id: P46379 gene_symbol: BAG6 product_type: PROTEIN taxon: id: NCBITaxon:9606 label: Homo sapiens description: BAG6 is a multifunctional nucleo-cytoplasmic proteostasis factor that sits at the boundary between the GET pathway and ubiquitin-proteasome-associated quality control. In the cytosol, the BAG6/UBL4A/GET4 (BAT3) complex captures hydrophobic tail-anchored or otherwise mislocalized secretory proteins, promotes their handoff to TRC40/ASNA1 for post-translational delivery to the endoplasmic reticulum, and routes failed clients toward ubiquitin-proteasome degradation. BAG6 also acts as a holdase for retrotranslocated ERAD substrates and contributes to ER stress-induced pre-emptive quality control. Additional nuclear and extracellular roles, including p53 acetylation after DNA damage and exosomal NKp30 ligand activity, are supported in specific contexts but are not the core conserved proteostasis functions. alternative_products: - name: '1' id: P46379-1 - name: '2' id: P46379-2 sequence_note: VSP_015695 - name: '3' id: P46379-3 sequence_note: VSP_015695, VSP_030519 - name: '4' id: P46379-4 sequence_note: VSP_015695, VSP_045910, VSP_045911, - name: '5' id: P46379-5 sequence_note: VSP_015695, VSP_045913 references: - id: file:human/BAG6/BAG6-notes.md title: BAG6 review notes - id: file:human/BAG6/BAG6-deep-research-falcon.md title: Falcon deep research report for BAG6 findings: - statement: Falcon research supports BAG6 as a cytosolic BAG6/UBL4A/TRC35 holdase and adaptor linking tail-anchored protein targeting with ERAD/proteasome quality control. supporting_text: BAG6 is embedded in this pathway as both a substrate-holding factor and a quality-control adaptor - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees - 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 - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data from the Human Protein Atlas - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods - id: PMID:20676083 title: A ribosome-associating factor chaperones tail-anchored membrane proteins. - id: PMID:21636303 title: A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. - id: PMID:21743475 title: Protein targeting and degradation are coupled for elimination of mislocalized proteins. - id: PMID:23129660 title: SGTA antagonizes BAG6-mediated protein triage. - id: PMID:23665563 title: A ubiquitin-like domain recruits an oligomeric chaperone to a retrotranslocation complex in endoplasmic reticulum-associated degradation. - id: PMID:24424410 title: USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation. - id: PMID:24981174 title: Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. - id: PMID:25535373 title: Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain. - id: PMID:25713138 title: 'Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis.' - id: PMID:29042515 title: Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35. - id: PMID:17403783 title: HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. - id: PMID:18055229 title: Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. - id: PMID:18852879 title: Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. - id: PMID:14667819 title: Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region. - id: PMID:14960581 title: Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. - id: PMID:18765639 title: BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. - id: PMID:19946888 title: Defining the membrane proteome of NK cells. - id: PMID:21903422 title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. - id: PMID:22046132 title: 'The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.' - id: PMID:22807449 title: The stalk domain and the glycosylation status of the activating natural killer cell receptor NKp30 are important for ligand binding. - id: PMID:23246001 title: SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation. - id: PMID:25036637 title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. - id: PMID:26876100 title: Selective Binding of AIRAPL Tandem UIMs to Lys48-Linked Tri-Ubiquitin Chains. - id: PMID:27113755 title: UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation. - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' - id: PMID:40105103 title: Definition of the human mitochondrial TOM interactome reveals TRABD as a new interacting protein. - id: PMID:26565908 title: Pre-emptive Quality Control Protects the ER from Protein Overload via the Proximity of ERAD Components and SRP. existing_annotations: - term: id: GO:0036503 label: ERAD pathway evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: Human BAG6 literature supports BAG6 complex function in ER-associated degradation (ERAD), so the phylogenetic propagation is directionally correct and consistent with the core proteostasis role. action: ACCEPT reason: Bag6 keeps retrotranslocated hydrophobic clients soluble and engaged with ERAD machinery, matching ERAD pathway membership. supported_by: - reference_id: PMID:20676083 - reference_id: PMID:21636303 - reference_id: PMID:25535373 - reference_id: file:human/BAG6/BAG6-notes.md - term: id: GO:0031593 label: polyubiquitin modification-dependent protein binding evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: BAG6 operates in ubiquitin-linked quality control, but the reviewed core papers support ligase/DUB recruitment and