autophagy, degradation of G protein-co...	NEW	Summary: BECN2 supports autophagosome assembly through ATG14/PI3KC3 autophagy-complex context. 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. Supporting Evidence: PMID:23954414 functions in autophagy and interacts with class III PI3K complex components and Bcl-2 PMID:23954414 heterozygous knockout mice have defective autophagy PMID:28218432 ATG14 binding to BECN/Beclin homologs is essential for autophagy PMID:28218432 the BECN2 CCD and ATG14 CCD form a parallel, curved heterodimer file:human/BECN2/BECN2-uniprot.txt GO; GO:0000045; P:autophagosome assembly; IBA:GO_Central

Core Functions

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.

Molecular Function:

phosphatidylinositol 3-kinase binding

Directly Involved In:

autophagosome assembly autophagy

Cellular Locations:

cytoplasm

In Complex:

phosphatidylinositol 3-kinase complex, class III, type I

Supporting Evidence:

PMID:23954414
functions in autophagy and interacts with class III PI3K complex components and Bcl-2
PMID:23954414
heterozygous knockout mice have defective autophagy
file:human/BECN2/BECN2-uniprot.txt
Interacts with AMBRA1, UVRAG and PIK3C3/VPS34
file:human/BECN2/BECN2-uniprot.txt
Interacts (via coiled-coil domain) with ATG14
PMID:28218432
ATG14 binding to BECN/Beclin homologs is essential for autophagy
PMID:28218432
the BECN2 CCD and ATG14 CCD form a parallel, curved heterodimer

BECN2 functions as an adaptor/regulator for GASP1/GPRASP1-dependent endolysosomal degradation of GPCRs, a BECN2-specific lysosomal degradation branch distinct from BECN1.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

endosome to lysosome transport G protein-coupled receptor catabolic process receptor catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:23954414
required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs)
PMID:23954414
through its interaction with GASP1
PMID:23954414
increased levels of brain cannabinoid 1 receptor
PMID:23954414
functions in an additional lysosomal degradation pathway
file:human/BECN2/BECN2-uniprot.txt
Regulates degradation in lysosomes of a variety of G-protein coupled receptors via its interaction with GPRASP1/GASP1

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:23954414

Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism.

PMID:28218432

BECN2 interacts with ATG14 through a metastable coiled-coil to mediate autophagy.

PMID:37409929

The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs.

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.

PMID:34152938

BECN2 (beclin 2) Negatively Regulates Inflammasome Sensors Through ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy.

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.

PMID:32865519

Beclin 2 negatively regulates innate immune signaling and tumor development.

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.

PMID:36719945

Deciphering functional roles and interplay between Beclin1 and Beclin2 in autophagosome formation and mitophagy.

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.

PMID:26071895

Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology.

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.

file:human/BECN2/BECN2-uniprot.txt

UniProtKB record for BECN2

file:human/BECN2/BECN2-notes.md

BECN2 review notes

Suggested Experiments

Experiment: Use BECN2 knockout/rescue with ATG14-binding coiled-coil mutants to measure PI3KC3 complex association, WIPI/LC3 recruitment, autophagosome assembly, and autophagic flux.

Hypothesis: BECN2 supports autophagosome assembly through ATG14/PI3KC3 complex recruitment rather than by a generic Beclin-family label alone.

Type: autophagy complex rescue assay

Experiment: Use BECN2 I80S/GASP1-binding mutants and GPCR ligand stimulation to separate GPCR lysosomal degradation from autophagy phenotypes in the same cellular background.

Hypothesis: BECN2 has separable autophagy and GPCR endolysosomal degradation functions, with GASP1 binding specifically required for GPCR turnover.

Type: separation-of-function GPCR degradation assay

Experiment: 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.

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.

Type: non-canonical autophagic degradation assay

Deep Research

Falcon

(BECN2-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 24 citations 2 artifacts 2026-06-07T05:08:04.972790

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000027 The document provides several figures detailing Beclin 2 (BECN2) domain architecture, its interaction with GASP1, and its role in G (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human BECN2 (Beclin-2) functional annotation (UniProt A8MW95)

Executive summary

BECN2 (Beclin-2) is a mammal-specific paralog of BECN1 (Beclin-1) that functions as (i) a scaffolding subunit of class III PI3K (PI3KC3/VPS34) complexes that support autophagy and membrane trafficking, and (ii) a specialized endolysosomal sorting factor required for lysosomal turnover of a subset of GPRASP1/GASP1-associated GPCRs through a direct N-terminal interaction with GASP1. In addition, BECN2 executes ATG9A/ULK1-dependent, LC3- and ATG16L1-independent “noncanonical autophagy” that targets innate immune signaling proteins (inflammasome sensors, TAK1, MEKK3) for lysosomal degradation, thereby restraining inflammatory signaling and lymphoma development in mouse models. (he2013beclin2functions pages 6-7, qiu2023thepotentbecn2atg14 pages 1-2, zhu2020beclin2negatively pages 1-2, deng2022becn2(beclin2) pages 1-3)

1) Key concepts and definitions (current understanding)

1.1 Beclin-family proteins and PI3KC3 complexes

Beclin proteins (Atg6 orthologs) are best understood as multi-domain scaffolds that assemble PI3KC3 lipid kinase complexes, coordinating membrane trafficking steps relevant to autophagy and endolysosomal pathways. Beclin-2 shares canonical Beclin-family architecture (BH3-like region, central coiled-coil, C-terminal conserved/BARA-like region), consistent with a scaffolding role. (he2013beclin2functions pages 1-2, levine2015beclinorthologsintegrative pages 7-9)

1.2 “Canonical” autophagy vs BECN2-linked noncanonical degradative routes

“Canonical” macroautophagy uses an LC3/ATG16L1-dependent conjugation system to form double-membrane autophagosomes. By contrast, multiple studies now support BECN2-driven ATG9A- and ULK1-dependent but LC3/ATG16L1-independent trafficking/degradation routes that still culminate in lysosomal degradation of specific signaling proteins, aligning with an “alternative/noncanonical autophagy” concept rather than classical LC3 lipidation-dependent autophagy. (deng2022becn2(beclin2) pages 12-13, deng2022becn2(beclin2) pages 1-3, zhu2020beclin2negatively pages 14-15)

1.3 Specialized GPCR downregulation via GASP1/GPRASP1

A key definitional feature of Beclin-2 is its direct binding to GPRASP1/GASP1 through the Beclin-2 N-terminus, which is required for post-endosomal sorting of select GPCRs for lysosomal degradation (rather than recycling). This distinguishes BECN2 from BECN1-centered autophagy initiation pathways. (he2013beclin2functions pages 6-7, levine2015beclinorthologsintegrative pages 7-9)

2) Gene/protein identity verification (critical disambiguation)

The literature retrieved and synthesized here is consistent with the UniProt-provided identity of human BECN2 / Beclin-2 as a Beclin-family protein with an Atg6/Beclin-related domain architecture and mammal-specific paralogy to BECN1. Primary studies describe Beclin-2 as an intronless gene mapping to chromosome 1q43 and as a protein of ~49 kDa predicted mass with an apparent ~53 kDa band on immunoblot; reported sequence lengths vary by annotation/construct (~431–447 aa), consistent with a single Beclin-family protein rather than a different gene/protein. (he2013beclin2functions pages 1-2, he2013beclin2functions pages 2-3, su2017becn2interactswith pages 1-5)

3) Molecular functions and pathways

3.1 Autophagy-supporting scaffold function through PI3KC3 assemblies

Beclin-2 co-immunoprecipitates with core PI3KC3 complex components (including VPS34/PI3KC3, p150/VPS15, ATG14, and UVRAG), supporting a model in which it scaffolds PI3KC3 complexes analogous to Beclin-1 complexes, thereby contributing to autophagic flux and autophagosome biogenesis in cells and in vivo. (su2017becn2interactswith pages 1-5, qiu2023thepotentbecn2atg14 pages 1-2)

Mechanistically, the BECN2 coiled-coil domain (CCD) forms metastable homodimers and stable heterodimers with ATG14; structure-guided mutations that stabilize homodimerization reduce ATG14 binding, supporting a structural basis for dynamic complex assembly. (su2017becn2interactswith pages 1-5)

3.2 Endolysosomal trafficking: GASP1-dependent GPCR degradation (BECN2 hallmark function)

The strongest, most distinctive functional evidence for BECN2 is its requirement for agonist-induced endolysosomal degradation of several GPCRs by binding GASP1.

