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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0036503
ERAD pathway
|
IBA
GO_REF:0000033 |
ACCEPT |
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.
Reason: Bag6 keeps retrotranslocated hydrophobic clients soluble and engaged with ERAD machinery, matching ERAD pathway membership.
|
|
GO:0031593
polyubiquitin modification-dependent protein binding
|
IBA
GO_REF:0000033 |
REMOVE |
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.
Reason: The conserved BAG6 literature does not establish polyubiquitin-selective binding as a defensible core molecular function.
|
|
GO:0051787
misfolded protein binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic propagation agrees with the human holdase literature: BAG6 preferentially captures aggregation-prone hydrophobic or misfolded clients during quality control.
Reason: This matches the experimentally supported BAG6 holdase role in ERAD and mislocalized-protein triage.
|
|
GO:0071818
BAT3 complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: The phylogenetic BAT3 complex annotation agrees with multiple human studies placing BAG6 in a heterotrimeric BAG6/UBL4A/GET4(TRC35) complex.
Reason: Complex membership is well supported and central to both GET-pathway and UPS-adjacent BAG6 functions.
|
|
GO:0001822
kidney development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Developmental annotations are plausible downstream consequences from mammalian loss-of-function studies, but they are not BAG6's core conserved proteostasis role.
Reason: Keep as contextual biology rather than a core molecular/process function.
|
|
GO:0006511
ubiquitin-dependent protein catabolic process
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
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.
Reason: Retain more specific proteostasis terms instead of this umbrella catabolic label.
|
|
GO:0007130
synaptonemal complex assembly
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: This reproductive annotation reflects secondary mammalian biology rather than BAG6's central proteostasis function.
Reason: Treat as contextual/non-core.
|
|
GO:0007283
spermatogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: This reproductive-process annotation is best treated as contextual because BAG6's conserved role is proteostasis triage, not gametogenesis machinery.
Reason: Keep as non-core.
|
|
GO:0007420
brain development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Any developmental nervous-system consequence is downstream/contextual rather than part of BAG6's main evolved role.
Reason: Keep as non-core.
|
|
GO:0030324
lung development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: This developmental annotation reflects contextual organismal phenotypes rather than BAG6's core GET/UPS-boundary biology.
Reason: Keep as non-core.
|
|
GO:0030544
Hsp70 protein binding
|
IEA
GO_REF:0000107 |
REMOVE |
Summary: This looks like over-propagation from BAG family naming. BAG6 is explicitly not a canonical BAG-domain Hsp70 nucleotide-exchange factor.
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.
|
|
GO:0031593
polyubiquitin modification-dependent protein binding
|
IEA
GO_REF:0000107 |
REMOVE |
Summary: This broad automated propagation is not well grounded in the direct BAG6 mechanistic literature.
Reason: The reviewed papers support client triage with E3s and DUBs, not a specific polyubiquitin-binding activity.
|
|
GO:0032435
negative regulation of proteasomal ubiquitin-dependent protein catabolic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: This regulatory proteolysis term reflects secondary spermatogenic/HSPA2 biology rather than BAG6's central proteostasis role.
Reason: Keep as contextual/non-core.
|
|
GO:0042981
regulation of apoptotic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Apoptosis-related effects exist in some contexts, but this broad automated term is not the best summary of BAG6 function.
Reason: Retain only as non-core context.
|
|
GO:0043161
proteasome-mediated ubiquitin-dependent protein catabolic process
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BAG6 contributes to selected proteasomal quality-control routes, but this automated term is broader and less informative than the specific BAG6-supported processes.
Reason: Prefer ERAD, tail-anchored insertion, or ER-stress pre-emptive quality control terms.
|
|
GO:0045861
negative regulation of proteolysis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: This negative-regulation term reflects context-specific stabilization biology rather than the main BAG6 proteostasis program.
Reason: Keep as non-core.
|
|
GO:0045995
regulation of embryonic development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Embryonic-development phenotypes are contextual downstream consequences and not the core conserved BAG6 role.
Reason: Keep as non-core.
|
|
GO:0050821
protein stabilization
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Protein stabilization is context-specific for selected partners and not the best core descriptor of BAG6.