client triage rather than a well-demonstrated direct polyubiquitin-binding activity. action: REMOVE reason: The conserved BAG6 literature does not establish polyubiquitin-selective binding as a defensible core molecular function. - term: id: GO:0051787 label: misfolded protein binding evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: 'Phylogenetic propagation agrees with the human holdase literature: BAG6 preferentially captures aggregation-prone hydrophobic or misfolded clients during quality control.' action: ACCEPT reason: This matches the experimentally supported BAG6 holdase role in ERAD and mislocalized-protein triage. supported_by: - reference_id: PMID:21636303 - reference_id: file:human/BAG6/BAG6-notes.md - term: id: GO:0071818 label: BAT3 complex evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: The phylogenetic BAT3 complex annotation agrees with multiple human studies placing BAG6 in a heterotrimeric BAG6/UBL4A/GET4(TRC35) complex. action: ACCEPT reason: Complex membership is well supported and central to both GET-pathway and UPS-adjacent BAG6 functions. supported_by: - reference_id: PMID:20676083 - reference_id: PMID:25535373 - term: id: GO:0001822 label: kidney development evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Developmental annotations are plausible downstream consequences from mammalian loss-of-function studies, but they are not BAG6's core conserved proteostasis role. action: KEEP_AS_NON_CORE reason: Keep as contextual biology rather than a core molecular/process function. - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: BAG6 helps channel selected clients toward ubiquitin-dependent degradation, but this broad process term loses the more informative GET/ERAD/pre-emptive-QC context. action: MARK_AS_OVER_ANNOTATED reason: Retain more specific proteostasis terms instead of this umbrella catabolic label. - term: id: GO:0007130 label: synaptonemal complex assembly evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This reproductive annotation reflects secondary mammalian biology rather than BAG6's central proteostasis function. action: KEEP_AS_NON_CORE reason: Treat as contextual/non-core. - term: id: GO:0007283 label: spermatogenesis evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This reproductive-process annotation is best treated as contextual because BAG6's conserved role is proteostasis triage, not gametogenesis machinery. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0007420 label: brain development evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Any developmental nervous-system consequence is downstream/contextual rather than part of BAG6's main evolved role. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0030324 label: lung development evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This developmental annotation reflects contextual organismal phenotypes rather than BAG6's core GET/UPS-boundary biology. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0030544 label: Hsp70 protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This looks like over-propagation from BAG family naming. BAG6 is explicitly not a canonical BAG-domain Hsp70 nucleotide-exchange factor. action: REMOVE reason: Structural work shows the BAG6 C terminus is a mock/noncanonical BAG-similar domain, so Hsp70 binding should not be assumed from family membership. supported_by: - reference_id: PMID:25535373 - reference_id: PMID:25713138 - reference_id: file:human/BAG6/BAG6-notes.md - term: id: GO:0031593 label: polyubiquitin modification-dependent protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This broad automated propagation is not well grounded in the direct BAG6 mechanistic literature. action: REMOVE reason: The reviewed papers support client triage with E3s and DUBs, not a specific polyubiquitin-binding activity. - term: id: GO:0032435 label: negative regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This regulatory proteolysis term reflects secondary spermatogenic/HSPA2 biology rather than BAG6's central proteostasis role. action: KEEP_AS_NON_CORE reason: Keep as contextual/non-core. - term: id: GO:0042981 label: regulation of apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Apoptosis-related effects exist in some contexts, but this broad automated term is not the best summary of BAG6 function. action: KEEP_AS_NON_CORE reason: Retain only as non-core context. - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: BAG6 contributes to selected proteasomal quality-control routes, but this automated term is broader and less informative than the specific BAG6-supported processes. action: MARK_AS_OVER_ANNOTATED reason: Prefer ERAD, tail-anchored insertion, or ER-stress pre-emptive quality control terms. - term: id: GO:0045861 label: negative regulation of proteolysis evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This negative-regulation term reflects context-specific stabilization biology rather than the main BAG6 proteostasis program. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0045995 label: regulation of embryonic development evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Embryonic-development phenotypes are contextual downstream consequences and not the core conserved BAG6 role. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0050821 label: protein stabilization evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Protein stabilization is context-specific for selected partners and not the best core descriptor of BAG6. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0070059 label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: ER-stress apoptosis is a context-dependent consequence, not BAG6's principal conserved function. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0070628 label: proteasome binding evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: The reviewed BAG6 papers place clients en route to the proteasome but do not establish a clean direct proteasome-binding activity. action: REMOVE reason: This term is too specific for the available evidence. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14667819 review: summary: The source interaction is too generic to retain as a useful BAG6 annotation. action: REMOVE reason: GO:0005515 is uninformative here and BAG6 already has more specific mechanistically grounded annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16189514 review: summary: The source interaction is too generic to retain as a useful BAG6 annotation. action: REMOVE reason: GO:0005515 is uninformative here and BAG6 already has more specific mechanistically grounded annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18852879 review: summary: The exosome/NK paper supports a contextual receptor-ligand role, not a useful standalone generic protein-binding annotation. action: REMOVE reason: Retain the more specific immune-context terms instead. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21903422 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22046132 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22807449 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25036637 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: Extracellular release is real but limited to stress/tumor exosome contexts rather than BAG6's main intracellular proteostasis role. action: KEEP_AS_NON_CORE reason: Keep as contextual, non-core localization. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: BAG6 is a bona fide nucleo-cytoplasmic protein, and nuclear localization is repeatedly observed in the literature and UniProt curation. action: ACCEPT reason: Nuclear localization is real even though the principal PN role is cytosolic. - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: Cytosolic localization is central to BAG6 GET/ERAD/mislocalized-protein triage functions. action: ACCEPT reason: The core proteostasis role depends on cytosolic BAG6 complex localization. - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 review: summary: Nucleoplasmic signal is compatible with BAG6's documented nuclear pool and DNA-damage-associated functions. action: ACCEPT reason: This is a defensible subnuclear localization. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 review: summary: Independent localization evidence also places BAG6 in the cytosol. action: ACCEPT reason: This is fully consistent with the core proteostasis model. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40105103 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0140597 label: protein carrier chaperone evidence_type: IDA original_reference_id: PMID:21636303 review: summary: This is one of the strongest BAG6 annotations. The 2011 Mol Cell study directly supports a holdase/carrier role for retrotranslocated hydrophobic clients. action: ACCEPT reason: Bag6 maintains aggregation-prone clients in an unfolded yet soluble state and helps deliver them within quality-control pathways. supported_by: - reference_id: PMID:21636303 - reference_id: PMID:20676083 - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: BAG6 is widely characterized as a chaperone/holdase that binds exposed hydrophobic segments - term: id: GO:0005829 label: cytosol evidence_type: NAS original_reference_id: PMID:25535373 review: summary: Cytosolic localization is consistent with the tail-anchor-targeting complex architecture and broader BAG6 literature, even if this individual assertion is author statement-level. action: ACCEPT reason: The BAG6 complex acts in the cytosol before ER insertion or proteasomal routing. - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:20676083 review: summary: PMID:20676083 is about ribosome-associated capture and handoff of tail-anchored proteins to TRC40, not a generic ubiquitin-dependent catabolic process. action: MODIFY reason: Replace with the specific GET-pathway process terms directly supported by the paper; the separate ribosome-binding molecular function is already captured by its own annotation. proposed_replacement_terms: - id: GO:0071816 label: tail-anchored membrane protein insertion into ER membrane - term: id: GO:0006620 label: post-translational protein targeting to endoplasmic reticulum membrane evidence_type: IDA original_reference_id: PMID:25535373 review: summary: This matches the PN GET-pathway mapping and the structural/biochemical literature on tail-anchor targeting. action: ACCEPT reason: BAG6 participates in post-translational delivery of tail-anchored proteins toward the ER membrane. supported_by: - reference_id: PMID:25535373 - reference_id: PMID:20676083 - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: BAG6 is embedded in this pathway as