Direct interaction: Beclin-2 binds GASP1; a Beclin-2 N-terminal segment encompassing aa 69–88 is required. GASP1-binding–defective Beclin-2 mutants (e.g., Δ69–88, I80S) fail to restore GPCR degradation in Beclin-2-depleted cells. (he2013beclin2functions pages 6-7)
Trafficking compartment logic: When Beclin-2 is depleted, internalized δ-opioid receptor (DOR) accumulates in EEA1+ early endosomes and fails to reach LAMP1+ lysosomes, consistent with a post-endosomal sorting defect. (he2013beclin2functions pages 6-7)
Functional separability from canonical autophagy initiation: In the same work, knockdown of BECN1, VPS34, or ATG14 did not reproduce the GPCR degradation defect, and Beclin-2 mutants that cannot bind GASP1 still rescued starvation-induced autophagy, indicating separable molecular functions. (he2013beclin2functions pages 6-7)

Collectively, these results justify annotating BECN2 as a GPCR post-endosomal sorting/lysosomal downregulation factor in addition to an autophagy scaffold. (he2013beclin2functions pages 6-7, levine2015beclinorthologsintegrative pages 7-9)

3.3 Innate immunity: BECN2-driven degradation of inflammasome sensors

BECN2 restrains inflammasome activity by targeting sensors for lysosomal degradation via a pathway that requires ULK1 and ATG9A, but is independent of the canonical Beclin-1/WIPI2/ATG16L1/LC3 axis.

Key findings include:
* Loss-of-function increases inflammasome activity: BECN2 deficiency enhances activity of NLRP3, AIM2, NLRP1, NLRC4 inflammasomes after ligand stimulation; overexpression decreases IL1B production and CASP1 cleavage. (deng2022becn2(beclin2) pages 1-3)
* Mechanism: BECN2 interacts with inflammasome sensors and promotes their lysosomal degradation; degradation is blocked by lysosome inhibitors and does not require ATG16L1 or LC3. (deng2022becn2(beclin2) pages 4-7, deng2022becn2(beclin2) pages 7-10)
* Compartment model: BECN2 recruits sensors to ATG9A+ vesicles upon ULK1 activation; SNARE proteins SEC22A, STX5, STX6 contribute to the membrane trafficking/fusion steps needed for sensor degradation. (deng2022becn2(beclin2) pages 10-11)

These data support a specific annotation: BECN2 is a negative regulator of inflammasome signaling by targeting sensors for ATG9A-dependent lysosomal degradation. (deng2022becn2(beclin2) pages 12-13, deng2022becn2(beclin2) pages 1-3)

3.4 Innate immune signaling and cancer phenotypes: TAK1/MEKK3 turnover

A related BECN2-dependent noncanonical degradative mechanism targets the MAPK/NF-κB upstream kinases TAK1 (MAP3K7) and MEKK3 (MAP3K3).

Post-transcriptional control: BECN2 deficiency increases TAK1/MEKK3 protein without corresponding mRNA changes, while increased BECN2 expression reduces endogenous kinase protein levels. (zhu2020beclin2negatively pages 5-7)
Pathway dependencies: MEKK3 degradation is blocked by ULK1 or ATG9A ablation and is described as independent of Beclin-1 and LC3/ATG16L-type conjugation. (zhu2020beclin2negatively pages 14-15)
In vivo outcomes: Becn2-null mice show increased ERK/NF-κB signaling, elevated pro-inflammatory cytokines, splenomegaly/lymphadenopathy, and increased lymphoma incidence; myeloid-specific MEKK3 ablation rescues these phenotypes, tying BECN2’s tumor-suppressive effects to kinase degradation. (zhu2020beclin2negatively pages 1-2)

4) Subcellular localization and compartment context

BECN2’s experimentally supported compartment context tracks its distinct functions:

GPCR degradation route: Early endosome (EEA1+) to lysosome (LAMP1+) trafficking is disrupted upon BECN2 depletion, indicating BECN2 acts in post-endosomal sorting steps for GPCR cargo. (he2013beclin2functions pages 6-7)
Noncanonical innate immune degradation: BECN2 promotes loading of inflammasome sensors onto ATG9A+ single-membrane vesicles and their subsequent appearance in autophagosomes/amphisomes/lysosomal compartments, supported by confocal quantification and EM/APEX2 labeling. (deng2022becn2(beclin2) pages 10-11)
Mitophagy localization divergence: In mitophagy, Beclin-1 (not Beclin-2) localizes to mitochondria–ER-associated membranes (MAMs), supporting functional specialization and arguing against a generic “Beclin redundancy” model. (quiles2023decipheringfunctionalroles pages 1-3)

5) Recent developments (prioritizing 2023–2024)

5.1 2023: Structural and selective interaction insight + a selective modulation strategy

A 2023 Autophagy study solved crystal structures of the BECN2 coiled-coil domain and the BECN2–ATG14 coiled-coil complex, highlighting imperfect residues that reduce BECN2 homodimer stability and may facilitate heteromerization. This study provided functional evidence that the BECN2–ATG14 interaction is selectively critical for endolysosomal degradation of GPRASP1-associated GPCRs (notably DRD2/D2R), whereas EGFR degradation depends more on BECN1–UVRAG interactions. The authors also developed stapled peptides that selectively enhance BECN2–ATG14 interaction and boost BECN2-dependent autophagy and DRD2 degradation without affecting BECN1-dependent EGFR turnover—an important proof-of-concept for selective Beclin-paralog modulation. (qiu2023thepotentbecn2atg14 pages 1-2)

Publication: Qiu et al., Autophagy, July 2023. DOI: 10.1080/15548627.2023.2233872. URL: https://doi.org/10.1080/15548627.2023.2233872 (qiu2023thepotentbecn2atg14 pages 1-2)

5.2 2023: Functional dissection of Beclin-1 vs Beclin-2 in mitophagy

A 2023 Science Signaling study found that although both homologs can contribute to autophagosome formation under some conditions, mitophagy defects occurred only with BECN1 loss, associated with Beclin-1 localization to MAMs and ULK1 phosphorylation of Beclin-1 Ser15. Beclin-2 did not localize to MAMs and was not required for mitophagy in those assays, clarifying division of labor between paralogs. (quiles2023decipheringfunctionalroles pages 1-3)

Publication: Quiles et al., Science Signaling, Jan 2023. DOI: 10.1126/scisignal.abo4457. URL: https://doi.org/10.1126/scisignal.abo4457 (quiles2023decipheringfunctionalroles pages 1-3)

5.3 2024: Authoritative synthesis on nonautophagic roles of ATG proteins

A 2024 Autophagy review emphasizes that autophagy-related proteins can have nonautophagic functions in signaling and trafficking, and explicitly cites BECN2 among ATG factors with roles beyond canonical autophagy (including its N-terminal interaction with GPRASP1 and its involvement in signaling/immune regulation). This is useful expert framing for functional annotation and for interpreting BECN2 phenotypes that are not explained solely by LC3 lipidation–dependent autophagy. (maheshwari2025thebiologicalrole pages 39-39)