Reason: Keep as non-core.
|
|
GO:0070059
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: ER-stress apoptosis is a context-dependent consequence, not BAG6's principal conserved function.
Reason: Keep as non-core.
|
|
GO:0070628
proteasome binding
|
IEA
GO_REF:0000107 |
REMOVE |
Summary: The reviewed BAG6 papers place clients en route to the proteasome but do not establish a clean direct proteasome-binding activity.
Reason: This term is too specific for the available evidence.
|
|
GO:0005515
protein binding
|
IPI
PMID:14667819 Analysis of a high-throughput yeast two-hybrid system and it... |
REMOVE |
Summary: The source interaction is too generic to retain as a useful BAG6 annotation.
Reason: GO:0005515 is uninformative here and BAG6 already has more specific mechanistically grounded annotations.
|
|
GO:0005515
protein binding
|
IPI
PMID:16189514 Towards a proteome-scale map of the human protein-protein in... |
REMOVE |
Summary: The source interaction is too generic to retain as a useful BAG6 annotation.
Reason: GO:0005515 is uninformative here and BAG6 already has more specific mechanistically grounded annotations.
|
|
GO:0005515
protein binding
|
IPI
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
REMOVE |
Summary: The exosome/NK paper supports a contextual receptor-ligand role, not a useful standalone generic protein-binding annotation.
Reason: Retain the more specific immune-context terms instead.
|
|
GO:0005515
protein binding
|
IPI
PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:22046132 The SARS-coronavirus-host interactome: identification of cyc... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:22807449 The stalk domain and the glycosylation status of the activat... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:25036637 A quantitative chaperone interaction network reveals the arc... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:26496610 A human interactome in three quantitative dimensions organiz... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:31515488 Extensive disruption of protein interactions by genetic vari... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005576
extracellular region
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: Extracellular release is real but limited to stress/tumor exosome contexts rather than BAG6's main intracellular proteostasis role.
Reason: Keep as contextual, non-core localization.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: BAG6 is a bona fide nucleo-cytoplasmic protein, and nuclear localization is repeatedly observed in the literature and UniProt curation.
Reason: Nuclear localization is real even though the principal PN role is cytosolic.
|
|
GO:0005829
cytosol
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Cytosolic localization is central to BAG6 GET/ERAD/mislocalized-protein triage functions.
Reason: The core proteostasis role depends on cytosolic BAG6 complex localization.
|
|
GO:0005654
nucleoplasm
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: Nucleoplasmic signal is compatible with BAG6's documented nuclear pool and DNA-damage-associated functions.
Reason: This is a defensible subnuclear localization.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: Independent localization evidence also places BAG6 in the cytosol.
Reason: This is fully consistent with the core proteostasis model.
|
|
GO:0005515
protein binding
|
IPI
PMID:40105103 Definition of the human mitochondrial TOM interactome reveal... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0140597
protein carrier chaperone
|
IDA
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: This is one of the strongest BAG6 annotations. The 2011 Mol Cell study directly supports a holdase/carrier role for retrotranslocated hydrophobic clients.
Reason: Bag6 maintains aggregation-prone clients in an unfolded yet soluble state and helps deliver them within quality-control pathways.
Supporting Evidence:
file:human/BAG6/BAG6-deep-research-falcon.md
BAG6 is widely characterized as a chaperone/holdase that binds exposed hydrophobic segments
|
|
GO:0005829
cytosol
|
NAS
PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module... |
ACCEPT |
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.
Reason: The BAG6 complex acts in the cytosol before ER insertion or proteasomal routing.
|
|
GO:0006511
ubiquitin-dependent protein catabolic process
|
IDA
PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr... |
MODIFY |
Summary: PMID:20676083 is about ribosome-associated capture and handoff of tail-anchored proteins to TRC40, not a generic ubiquitin-dependent catabolic process.
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 replacements:
tail-anchored membrane protein insertion into ER membrane
|
|
GO:0006620
post-translational protein targeting to endoplasmic reticulum membrane
|
IDA
PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module... |
ACCEPT |
Summary: This matches the PN GET-pathway mapping and the structural/biochemical literature on tail-anchor targeting.