both a substrate-holding factor and a quality-control adaptor - term: id: GO:0031647 label: regulation of protein stability evidence_type: IDA original_reference_id: PMID:21636303 review: summary: The paper supports holdase/chaperone behavior rather than a broad generic regulation-of-stability process. action: MODIFY reason: A molecular chaperone/carrier term is a more faithful representation of the evidence. proposed_replacement_terms: - id: GO:0140597 label: protein carrier chaperone - term: id: GO:0048018 label: receptor ligand activity evidence_type: IDA original_reference_id: PMID:18852879 review: summary: Exosomal BAG6 can act as an NKp30 ligand, but this immune signaling role is contextual and not the core conserved BAG6 function. action: KEEP_AS_NON_CORE reason: Keep as non-core context. supported_by: - reference_id: PMID:18852879 - reference_id: PMID:18055229 - term: id: GO:0051132 label: NK T cell activation evidence_type: IDA original_reference_id: PMID:18852879 review: summary: The paper concerns NK-cell activation, not NK T-cell activation. action: MODIFY reason: Replace with natural killer cell activation to match the actual experiment. proposed_replacement_terms: - id: GO:0030101 label: natural killer cell activation - term: id: GO:0036503 label: ERAD pathway evidence_type: NAS original_reference_id: PMID:21636303 review: summary: Although this is an author statement-level annotation, the underlying study directly demonstrates a BAG6 holdase role that improves ERAD efficiency. action: ACCEPT reason: The evidence supports ERAD pathway participation. supported_by: - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: BAG6 helps route failed membrane/secretory protein biogenesis products and certain ERAD substrates into ubiquitin-proteasome degradation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25713138 review: summary: The structural paper supports complex architecture and adaptor function, not a useful generic protein-binding annotation. action: REMOVE reason: Retain the specific adaptor/core-complex annotations instead. - term: id: GO:0060090 label: molecular adaptor activity evidence_type: EXP original_reference_id: PMID:25713138 review: summary: BAG6 organizes UBL4A and TRC35/GET4 and supports substrate handoff, which is well captured by molecular adaptor activity. action: ACCEPT reason: This term fits BAG6's bridge/scaffold role at the GET-pathway and cytosolic quality-control boundary. supported_by: - reference_id: PMID:25713138 - reference_id: PMID:25535373 - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: BAG6’s C-terminal region is a structural part of the substrate-loading complex - term: id: GO:0140677 label: molecular function activator activity evidence_type: IEP original_reference_id: PMID:25713138 review: summary: The cited paper does not establish BAG6 as a direct molecular-function activator of another enzyme or receptor. action: REMOVE reason: This annotation overstates the structural/adaptor evidence. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27113755 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0045995 label: regulation of embryonic development evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Orthology-based developmental regulation is plausible but not part of BAG6's core proteostasis identity. action: KEEP_AS_NON_CORE reason: Keep as non-core context. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29042515 review: summary: This paper is informative for localization regulation, but GO:0005515 remains too generic. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:29042515 review: summary: This study directly addresses BAG6 nucleo-cytoplasmic partitioning and supports nuclear localization. action: ACCEPT reason: Nuclear BAG6 is real and regulated by TRC35/GET4 binding. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:29042515 review: summary: This study directly supports cytosolic retention of BAG6 by TRC35/GET4. action: ACCEPT reason: Cytosolic BAG6 is the state associated with core proteostasis functions. - term: id: GO:0071816 label: tail-anchored membrane protein insertion into ER membrane evidence_type: IDA original_reference_id: PMID:25535373 review: summary: The minimal BAG6 complex directly supports transfer of tail-anchored substrates into the TRC40/GET pathway. action: ACCEPT reason: This is core PN-supported biology. supported_by: - reference_id: PMID:25535373 - reference_id: PMID:20676083 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26876100 review: summary: This generic interaction term adds no useful BAG6-specific functional information. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14960581 review: summary: The ricin paper is informative for apoptosis context, but GO:0005515 remains too generic. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0061857 label: endoplasmic reticulum stress-induced pre-emptive quality control evidence_type: IMP original_reference_id: PMID:26565908 review: summary: This is a specific stress-responsive proteostasis process that the paper directly supports. action: ACCEPT reason: Bag6 contributes to degradation of rerouted ER pre-emptive quality-control substrates under ER stress. supported_by: - reference_id: PMID:26565908 - term: id: GO:0010498 label: proteasomal protein catabolic process evidence_type: IMP original_reference_id: PMID:26565908 review: summary: The specific process shown in the paper is ER stress-induced pre-emptive quality control, not a generic proteasomal catabolic pathway in isolation. action: MARK_AS_OVER_ANNOTATED reason: Keep the more specific GO:0061857 annotation instead. - term: id: GO:0036503 label: ERAD pathway evidence_type: IMP original_reference_id: PMID:26565908 review: summary: PMID:26565908 is about ER stress-induced pre-emptive quality control, which is related to but distinct from canonical ERAD. action: MODIFY reason: Replace with the specific ER pQC term. proposed_replacement_terms: - id: GO:0061857 label: endoplasmic reticulum stress-induced pre-emptive quality control - term: id: GO:0016020 label: membrane evidence_type: HDA original_reference_id: PMID:19946888 review: summary: A broad membrane term is too imprecise for BAG6, which is mainly cytosolic/nuclear with regulated ER-membrane association in specific QC contexts. action: MARK_AS_OVER_ANNOTATED reason: If membrane association is retained, it should be ER-membrane-specific rather than generic membrane. - term: id: GO:0002429 label: immune response-activating cell surface receptor signaling pathway evidence_type: IDA original_reference_id: PMID:18852879 review: summary: This immune signaling annotation is supported in exosome/NK-cell contexts but is clearly contextual rather than core BAG6 biology. action: KEEP_AS_NON_CORE reason: Keep as non-core. supported_by: - reference_id: PMID:18852879 - reference_id: PMID:18055229 - term: id: GO:0005102 label: signaling receptor binding evidence_type: IPI original_reference_id: PMID:18852879 review: summary: The immune paper is better captured by receptor ligand activity than a generic signaling receptor binding term. action: MODIFY reason: Replace with receptor ligand activity. proposed_replacement_terms: - id: GO:0048018 label: receptor ligand activity - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:14960581 review: summary: The ricin study also observed nuclear BAG6, consistent with BAG6's established nucleo-cytoplasmic distribution. action: ACCEPT reason: Nuclear localization is defensible. - term: id: GO:0006915 label: apoptotic process evidence_type: IDA original_reference_id: PMID:14960581 review: summary: Ricin-induced apoptosis is a real contextual role but not BAG6's core conserved proteostasis function. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0030101 label: natural killer cell activation evidence_type: IDA original_reference_id: PMID:18852879 review: summary: Natural killer cell activation is experimentally supported for exosomal BAG6 but remains a contextual immune role. action: KEEP_AS_NON_CORE reason: Keep as non-core. supported_by: - reference_id: PMID:18852879 - reference_id: PMID:18055229 - term: id: GO:0070062 label: extracellular exosome evidence_type: IDA original_reference_id: PMID:18852879 review: summary: Exosomal BAG6 is experimentally documented, but this is a conditional extracellular context rather than the main cellular location. action: KEEP_AS_NON_CORE reason: Keep as non-core localization. supported_by: - reference_id: PMID:18852879 - term: id: GO:0036503 label: ERAD pathway evidence_type: IDA original_reference_id: PMID:23129660 review: summary: This paper studies SGTA antagonism of BAG6-mediated triage of mislocalized proteins in the cytosol, not canonical ERAD. action: MODIFY reason: Replace with the narrower protein-quality-control term that better fits cytosolic degradation of mislocalized hydrophobic clients. proposed_replacement_terms: - id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins - term: id: GO:0036503 label: ERAD pathway evidence_type: IDA original_reference_id: PMID:24981174 review: summary: PMID:24981174 defines RNF126-dependent cytosolic quality control of mislocalized proteins rather than general ERAD. action: MODIFY reason: Replace with the more specific protein-quality-control term rather than the broader ubiquitin-dependent catabolic umbrella term. proposed_replacement_terms: - id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins - term: id: GO:1904294 label: positive regulation of ERAD pathway evidence_type: IMP original_reference_id: PMID:24424410 review: summary: BAG6 is part of ERAD-associated machinery; this paper mostly shows that USP13 preserves BAG6 complex function rather than BAG6 acting as an upstream regulator of ERAD. action: MODIFY reason: The direct BAG6 claim is better captured as ERAD pathway participation. proposed_replacement_terms: - id: GO:0036503 label: ERAD pathway - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:21636303 review: summary: Whole-cell cytoplasmic localization is fully consistent with the BAG6 complex's proteostasis role. action: ACCEPT reason: This is a defensible localization term. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25535373 review: summary: The structural complex paper supports specific adaptor/complex roles, not generic protein binding. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0071818 label: BAT3 complex evidence_type: IDA original_reference_id: PMID:25535373 review: summary: This paper directly analyzes the BAG6 heterotrimeric complex architecture. action: ACCEPT reason: BAT3 complex membership is well supported. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23246001 review: summary: This ERAD paper supports specific SGTA/BAG6 pathway functions rather than a useful generic binding term. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:23246001 review: summary: The SGTA/BAG6 ERAD paper supports a cytosolic BAG6 pool. action: ACCEPT reason: This matches the core QC role. - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:23246001 review: summary: The paper supports regulated ER-membrane association through ERAD machinery rather than a generic membrane localization. action: MODIFY reason: Use endoplasmic reticulum membrane as the more faithful location. proposed_replacement_terms: - id: GO:0005789 label: endoplasmic reticulum membrane - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:21636303 review: summary: The 2011 ERAD study notes nuclear sequestration when Trc35 is absent, consistent with BAG6's known dynamic localization. action: ACCEPT reason: Nuclear localization is supported. - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:21636303 review: summary: Bag6 physically associates with ERAD E3 ligases such as gp78/AMFR and SYVN1, which is central to its UPS-adjacent chaperone role. action: ACCEPT reason: This specific binding term is mechanistically informative and supported. supported_by: - reference_id: PMID:21636303 - term: id: GO:0051787 label: misfolded protein binding evidence_type: IDA original_reference_id: PMID:21636303 review: summary: This is the key direct evidence for BAG6 recognizing aggregation-prone hydrophobic/misfolded clients. action: ACCEPT reason: The term accurately captures BAG6 holdase specificity. supported_by: - reference_id: PMID:21636303 - term: id: GO:0071818 label: BAT3 complex evidence_type: IDA original_reference_id: PMID:21636303 review: summary: The paper directly studies the BAG6/Ubl4A/Trc35 complex. action: ACCEPT reason: Complex membership is well supported. - term: id: GO:1990381 label: ubiquitin-specific protease binding evidence_type: IPI original_reference_id: PMID:24424410 review: summary: Direct interaction with USP13 is well supported, but this is a specific partner interaction rather than the best core BAG6 function summary. action: KEEP_AS_NON_CORE reason: Keep as non-core mechanistic context. supported_by: - reference_id: PMID:24424410 - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:24981174 review: summary: RNF126 recruitment to the BAG6 UBL domain is a core mechanistic part of mislocalized-protein triage. action: ACCEPT reason: This specific ligase-binding annotation is supported and informative. supported_by: - reference_id: PMID:24981174 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18765639 review: summary: The chromatin-regulator interaction paper does not justify retaining a generic protein-binding term. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0001822 label: kidney development evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Mouse-based developmental evidence is plausible but not core to human BAG6 proteostasis biology. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17403783 review: summary: The p53 acetylation paper supports a specific nuclear scaffold role, not a useful generic protein-binding annotation. action: REMOVE reason: Remove generic protein-binding carryover. - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:17403783 review: summary: This paper supports nuclear BAG6 during DNA-damage signaling. action: ACCEPT reason: Nuclear localization is well supported. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:17403783 review: summary: This paper also supports the broader nucleo-cytoplasmic distribution of BAG6. action: ACCEPT reason: Cytosolic BAG6 is consistent with its principal proteostasis role. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:20676083 review: summary: The ribosome-associated TA-targeting study places BAG6 complex function in the cytosol. action: ACCEPT reason: Cytosolic localization is central to GET-pathway capture/handoff. - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: The broad catabolic-process inference is directionally consistent with BAG6 QC biology but loses specificity. action: KEEP_AS_NON_CORE reason: Keep as non-core rather than using it as a core summary term. - term: id: GO:0007130 label: synaptonemal complex assembly evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Orthology-based reproductive biology is secondary/contextual. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0007283 label: spermatogenesis evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Orthology-based reproductive biology is secondary/contextual. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0007420 label: brain development evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Orthology-based developmental biology is secondary/contextual. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0018393 label: internal peptidyl-lysine acetylation evidence_type: IDA original_reference_id: PMID:17403783 review: summary: BAG6 scaffolds p300-dependent p53 acetylation after DNA damage, but this is a specialized nuclear stress-response role rather than the core proteostasis function. action: KEEP_AS_NON_CORE reason: Keep as non-core context. supported_by: - reference_id: PMID:17403783 - term: id: GO:0030324 label: lung development evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Orthology-based developmental biology is secondary/contextual. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0031593 label: polyubiquitin modification-dependent protein binding evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: The BAG6 literature reviewed here does not provide a solid basis for a direct polyubiquitin-binding activity. action: REMOVE reason: Remove this inferred binding term. - term: id: GO:0032435 label: negative regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: This reflects secondary stabilization biology rather than BAG6's central PN role. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0042771 label: intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator evidence_type: IMP original_reference_id: PMID:17403783 review: summary: This DNA-damage apoptosis role is well supported but context-specific. action: KEEP_AS_NON_CORE reason: Keep as non-core nuclear stress biology. supported_by: - reference_id: PMID:17403783 - term: id: GO:0043022 label: ribosome binding evidence_type: IDA original_reference_id: PMID:20676083 review: summary: Ribosome association is an important mechanistic feature of the GET-pathway capture step, but it is not the best standalone summary of BAG6 core function. action: KEEP_AS_NON_CORE reason: Keep as mechanistically informative but non-core. - term: id: GO:0045861 label: negative regulation of proteolysis evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Secondary stabilization/proteolysis control is contextual rather than core. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0050821 label: protein stabilization evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Selected-client stabilization is context-specific and not the main BAG6 role. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0070059 label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: ER-stress apoptosis is context-dependent and not BAG6's principal conserved function. action: KEEP_AS_NON_CORE reason: Keep as non-core. - term: id: GO:0070628 label: proteasome binding evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Direct proteasome binding is not clearly established by the BAG6 papers reviewed here. action: REMOVE reason: Remove the inferred binding term. - term: id: GO:0071816 label: tail-anchored membrane protein insertion into ER membrane evidence_type: IDA original_reference_id: PMID:20676083 review: summary: This is the direct GET-pathway core BAG6 process supported by the landmark ribosome-associated TA-targeting paper. action: ACCEPT reason: The evidence specifically fits tail-anchored membrane protein insertion into the ER membrane. supported_by: - reference_id: PMID:20676083 - term: id: GO:0071818 label: BAT3 complex evidence_type: IDA original_reference_id: PMID:20676083 review: summary: The 2010 Nature study defines the Bat3/Trc35/Ubl4A complex as the relevant functional unit. action: ACCEPT reason: BAT3 complex membership is directly supported. core_functions: - molecular_function: id: GO:0140597 label: protein carrier chaperone directly_involved_in: - id: GO:0036503 label: ERAD pathway - id: GO:0071816 label: tail-anchored membrane protein insertion into ER membrane locations: - id: GO:0005829 label: cytosol in_complex: id: GO:0071818 label: BAT3 complex description: BAG6 acts as an ATP-independent holdase/carrier for hydrophobic, misfolded, retrotranslocated, or tail-anchored client proteins, keeping them soluble long enough for productive ER delivery or proteasome-directed quality control. supported_by: - reference_id: PMID:21636303 - reference_id: PMID:20676083 - reference_id: PMID:25535373 - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: BAG6 captures long hydrophobic TMDs with slow off-rate, recruits RNF126 via its UBL domain for ubiquitination - molecular_function: id: GO:0060090 label: molecular adaptor activity directly_involved_in: - id: GO:0071816 label: tail-anchored membrane protein insertion into ER membrane locations: - id: GO:0005829 label: cytosol in_complex: id: GO:0071818 label: BAT3 complex description: Within the BAG6/UBL4A/GET4 complex, BAG6 provides the scaffold/adaptor surface that links SGTA-bound hydrophobic clients to the TRC40/GET pathway and organizes the pretargeting complex architecture. supported_by: - reference_id: PMID:25535373 - reference_id: PMID:25713138 - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: C-terminal region is a structural part of the substrate-loading complex that bridges UBL4A/SGTA to TRC35/TRC40 - molecular_function: id: GO:0051787 label: misfolded protein binding directly_involved_in: - id: GO:0036503 label: ERAD pathway - id: GO:0061857 label: endoplasmic reticulum stress-induced pre-emptive quality control locations: - id: GO:0005829 label: cytosol in_complex: id: GO:0071818 label: BAT3 complex description: BAG6 preferentially recognizes aggregation-prone hydrophobic or misfolded clients generated during ERAD, cytosolic mislocalization, or ER stress rerouting, linking substrate capture to downstream quality-control decisions. supported_by: - reference_id: PMID:21636303 - reference_id: PMID:26565908 - reference_id: file:human/BAG6/BAG6-deep-research-falcon.md supporting_text: BAG6 captures hydrophobic or mislocalized clients, keeps them soluble, recruits ubiquitination machinery status: COMPLETE