Publication: Shang et al., Autophagy, online Sep 2024 (per citation metadata). DOI: 10.1080/15548627.2023.2254664. URL: https://doi.org/10.1080/15548627.2023.2254664 (maheshwari2025thebiologicalrole pages 39-39)

5.4 2024: Disease-model report proposing sesamin→BECN2 modulation in lumbar disc degeneration

A 2024 study in Aging (Albany NY) reported that sesamin increases BECN2 expression in an LPS-induced chondrocyte degeneration model (ATDC5) and associated in vivo lumbar disc degeneration phenotypes. The authors report that BECN2 overexpression improved viability and reduced apoptosis while decreasing markers they interpret as autophagy and inflammasome activation (including ATG14/VPS34/GASP1 and NLRP3/AIM2-related proteins). These results represent a recent disease-model “application” of BECN2 modulation, though directionality (increased BECN2 with decreased autophagy markers) should be interpreted cautiously alongside the foundational mechanistic literature that links BECN2 to autophagy support and lysosomal trafficking. (zhang2024sesaminmediatedhighexpression pages 1-2, he2013beclin2functions pages 6-7)

Publication: Zhang et al., Aging (Albany NY), Jan 2024. DOI: 10.18632/aging.205386. URL: https://doi.org/10.18632/aging.205386 (zhang2024sesaminmediatedhighexpression pages 1-2)

6) Current applications and real-world implementations

Selective pharmacologic modulation concepts (preclinical): The 2023 stapled peptides that selectively enhance BECN2–ATG14 interactions represent a concrete strategy to modulate BECN2-dependent GPCR downregulation (e.g., DRD2/D2R) without broadly perturbing BECN1-dependent EGFR trafficking, suggesting a route toward more targeted autophagy/trafficking interventions. (qiu2023thepotentbecn2atg14 pages 1-2)
Disease model targeting (preclinical): Sesamin-mediated BECN2 upregulation has been proposed as a therapeutic mechanism in lumbar disc degeneration models, linking nutraceutical-like compounds to BECN2-regulated autophagy/inflammation pathways. (zhang2024sesaminmediatedhighexpression pages 1-2)
Inflammation/cancer axis (mechanism-driven targets): Genetic data in mice suggest that increasing BECN2 activity (or mimicking its ATG9A-dependent degradation of TAK1/MEKK3 and inflammasome sensors) could be a therapeutic concept for inflammatory disease or inflammation-driven tumorigenesis, though no BECN2-specific clinical interventions were identified in the retrieved evidence. (zhu2020beclin2negatively pages 1-2, deng2022becn2(beclin2) pages 1-3)

7) Expert opinions and authoritative synthesis

A highly cited Trends in Cell Biology review positions Beclin proteins as integrative hubs for membrane trafficking and signaling, and highlights Beclin-2’s unique role in lysosomal degradation of certain GPCRs via GASP1 that is not shared by other PI3KC3 complex members. (levine2015beclinorthologsintegrative pages 7-9)

Publication: Levine et al., Trends in Cell Biology, Sep 2015. DOI: 10.1016/j.tcb.2015.05.004. URL: https://doi.org/10.1016/j.tcb.2015.05.004 (levine2015beclinorthologsintegrative pages 7-9)

8) Statistics and data points from recent and foundational studies

Protein size/biochemistry: Beclin-2 reported as a predicted ~49 kDa protein detected at ~53 kDa by immunoblot in the discovery study; sequence length annotations include ~447 aa (discovery context) and ~431 aa (structural work). (he2013beclin2functions pages 2-3, he2013beclin2functions pages 1-2, su2017becn2interactswith pages 1-5)
Defined functional motif interval: GASP1 binding requires an N-terminal region including aa 69–88; mutants disrupting this region abolish GPCR degradation rescue. (he2013beclin2functions pages 6-7)
Defined compartment markers: GPCR trafficking defect visualized as retention in EEA1+ structures and failure to reach LAMP1+ lysosomes. (he2013beclin2functions pages 6-7)
Defined pathway dependencies (innate immunity): Inflammasome sensor degradation is ULK1- and ATG9A-dependent, but independent of ATG16L1 and LC3 (and other canonical factors in the cited experiments). (deng2022becn2(beclin2) pages 1-3, deng2022becn2(beclin2) pages 7-10)

9) Figures (visual evidence)

The discovery paper includes schematics and microscopy images supporting domain architecture and trafficking models for Beclin-2:
* Domain architecture and alignment with Beclin-1; interaction schematics with GASP1; and microscopy showing EEA1-to-LAMP1 trafficking defects for GPCR cargo upon BECN2 loss. (he2013beclin2functions media 9cc1242f, he2013beclin2functions media 3a815a64, he2013beclin2functions media 17df886f, he2013beclin2functions media 4084183b)

10) Practical functional annotation (recommended text)

Recommended primary-function annotation:
BECN2 encodes Beclin-2, a Beclin-family scaffold that participates in PI3KC3 complexes supporting autophagy and endolysosomal trafficking and has a specialized role in post-endosomal sorting/lysosomal degradation of GPRASP1-associated GPCRs via direct GASP1 binding; additionally, BECN2 mediates ATG9A/ULK1-dependent noncanonical lysosomal degradation of specific innate immune signaling proteins (inflammasome sensors and MAP3K kinases), thereby restraining inflammatory signaling. (he2013beclin2functions pages 6-7, su2017becn2interactswith pages 1-5, zhu2020beclin2negatively pages 1-2, deng2022becn2(beclin2) pages 1-3)