Reason: BAG6 participates in post-translational delivery of tail-anchored proteins toward the ER membrane.
Supporting Evidence:
file:human/BAG6/BAG6-deep-research-falcon.md
BAG6 is embedded in this pathway as both a substrate-holding factor and a quality-control adaptor
|
|
GO:0031647
regulation of protein stability
|
IDA
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
MODIFY |
Summary: The paper supports holdase/chaperone behavior rather than a broad generic regulation-of-stability process.
Reason: A molecular chaperone/carrier term is a more faithful representation of the evidence.
Proposed replacements:
protein carrier chaperone
|
|
GO:0048018
receptor ligand activity
|
IDA
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
KEEP AS NON CORE |
Summary: Exosomal BAG6 can act as an NKp30 ligand, but this immune signaling role is contextual and not the core conserved BAG6 function.
Reason: Keep as non-core context.
|
|
GO:0051132
NK T cell activation
|
IDA
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
MODIFY |
Summary: The paper concerns NK-cell activation, not NK T-cell activation.
Reason: Replace with natural killer cell activation to match the actual experiment.
Proposed replacements:
natural killer cell activation
|
|
GO:0036503
ERAD pathway
|
NAS
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: Although this is an author statement-level annotation, the underlying study directly demonstrates a BAG6 holdase role that improves ERAD efficiency.
Reason: The evidence supports ERAD pathway participation.
Supporting Evidence:
file:human/BAG6/BAG6-deep-research-falcon.md
BAG6 helps route failed membrane/secretory protein biogenesis products and certain ERAD substrates into ubiquitin-proteasome degradation
|
|
GO:0005515
protein binding
|
IPI
PMID:25713138 Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (u... |
REMOVE |
Summary: The structural paper supports complex architecture and adaptor function, not a useful generic protein-binding annotation.
Reason: Retain the specific adaptor/core-complex annotations instead.
|
|
GO:0060090
molecular adaptor activity
|
EXP
PMID:25713138 Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (u... |
ACCEPT |
Summary: BAG6 organizes UBL4A and TRC35/GET4 and supports substrate handoff, which is well captured by molecular adaptor activity.
Reason: This term fits BAG6's bridge/scaffold role at the GET-pathway and cytosolic quality-control boundary.
Supporting Evidence:
file:human/BAG6/BAG6-deep-research-falcon.md
BAG6’s C-terminal region is a structural part of the substrate-loading complex
|
|
GO:0140677
molecular function activator activity
|
IEP
PMID:25713138 Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (u... |
REMOVE |
Summary: The cited paper does not establish BAG6 as a direct molecular-function activator of another enzyme or receptor.
Reason: This annotation overstates the structural/adaptor evidence.
|
|
GO:0005515
protein binding
|
IPI
PMID:27113755 UBQLN4 recognizes mislocalized transmembrane domain proteins... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0045995
regulation of embryonic development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Orthology-based developmental regulation is plausible but not part of BAG6's core proteostasis identity.
Reason: Keep as non-core context.
|
|
GO:0005515
protein binding
|
IPI
PMID:29042515 Structural basis for regulation of the nucleo-cytoplasmic di... |
REMOVE |
Summary: This paper is informative for localization regulation, but GO:0005515 remains too generic.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005634
nucleus
|
IDA
PMID:29042515 Structural basis for regulation of the nucleo-cytoplasmic di... |
ACCEPT |
Summary: This study directly addresses BAG6 nucleo-cytoplasmic partitioning and supports nuclear localization.
Reason: Nuclear BAG6 is real and regulated by TRC35/GET4 binding.
|
|
GO:0005829
cytosol
|
IDA
PMID:29042515 Structural basis for regulation of the nucleo-cytoplasmic di... |
ACCEPT |
Summary: This study directly supports cytosolic retention of BAG6 by TRC35/GET4.