Embedded evidence map

Function/process	Mechanism/complexes and key partners	Key experimental evidence (assay/model)	Notes on selectivity vs BECN1	Primary citation with year, DOI, URL
Identity / core annotation	Human BECN2 / Beclin-2 is a mammal-specific Beclin-family paralog of BECN1; reported as ~431 aa in structural work and ~447 aa/predicted ~49 kDa in the discovery paper; contains Beclin-family BH3-like region, coiled-coil domain (CCD), and C-terminal evolutionarily conserved/BARA-like domain; acts as a scaffold in membrane-trafficking/autophagy pathways (he2013beclin2functions pages 2-3, he2013beclin2functions pages 1-2, su2017becn2interactswith pages 1-5, levine2015beclinorthologsintegrative pages 7-9)	Sequence/domain comparison, immunoblot detection, phylogenetic/genomic analysis in human and mouse; co-IP with Beclin-network factors (he2013beclin2functions pages 2-3, su2017becn2interactswith pages 1-5)	Distinct from BECN1 by mammal-specific origin, divergent N-terminus, stronger AMBRA1 binding, lack of Rubicon binding, and constitutive BCL2 association under starvation conditions (zhang2014regulationofplasma pages 1-2, su2017becn2interactswith pages 1-5, levine2015beclinorthologsintegrative pages 7-9)	He et al., 2013. DOI: 10.1016/j.cell.2013.07.035. URL: https://doi.org/10.1016/j.cell.2013.07.035 (he2013beclin2functions pages 2-3, he2013beclin2functions pages 1-2)
Canonical/autophagy-supporting scaffold role	BECN2 associates with class III PI3K/PtdIns3K complex components including PIK3C3/VPS34, PIK3R4/VPS15 (p150), ATG14, UVRAG, AMBRA1, supporting autophagosome biogenesis and autophagic flux (qiu2023thepotentbecn2atg14 pages 1-2, su2017becn2interactswith pages 1-5)	Co-immunoprecipitation, structural CCD studies, Becn2 knockdown/knockout cells and mice showing reduced autophagy markers, reduced long-lived protein degradation, fewer autophagic structures, altered LC3/p62 readouts (he2013beclin2functions pages 6-7, su2017becn2interactswith pages 1-5)	BECN2 overlaps with BECN1 in autophagy initiation but is biochemically distinct: stronger AMBRA1 interaction, no Rubicon co-IP, and starvation does not disrupt BECN2-BCL2 interaction as reported for BECN1-regulated complexes (he2013beclin2functions pages 12-13, su2017becn2interactswith pages 1-5)	Su et al., 2017. DOI: 10.1002/pro.3140. URL: https://doi.org/10.1002/pro.3140 (su2017becn2interactswith pages 1-5)
Ligand-induced lysosomal degradation of select GPCRs	BECN2 binds GPRASP1/GASP1 via an N-terminal region including aa 69-88 and promotes post-endosomal sorting of GASP1-associated GPCRs to LAMP1+ lysosomes; cargos include OPRD1/DOR, CNR1/CB1R, DRD2/D2R and other GASP1-regulated receptors (he2013beclin2functions pages 6-7, qiu2023thepotentbecn2atg14 pages 1-2, he2013beclin2functions media 9cc1242f)	Yeast two-hybrid and co-IP for BECN2-GASP1 binding; receptor internalization/degradation assays; microscopy showing receptor retention in EEA1+ early endosomes and failure to reach lysosomes after BECN2 loss; rescue by WT but not GASP1-binding-defective BECN2 mutants (he2013beclin2functions pages 6-7, he2013beclin2functions media 9cc1242f)	This GPCR-trafficking role is a major BECN2-specific distinction: BECN1, VPS34, and ATG14 knockdown did not phenocopy BECN2 loss in the original GPCR degradation assays, supporting a separable trafficking function beyond shared autophagy roles (he2013beclin2functions pages 6-7, levine2015beclinorthologsintegrative pages 7-9)	He et al., 2013. DOI: 10.1016/j.cell.2013.07.035. URL: https://doi.org/10.1016/j.cell.2013.07.035 (he2013beclin2functions pages 6-7, he2013beclin2functions media 9cc1242f)
Structural basis of autophagy/trafficking selectivity	BECN2 CCD forms a metastable antiparallel homodimer with imperfect interface residues and also a BECN2-ATG14 heterodimer; this structural plasticity supports selective assembly of BECN2-containing complexes for autophagy and endolysosomal trafficking (qiu2023thepotentbecn2atg14 pages 1-2)	Crystal structures of BECN2 CCD and BECN2-ATG14 CCD complex; mutational/biophysical analyses showing weaker homodimer but tighter ATG14 binding; function tested in receptor degradation assays (qiu2023thepotentbecn2atg14 pages 1-2, su2017becn2interactswith pages 1-5)	2023 work argues BECN2-ATG14 is especially important for BECN2-specific cargo handling, whereas BECN1-UVRAG is more important for EGFR trafficking; thus similar Beclin architectures support non-identical cargo selectivity (qiu2023thepotentbecn2atg14 pages 1-2)	Qiu et al., 2023. DOI: 10.1080/15548627.2023.2233872. URL: https://doi.org/10.1080/15548627.2023.2233872 (qiu2023thepotentbecn2atg14 pages 1-2)
Selective endolysosomal degradation of DRD2 and other GPRASP1-associated GPCRs	Potent BECN2-ATG14 interaction is selectively required for degradation of GPRASP1-associated GPCRs, especially DRD2/D2R; BECN2 N-terminus binds GPRASP1 while the CCD engages ATG14 to support trafficking/degradation (qiu2023thepotentbecn2atg14 pages 1-2)	Functional mutagenesis plus receptor degradation assays in cells; comparison with EGFR cargo; stapled peptide enhancers of BECN2-ATG14 interaction tested for effects on autophagy and DRD2 turnover (qiu2023thepotentbecn2atg14 pages 1-2)	Clear cargo selectivity versus BECN1: EGFR depends more on BECN1-UVRAG, whereas DRD2 depends more on BECN2-ATG14 (qiu2023thepotentbecn2atg14 pages 1-2)	Qiu et al., 2023. DOI: 10.1080/15548627.2023.2233872. URL: https://doi.org/10.1080/15548627.2023.2233872 (qiu2023thepotentbecn2atg14 pages 1-2)
Chemical/biophysical modulation of BECN2 function	2023 study designed stapled peptides that selectively bind the BECN2 CCD and enhance BECN2-ATG14 interaction, increasing BECN2-dependent autophagy and DRD2 degradation without altering BECN1-dependent EGFR turnover (qiu2023thepotentbecn2atg14 pages 1-2)	Structural design, peptide binding, cellular autophagy assays, and cargo degradation assays for DRD2 versus EGFR (qiu2023thepotentbecn2atg14 pages 1-2)	Provides one of the first selective BECN2-directed modulatory strategies rather than pan-autophagy manipulation; experimental support is preclinical/cell-based (qiu2023thepotentbecn2atg14 pages 1-2)	Qiu et al., 2023. DOI: 10.1080/15548627.2023.2233872. URL: https://doi.org/10.1080/15548627.2023.2233872 (qiu2023thepotentbecn2atg14 pages 1-2)
Mitophagy and autophagosome formation: divergence from BECN1	BECN2 contributes to basal/stress autophagosome formation in some settings, but selective mitophagy is chiefly a BECN1 function linked to ULK1-phosphorylated Ser15 and localization to mitochondria-associated membranes (MAMs); BECN2 does not substitute for this mitophagy-specific role (quiles2023decipheringfunctionalroles pages 1-3)	BECN1/BECN2 knockout HeLa cells and MEFs; mitophagy assays after mitochondrial damage; localization analyses at MAMs; rescue experiments with BECN1 variants (quiles2023decipheringfunctionalroles pages 1-3)	Major 2023 clarification: BECN2 is not simply redundant with BECN1; BECN1 loss impairs mitophagy, whereas BECN2 loss does not in the same assays (quiles2023decipheringfunctionalroles pages 1-3)	Quiles et al., 2023. DOI: 10.1126/scisignal.abo4457. URL: https://doi.org/10.1126/scisignal.abo4457 (quiles2023decipheringfunctionalroles pages 1-3)
Noncanonical degradation of inflammasome sensors	BECN2 negatively regulates NLRP3, AIM2, NLRP1, NLRC4 by promoting their lysosomal degradation through a ULK1- and ATG9A-dependent, but BECN1/ATG16L1/LC3-independent pathway; BECN2 recruits sensors to ATG9A+ vesicles and cooperates with SEC22A, STX5, STX6 (deng2022becn2(beclin2) pages 12-13, deng2022becn2(beclin2) pages 1-3, deng2022becn2(beclin2) pages 10-11, deng2022becn2(beclin2) pages 7-10)	CRISPR/KO macrophages and THP-1 cells; co-IP and colocalization; half-life and inhibitor studies showing lysosome dependence; inflammasome activation readouts (IL1B, CASP1 cleavage); alum-induced peritonitis in mice (deng2022becn2(beclin2) pages 12-13, deng2022becn2(beclin2) pages 1-3, deng2022becn2(beclin2) pages 7-10)	This pathway is explicitly noncanonical and largely independent of canonical BECN1-LC3 autophagy machinery, underscoring a unique BECN2 degradative route in innate immunity (deng2022becn2(beclin2) pages 1-3, deng2022becn2(beclin2) pages 4-7, deng2022becn2(beclin2) pages 7-10)	Deng et al., 2022. DOI: 10.1080/15548627.2021.1934270. URL: https://doi.org/10.1080/15548627.2021.1934270 (deng2022becn2(beclin2) pages 12-13, deng2022becn2(beclin2) pages 1-3)
Negative regulation of MAPK/NF-kB inflammatory signaling	BECN2 targets MEKK3/MAP3K3 and TAK1/MAP3K7 for degradation via ULK1-ATG9A-dependent noncanonical autophagy; this suppresses ERK1/2, NF-kB, and STAT3-linked inflammatory outputs (zhu2020beclin2negatively pages 1-2, zhu2020beclin2negatively pages 14-15, zhu2020beclin2negatively pages 5-7)	Endogenous interaction assays; gain/loss of BECN2 in innate immune cells; protein-versus-mRNA comparisons showing post-translational control; lysosome/autophagy inhibitor studies; genetic rescue by myeloid Map3k3 ablation (zhu2020beclin2negatively pages 1-2, zhu2020beclin2negatively pages 14-15, zhu2020beclin2negatively pages 5-7)	Again distinct from canonical BECN1 autophagy: degradation reported as ATG9A-dependent but BECN1-, ATG16L-, and LC3-independent (zhu2020beclin2negatively pages 1-2, zhu2020beclin2negatively pages 14-15)	Zhu et al., 2020. DOI: 10.1172/JCI133283. URL: https://doi.org/10.1172/jci133283 (zhu2020beclin2negatively pages 1-2, zhu2020beclin2negatively pages 14-15)
In vivo immune/tumor phenotypes	Loss of Becn2 in mice causes splenomegaly, lymphadenopathy, increased inflammatory cytokines, persistent STAT3 activation, and higher lymphoma incidence; BECN2 thus behaves as a suppressor of inflammation-driven tumorigenesis in these models (zhu2020beclin2negatively pages 1-2, zhu2020beclin2negatively pages 14-15)	Whole-animal knockout phenotyping, cytokine measurements, histology, and genetic rescue through Map3k3 deletion in myeloid cells (zhu2020beclin2negatively pages 1-2)	These phenotypes have not been attributed equivalently to BECN1 in the cited work and are mechanistically tied to the BECN2-specific ATG9A route (zhu2020beclin2negatively pages 1-2)	Zhu et al., 2020. DOI: 10.1172/JCI133283. URL: https://doi.org/10.1172/jci133283 (zhu2020beclin2negatively pages 1-2)
Metabolic physiology / receptor homeostasis	Becn2 insufficiency impairs autophagy in vivo and increases brain CB1R/CNR1 abundance with hyperphagia, obesity, and insulin resistance; metabolic effects are thought to relate in part to receptor turnover and autophagic regulation (su2017becn2interactswith pages 1-5, qiu2023thepotentbecn2atg14 pages 1-2)	Heterozygous and knockout mouse phenotyping; receptor abundance measurements and metabolic characterization (su2017becn2interactswith pages 1-5, qiu2023thepotentbecn2atg14 pages 1-2)	Phenotype highlights that BECN2 has physiologic roles not fully captured by BECN1-centric autophagy models, especially via selective GPCR regulation (levine2015beclinorthologsintegrative pages 7-9, qiu2023thepotentbecn2atg14 pages 1-2)	He et al., 2013. DOI: 10.1016/j.cell.2013.07.035. URL: https://doi.org/10.1016/j.cell.2013.07.035 (he2013beclin2functions pages 6-7)
2024 disease-model application: cartilage endplate degeneration	In LPS-treated chondrocyte/ATDC5 and lumbar disc degeneration models, sesamin upregulated BECN2, improving viability and reducing apoptosis; reported downstream effects included lower ATG14, VPS34, GASP1, reduced autophagy markers, and lower inflammasome proteins (NLRP3, NLRC4, NLRP1, AIM2) (zhang2024sesaminmediatedhighexpression pages 1-2)	Transcriptomics, adenoviral BECN2 overexpression/knockdown, viability/apoptosis assays, autophagy readouts, and in vivo LDD model (zhang2024sesaminmediatedhighexpression pages 1-2)	Useful as a recent disease-model application, but interpretation should be cautious because some reported directionality (higher BECN2 with lower autophagy) differs from foundational BECN2 autophagy literature (zhang2024sesaminmediatedhighexpression pages 1-2, he2013beclin2functions pages 6-7)	Zhang et al., 2024. DOI: 10.18632/aging.205386. URL: https://doi.org/10.18632/aging.205386 (zhang2024sesaminmediatedhighexpression pages 1-2)
2024 expert synthesis on nonautophagic ATG functions	Review literature positions BECN2 as an example of an autophagy-related protein with important noncanonical/nonautophagic trafficking and immune functions, especially GPCR sorting through GPRASP1 and inflammatory control beyond canonical LC3 pathways (maheshwari2025thebiologicalrole pages 39-39)	Narrative expert review integrating primary studies on GPCR trafficking, immune regulation, and signaling functions of ATG proteins (maheshwari2025thebiologicalrole pages 39-39)	Reinforces that BECN2 should not be annotated only as a generic autophagy factor; it has distinct cargo-sorting and signaling roles relative to BECN1 (maheshwari2025thebiologicalrole pages 39-39)	Shang et al., 2024. DOI: 10.1080/15548627.2023.2254664. URL: https://doi.org/10.1080/15548627.2023.2254664 (maheshwari2025thebiologicalrole pages 39-39)

Table: This table summarizes experimentally supported functions, mechanisms, selectivity, and recent updates for human BECN2/Beclin-2. It is useful as a compact evidence map linking core biology to specific assays, pathways, and citations.

References

(he2013beclin2functions pages 6-7): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(qiu2023thepotentbecn2atg14 pages 1-2): Xianxiu Qiu, Na Li, Qifan Yang, Shuai Wu, Xiaohua Li, Xuehua Pan, Soh Yamamoto, Xiaozhe Zhang, Jincheng Zeng, Jiahao Liao, Congcong He, Renxiao Wang, and Yanxiang Zhao. The potent becn2-atg14 coiled-coil interaction is selectively critical for endolysosomal degradation of gprasp1/gasp1-associated gpcrs. Autophagy, 19:2884-2898, Jul 2023. URL: https://doi.org/10.1080/15548627.2023.2233872, doi:10.1080/15548627.2023.2233872. This article has 4 citations and is from a domain leading peer-reviewed journal.
(zhu2020beclin2negatively pages 1-2): Motao Zhu, Guangtong Deng, Peng Tan, Changsheng Xing, Cuiping Guan, Chongming Jiang, Yinlong Zhang, Bo Ning, Chaoran Li, Bingnan Yin, Kaifu Chen, Yuliang Zhao, Helen Y. Wang, Beth Levine, Guangjun Nie, and Rong-Fu Wang. Beclin 2 negatively regulates innate immune signaling and tumor development. The Journal of clinical investigation, 130:5349-5369, Aug 2020. URL: https://doi.org/10.1172/jci133283, doi:10.1172/jci133283. This article has 31 citations.
(deng2022becn2(beclin2) pages 1-3): Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y. Wang, Motao Zhu, and Rong-Fu Wang. Becn2 (beclin 2) negatively regulates inflammasome sensors through atg9a-dependent but atg16l1- and lc3-independent non-canonical autophagy. Autophagy, 18:340-356, Jun 2022. URL: https://doi.org/10.1080/15548627.2021.1934270, doi:10.1080/15548627.2021.1934270. This article has 33 citations and is from a domain leading peer-reviewed journal.
(he2013beclin2functions pages 1-2): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(levine2015beclinorthologsintegrative pages 7-9): Beth Levine, Rong Liu, Xiaonan Dong, and Qing Zhong. Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology. Trends in Cell Biology, 25:533-544, Sep 2015. URL: https://doi.org/10.1016/j.tcb.2015.05.004, doi:10.1016/j.tcb.2015.05.004. This article has 200 citations and is from a domain leading peer-reviewed journal.
(deng2022becn2(beclin2) pages 12-13): Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y. Wang, Motao Zhu, and Rong-Fu Wang. Becn2 (beclin 2) negatively regulates inflammasome sensors through atg9a-dependent but atg16l1- and lc3-independent non-canonical autophagy. Autophagy, 18:340-356, Jun 2022. URL: https://doi.org/10.1080/15548627.2021.1934270, doi:10.1080/15548627.2021.1934270. This article has 33 citations and is from a domain leading peer-reviewed journal.
(zhu2020beclin2negatively pages 14-15): Motao Zhu, Guangtong Deng, Peng Tan, Changsheng Xing, Cuiping Guan, Chongming Jiang, Yinlong Zhang, Bo Ning, Chaoran Li, Bingnan Yin, Kaifu Chen, Yuliang Zhao, Helen Y. Wang, Beth Levine, Guangjun Nie, and Rong-Fu Wang. Beclin 2 negatively regulates innate immune signaling and tumor development. The Journal of clinical investigation, 130:5349-5369, Aug 2020. URL: https://doi.org/10.1172/jci133283, doi:10.1172/jci133283. This article has 31 citations.
(he2013beclin2functions pages 2-3): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(su2017becn2interactswith pages 1-5): Minfei Su, Yue Li, Shane Wyborny, David Neau, Srinivas Chakravarthy, Beth Levine, Christopher L. Colbert, and Sangita C. Sinha. Becn2 interacts with atg14 through a metastable coiled‐coil to mediate autophagy. Protein Science, 26:972-984, May 2017. URL: https://doi.org/10.1002/pro.3140, doi:10.1002/pro.3140. This article has 16 citations and is from a peer-reviewed journal.
(deng2022becn2(beclin2) pages 4-7): Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y. Wang, Motao Zhu, and Rong-Fu Wang. Becn2 (beclin 2) negatively regulates inflammasome sensors through atg9a-dependent but atg16l1- and lc3-independent non-canonical autophagy. Autophagy, 18:340-356, Jun 2022. URL: https://doi.org/10.1080/15548627.2021.1934270, doi:10.1080/15548627.2021.1934270. This article has 33 citations and is from a domain leading peer-reviewed journal.
(deng2022becn2(beclin2) pages 7-10): Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y. Wang, Motao Zhu, and Rong-Fu Wang. Becn2 (beclin 2) negatively regulates inflammasome sensors through atg9a-dependent but atg16l1- and lc3-independent non-canonical autophagy. Autophagy, 18:340-356, Jun 2022. URL: https://doi.org/10.1080/15548627.2021.1934270, doi:10.1080/15548627.2021.1934270. This article has 33 citations and is from a domain leading peer-reviewed journal.
(deng2022becn2(beclin2) pages 10-11): Guangtong Deng, Chaoran Li, Lang Chen, Changsheng Xing, Chuntang Fu, Chen Qian, Xin Liu, Helen Y. Wang, Motao Zhu, and Rong-Fu Wang. Becn2 (beclin 2) negatively regulates inflammasome sensors through atg9a-dependent but atg16l1- and lc3-independent non-canonical autophagy. Autophagy, 18:340-356, Jun 2022. URL: https://doi.org/10.1080/15548627.2021.1934270, doi:10.1080/15548627.2021.1934270. This article has 33 citations and is from a domain leading peer-reviewed journal.
(zhu2020beclin2negatively pages 5-7): Motao Zhu, Guangtong Deng, Peng Tan, Changsheng Xing, Cuiping Guan, Chongming Jiang, Yinlong Zhang, Bo Ning, Chaoran Li, Bingnan Yin, Kaifu Chen, Yuliang Zhao, Helen Y. Wang, Beth Levine, Guangjun Nie, and Rong-Fu Wang. Beclin 2 negatively regulates innate immune signaling and tumor development. The Journal of clinical investigation, 130:5349-5369, Aug 2020. URL: https://doi.org/10.1172/jci133283, doi:10.1172/jci133283. This article has 31 citations.
(quiles2023decipheringfunctionalroles pages 1-3): Justin M. Quiles, Rita H. Najor, Eileen Gonzalez, Monica Jeung, Wenjing Liang, Sarah M. Burbach, Erika A. Zumaya, Rachel Y. Diao, Mark A. Lampert, and Åsa B. Gustafsson. Deciphering functional roles and interplay between beclin1 and beclin2 in autophagosome formation and mitophagy. Science Signaling, Jan 2023. URL: https://doi.org/10.1126/scisignal.abo4457, doi:10.1126/scisignal.abo4457. This article has 55 citations and is from a domain leading peer-reviewed journal.
(maheshwari2025thebiologicalrole pages 39-39): Chinmay Maheshwari, Andrea Castiglioni, Uthman Walusimbi, Chiara Vidoni, Alessandra Ferraresi, Danny N. Dhanasekaran, and Ciro Isidoro. The biological role and clinical significance of beclin-1 in cancer. Unknown journal, Jul 2025. URL: https://doi.org/10.20944/preprints202507.2396.v1, doi:10.20944/preprints202507.2396.v1.
(zhang2024sesaminmediatedhighexpression pages 1-2): Baining Zhang, Zhiwei He, Jialin Guo, Feng Li, Zhi Huang, Wenkai Zheng, Wenhua Xing, Manglai Li, Yong Zhu, and Xuejun Yang. Sesamin-mediated high expression of becn2 ameliorates cartilage endplate degeneration by reducing autophagy and inflammation. Aging (Albany NY), 16:1145-1160, Jan 2024. URL: https://doi.org/10.18632/aging.205386, doi:10.18632/aging.205386. This article has 11 citations.
(he2013beclin2functions media 9cc1242f): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(he2013beclin2functions media 3a815a64): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(he2013beclin2functions media 17df886f): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(he2013beclin2functions media 4084183b): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.
(zhang2014regulationofplasma pages 1-2): Weiran Zhang and Congcong He. Regulation of plasma membrane receptors by a new autophagy-related becn/beclin family member. Autophagy, 10:1472-1473-99, Jun 2014. URL: https://doi.org/10.4161/auto.29414, doi:10.4161/auto.29414. This article has 7 citations and is from a domain leading peer-reviewed journal.
(he2013beclin2functions pages 12-13): Congcong He, Yongjie Wei, Kai Sun, Binghua Li, Xiaonan Dong, Zhongju Zou, Yang Liu, Lisa N. Kinch, Shaheen Khan, Sangita Sinha, Ramnik J. Xavier, Nick V. Grishin, Guanghua Xiao, Eeva-Liisa Eskelinen, Philipp E. Scherer, Jennifer L. Whistler, and Beth Levine. Beclin 2 functions in autophagy, degradation of g protein-coupled receptors, and metabolism. Cell, 154:1085-1099, Aug 2013. URL: https://doi.org/10.1016/j.cell.2013.07.035, doi:10.1016/j.cell.2013.07.035. This article has 177 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

quiles2023decipheringfunctionalroles pages 1-3
maheshwari2025thebiologicalrole pages 39-39
zhang2024sesaminmediatedhighexpression pages 1-2
levine2015beclinorthologsintegrative pages 7-9
zhang2014regulationofplasma pages 1-2
https://doi.org/10.1080/15548627.2023.2233872
https://doi.org/10.1126/scisignal.abo4457
https://doi.org/10.1080/15548627.2023.2254664
https://doi.org/10.18632/aging.205386
https://doi.org/10.1016/j.tcb.2015.05.004
https://doi.org/10.1016/j.cell.2013.07.035
https://doi.org/10.1002/pro.3140
https://doi.org/10.1080/15548627.2021.1934270
https://doi.org/10.1172/jci133283
https://doi.org/10.1016/j.cell.2013.07.035,
https://doi.org/10.1080/15548627.2023.2233872,
https://doi.org/10.1172/jci133283,
https://doi.org/10.1080/15548627.2021.1934270,
https://doi.org/10.1016/j.tcb.2015.05.004,
https://doi.org/10.1002/pro.3140,
https://doi.org/10.1126/scisignal.abo4457,
https://doi.org/10.20944/preprints202507.2396.v1,
https://doi.org/10.18632/aging.205386,
https://doi.org/10.4161/auto.29414,

📚 Additional Documentation

Notes

(BECN2-notes.md)

BECN2 review notes

Review started from just fetch-gene human BECN2. The proteostasis network places BECN2 under Autophagy-Lysosome Pathway > Autophagophore initiation and elongation > Class 3 PI3K complex 1, direct > Class 3 PI3K complex 1 component.

Falcon deep research was requested with just deep-research-falcon human BECN2, but the provider timed out after 600 seconds and no BECN2-deep-research-falcon.md file was produced. I am completing the review using the cached primary literature, UniProt record, GOA seed, and notes below.

BECN2 is a mammalian Beclin-family protein with two supported lysosomal degradation roles: autophagy and G-protein-coupled receptor (GPCR) turnover. The primary Cell paper reports that Beclin 2 functions in autophagy, interacts with class III PI3K complex components and Bcl-2, and has an additional lysosomal degradation role not shared by BECN1 [PMID:23954414 "functions in autophagy and interacts with class III PI3K complex components and Bcl-2" and "functions in an additional lysosomal degradation pathway"].

BECN2's GPCR role is direct and should remain core. Beclin 2 is required for ligand-induced endolysosomal degradation of several GPCRs through interaction with GASP1/GPRASP1, and heterozygous knockout mice accumulate brain cannabinoid receptor 1 [PMID:23954414 "required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1" and "increased levels of brain cannabinoid 1 receptor"].

The PI3KC3-C1/autophagy-initiation connection is supported by the Cell paper, UniProt, and the ATG14 structural abstract. UniProt lists BECN2 in class III PI3K type I/type II complexes and notes interactions with ATG14, AMBRA1, UVRAG, and PIK3C3/VPS34 [file:human/BECN2/BECN2-uniprot.txt "Interacts ... with ATG14" and "Interacts with AMBRA1, UVRAG and PIK3C3/VPS34"]. The structural paper reports that ATG14 binding to BECN/Beclin homologs is essential for autophagy and that BECN2:ATG14 forms a coiled-coil heterodimer [PMID:28218432 "ATG14 binding to BECN/Beclin homologs is essential for autophagy" and "the BECN2 CCD and ATG14 CCD form a parallel, curved heterodimer"].

Mitophagy is too specific for the accessible BECN2 evidence. BECN2 has general autophagy/autophagosome assembly support, but the cached human paper and UniProt summaries do not establish a BECN2-specific mitophagy role. I will modify the mitophagy row to autophagosome assembly rather than retaining cargo-specific mitophagy.

The vacuole transport row is a yeast-style transfer and should be converted to the directly supported human endosome-to-lysosome transport/GPCR degradation role. Generic protein binding rows are not useful as molecular-function annotations; the evidence should be captured as protein-macromolecule adaptor activity, phosphatidylinositol 3-kinase binding, complex membership, and GASP1-dependent GPCR catabolism.

Curation stance:
- Core: autophagy/autophagosome assembly, class III PI3K type I/type II complex context, phosphatidylinositol 3-kinase binding, protein-macromolecule adaptor activity, endosome-to-lysosome transport, GPCR catabolic process, cytoplasm.
- Modify: mitophagy to autophagosome assembly; late endosome-to-vacuole transport to endosome-to-lysosome transport; protein-containing complex binding to adaptor activity.
- Keep as non-core: cellular response to nitrogen starvation as autophagy context.
- Mark over-annotated: generic protein binding rows.

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

Moved out of the YAML description: the prior wording tied the PI3KC3-C1 interpretation to a Proteostasis Network leaf and contrasted that shared role with the BECN2-specific GPCR catabolic branch.

Falcon deep research findings (2026-06-07)

The Falcon report (BECN2-deep-research-falcon.md) was generated after the original review was completed (the earlier notes recorded a Falcon timeout). It is consistent with the existing review and adds a substantial body of post-2013 BECN2 literature that was NOT previously captured. PMIDs below were resolved from the report's DOIs via the PubMed ID converter. Synthesis of KEY findings:

NEW — Noncanonical degradation of inflammasome sensors (innate immunity). BECN2 negatively regulates NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes by mediating lysosomal degradation of the sensors through a ULK1- and ATG9A-dependent, but BECN1/WIPI2/ATG16L1/LC3-independent, non-canonical autophagic pathway; sensors are recruited onto ATG9A+ vesicles and SNAREs SEC22A/STX5/STX6 mediate fusion; Becn2 loss worsens alum-induced peritonitis [PMID:34152938 "loss of BECN2 enhanced the activities of NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes" ; "ATG9A-Dependent but ATG16L1- and LC3-Independent Non-Canonical Autophagy"] (Deng et al. 2022, Autophagy, DOI:10.1080/15548627.2021.1934270). This is a distinct biological process not represented in existing_annotations.
NEW — Negative regulation of innate immune signaling and tumor suppression. BECN2 targets the upstream MAP3Ks MEKK3 (MAP3K3) and TAK1 (MAP3K7) for ATG9A-dependent (ATG16L/Beclin1/LC3-independent) autophagic degradation, restraining ERK1/2 and NF-kB signaling. Becn2-null mice develop splenomegaly, lymphadenopathy, increased proinflammatory cytokines, persistent STAT3 activation, and increased lymphoma incidence; myeloid Map3k3 ablation rescues these phenotypes, implicating BECN2 as a suppressor of inflammation-driven tumorigenesis [PMID:32865519 "Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation" ; "markedly increased incidence of lymphoma development"] (Zhu et al. 2020, J Clin Invest, DOI:10.1172/JCI133283). New process/disease dimension.
CONFIRMS — Mitophagy is a BECN1, not BECN2, function. In BECN1- vs BECN2-deficient HeLa cells and MEFs, selective mitophagy was compromised only by BECN1 loss (requiring ULK1 phosphorylation of Beclin-1 Ser15 and MAM localization); BECN2 contributed to general autophagosome formation but was not required for mitophagy PMID:36719945 (Quiles et al. 2023, Sci Signal, DOI:10.1126/scisignal.abo4457). This independently supports the existing review's MODIFY decision converting the IBA mitophagy annotation to autophagosome assembly.
NEW (mechanistic refinement) — BECN2-ATG14 selectivity for GPCR cargo. Crystal structures of the BECN2 coiled-coil and BECN2-ATG14 heterodimer show the potent 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; stapled peptides that enhance BECN2-ATG14 selectively boost BECN2-dependent autophagy and DRD2 turnover PMID:37409929 (Qiu et al. 2023, Autophagy, DOI:10.1080/15548627.2023.2233872). Note: this is a SEPARATE 2023 paper from PMID:28218432 (Su et al. 2017, Protein Science, DOI:10.1002/pro.3140), which is the structural reference already cited in the review (the converter confirms 28218432 = Su 2017, correctly titled in the existing references).
CONFIRMS / context — Beclin-ortholog review framing. A highly cited review positions Beclin proteins as integrative hubs of cell signaling and membrane trafficking and highlights BECN2's unique GASP1-dependent GPCR degradation role not shared by other PI3KC3 members PMID:26071895 (Levine et al. 2015, Trends Cell Biol, DOI:10.1016/j.tcb.2015.05.004). Supports existing GPCR-catabolism and PI3KC3-context annotations.
PROVISIONAL / low-confidence — do NOT use for annotation. The report cites a sesamin/lumbar-disc-degeneration disease-model paper (Zhang et al. 2024, Aging, DOI:10.18632/aging.205386) whose reported directionality (higher BECN2 with lower autophagy markers) conflicts with foundational BECN2 autophagy biology, and a 2025 preprint review (DOI:10.20944/preprints202507.2396.v1, not peer-reviewed). These are noted for completeness only and are NOT used to change any annotation.

Curation impact

Conservative enrichment only — the review is COMPLETE and these findings augment rather than overturn it. The new immune/tumor-suppression functions (inflammasome sensor degradation; MAP3K7/MAP3K3 degradation; negative regulation of NF-kB/innate immune signaling) are real BECN2 functions but are NOT present in the existing GOA-seeded existing_annotations, so they belong in references/suggested follow-ups rather than as fabricated existing-annotation rows. I added the four primary PMIDs (34152938, 32865519, 36719945, 37409929) and the Levine 2015 review (26071895) to references: as statement-only entries, plus suggested questions/experiments. No existing annotation action was changed; Quiles 2023 reinforces (does not contradict) the existing mitophagy MODIFY.

Pn Notes

(BECN2-pn-notes.md)

BECN2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: A8MW95
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/BECN2/BECN2-ai-review.yaml
AIGR review HTML: present - genes/human/BECN2/BECN2-ai-review.html
Gene notes: present - genes/human/BECN2/BECN2-notes.md
GOA TSV: present - genes/human/BECN2/BECN2-goa.tsv
UniProt record: present - genes/human/BECN2/BECN2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/BECN2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/BECN2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/BECN2/BECN2-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 15; KEEP_AS_NON_CORE: 1; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 3; NEW: 1

PN Consistency Summary

Consistency: Consistent. The review ACCEPTs GO:0034271 (PI3KC3-C1, IBA) and adds a NEW IMP autophagosome-assembly row, matching the PN "C1 component" placement. The review goes beyond PN in flagging the BECN2-specific, non-shared GPCR/GASP1 endolysosomal-degradation branch (GO:1990172, GO:0008333) — PN's single ALP row does not capture that, but the PN Notes explicitly mention "lysosomal degradation of GPCRs," so the two are aligned in spirit, not contradictory.
PN story / NEW pressure: Already captured (and exceeded). PN asserts only C1 membership = projected GO:0034271, already_in_goa_exact and ACCEPTed. The distinctive GPCR-catabolism role (the real "new" biology) is already minted by the review as core GO:1990172. No additional GO term warranted from the PN placement; PN under-represents BECN2 rather than over-reaching.
Evidence alignment: Strong overlap. PN cites the single ScienceDirect "Beclin 2 Functions in Autophagy, Degradation of GPCRs, and Metabolism" = review's central PMID:23954414. Review adds PMID:28218432, 36719945, 37409929, 34152938, 32865519 (none in PN). Convergent on the founding paper; review is far richer.
Verdict: Fully consistent; PN captures the shared C1 role, review additionally captures the BECN2-specific GPCR branch. No edits needed.

Full Consistency Review

UniProt: A8MW95 · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: 1 row, ALP — Autophagophore initiation and elongation → Class 3 PI3K complex 1, direct → Class 3 PI3K complex 1 component. PN-node mapping: component leaf=mapped→GO:0034271; ancestors context_only (GO:0035032, GO:0016236). Projected: GO:0034271 (goa_status=already_in_goa_exact).
Consistency: Consistent. The review ACCEPTs GO:0034271 (PI3KC3-C1, IBA) and adds a NEW IMP autophagosome-assembly row, matching the PN "C1 component" placement. The review goes beyond PN in flagging the BECN2-specific, non-shared GPCR/GASP1 endolysosomal-degradation branch (GO:1990172, GO:0008333) — PN's single ALP row does not capture that, but the PN Notes explicitly mention "lysosomal degradation of GPCRs," so the two are aligned in spirit, not contradictory.
PN story / NEW pressure: Already captured (and exceeded). PN asserts only C1 membership = projected GO:0034271, already_in_goa_exact and ACCEPTed. The distinctive GPCR-catabolism role (the real "new" biology) is already minted by the review as core GO:1990172. No additional GO term warranted from the PN placement; PN under-represents BECN2 rather than over-reaching.
Mapping strategy: No change. GO:0034271 propagation is safe (already in GOA exact, supported by PMID:28218432 BECN2-ATG14 coiled-coil). Inclusion of BECN2 does not destabilize the node. The review's open question (curate C1/C2 membership as direct vs Beclin-family inference) is a curator nuance, not a mapping-strategy problem.
Evidence alignment: Strong overlap. PN cites the single ScienceDirect "Beclin 2 Functions in Autophagy, Degradation of GPCRs, and Metabolism" = review's central PMID:23954414. Review adds PMID:28218432, 36719945, 37409929, 34152938, 32865519 (none in PN). Convergent on the founding paper; review is far richer.
Verdict: Fully consistent; PN captures the shared C1 role, review additionally captures the BECN2-specific GPCR branch. No edits needed.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/BECN2/BECN2-ai-review.yaml
PN workbook rows: 1

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Class 3 PI3K complex 1, direct | Class 3 PI3K complex 1 component

UniProt: A8MW95
In branches: ALP
Notes: Paralog of BECN1 that can also be part of the class III PI3K complex 1. Also required for lysosomal degradation of GPCRs.
PN references (titles):
- Beclin 2 Functions in Autophagy, Degradation of G Protein-Coupled Receptors, and Metabolism - ScienceDirect
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I]
  rationale: This PN type is a curated component class for the direct autophagy- promoting class III PI3K complex 1. Propagation to the matching GO cellular-component term is appropriate, although the source is a component-role category rather than the complex term itself.
- [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct
  status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
  rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
- [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
  status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
  rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|Class 3 PI3K complex 1, direct|Class 3 PI3K complex 1 component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

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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.

BECN2

Gene Description

Existing Annotations Review

Core Functions

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.

BECN2 functions as an adaptor/regulator for GASP1/GPRASP1-dependent endolysosomal degradation of GPCRs, a BECN2-specific lysosomal degradation branch distinct from BECN1.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human BECN2 (Beclin-2) functional annotation (UniProt A8MW95)

Executive summary

1) Key concepts and definitions (current understanding)

1.1 Beclin-family proteins and PI3KC3 complexes

1.2 “Canonical” autophagy vs BECN2-linked noncanonical degradative routes

1.3 Specialized GPCR downregulation via GASP1/GPRASP1

2) Gene/protein identity verification (critical disambiguation)

3) Molecular functions and pathways

3.1 Autophagy-supporting scaffold function through PI3KC3 assemblies

3.2 Endolysosomal trafficking: GASP1-dependent GPCR degradation (BECN2 hallmark function)

3.3 Innate immunity: BECN2-driven degradation of inflammasome sensors

3.4 Innate immune signaling and cancer phenotypes: TAK1/MEKK3 turnover

4) Subcellular localization and compartment context

5) Recent developments (prioritizing 2023–2024)

5.1 2023: Structural and selective interaction insight + a selective modulation strategy

5.2 2023: Functional dissection of Beclin-1 vs Beclin-2 in mitophagy

5.3 2024: Authoritative synthesis on nonautophagic roles of ATG proteins

5.4 2024: Disease-model report proposing sesamin→BECN2 modulation in lumbar disc degeneration

6) Current applications and real-world implementations

7) Expert opinions and authoritative synthesis

8) Statistics and data points from recent and foundational studies

9) Figures (visual evidence)

10) Practical functional annotation (recommended text)

Embedded evidence map

Artifacts

Citations

📚 Additional Documentation

Notes

BECN2 review notes

Description cleanup note

Falcon deep research findings (2026-06-07)

Curation impact

Pn Notes

BECN2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | Class 3 PI3K complex 1, direct | Class 3 PI3K complex 1 component

Projected GO annotations (1)

Note

📄 View Raw YAML