Reason: Cytosolic BAG6 is the state associated with core proteostasis functions.
|
|
GO:0071816
tail-anchored membrane protein insertion into ER membrane
|
IDA
PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module... |
ACCEPT |
Summary: The minimal BAG6 complex directly supports transfer of tail-anchored substrates into the TRC40/GET pathway.
Reason: This is core PN-supported biology.
|
|
GO:0005515
protein binding
|
IPI
PMID:26876100 Selective Binding of AIRAPL Tandem UIMs to Lys48-Linked Tri-... |
REMOVE |
Summary: This generic interaction term adds no useful BAG6-specific functional information.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005515
protein binding
|
IPI
PMID:14960581 Ricin triggers apoptotic morphological changes through caspa... |
REMOVE |
Summary: The ricin paper is informative for apoptosis context, but GO:0005515 remains too generic.
Reason: Remove generic protein-binding carryover.
|
|
GO:0061857
endoplasmic reticulum stress-induced pre-emptive quality control
|
IMP
PMID:26565908 Pre-emptive Quality Control Protects the ER from Protein Ove... |
ACCEPT |
Summary: This is a specific stress-responsive proteostasis process that the paper directly supports.
Reason: Bag6 contributes to degradation of rerouted ER pre-emptive quality-control substrates under ER stress.
Supporting Evidence:
|
|
GO:0010498
proteasomal protein catabolic process
|
IMP
PMID:26565908 Pre-emptive Quality Control Protects the ER from Protein Ove... |
MARK AS OVER ANNOTATED |
Summary: The specific process shown in the paper is ER stress-induced pre-emptive quality control, not a generic proteasomal catabolic pathway in isolation.
Reason: Keep the more specific GO:0061857 annotation instead.
|
|
GO:0036503
ERAD pathway
|
IMP
PMID:26565908 Pre-emptive Quality Control Protects the ER from Protein Ove... |
MODIFY |
Summary: PMID:26565908 is about ER stress-induced pre-emptive quality control, which is related to but distinct from canonical ERAD.
Reason: Replace with the specific ER pQC term.
Proposed replacements:
endoplasmic reticulum stress-induced pre-emptive quality control
|
|
GO:0016020
membrane
|
HDA
PMID:19946888 Defining the membrane proteome of NK cells. |
MARK AS OVER ANNOTATED |
Summary: A broad membrane term is too imprecise for BAG6, which is mainly cytosolic/nuclear with regulated ER-membrane association in specific QC contexts.
Reason: If membrane association is retained, it should be ER-membrane-specific rather than generic membrane.
|
|
GO:0002429
immune response-activating cell surface receptor signaling pathway
|
IDA
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
KEEP AS NON CORE |
Summary: This immune signaling annotation is supported in exosome/NK-cell contexts but is clearly contextual rather than core BAG6 biology.
Reason: Keep as non-core.
|
|
GO:0005102
signaling receptor binding
|
IPI
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
MODIFY |
Summary: The immune paper is better captured by receptor ligand activity than a generic signaling receptor binding term.
Reason: Replace with receptor ligand activity.
Proposed replacements:
receptor ligand activity
|
|
GO:0005634
nucleus
|
IDA
PMID:14960581 Ricin triggers apoptotic morphological changes through caspa... |
ACCEPT |
Summary: The ricin study also observed nuclear BAG6, consistent with BAG6's established nucleo-cytoplasmic distribution.
Reason: Nuclear localization is defensible.
|
|
GO:0006915
apoptotic process
|
IDA
PMID:14960581 Ricin triggers apoptotic morphological changes through caspa... |
KEEP AS NON CORE |
Summary: Ricin-induced apoptosis is a real contextual role but not BAG6's core conserved proteostasis function.
Reason: Keep as non-core.
|
|
GO:0030101
natural killer cell activation
|
IDA
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
KEEP AS NON CORE |
Summary: Natural killer cell activation is experimentally supported for exosomal BAG6 but remains a contextual immune role.
Reason: Keep as non-core.
|
|
GO:0070062
extracellular exosome
|
IDA
PMID:18852879 Dendritic cells release HLA-B-associated transcript-3 positi... |
KEEP AS NON CORE |
Summary: Exosomal BAG6 is experimentally documented, but this is a conditional extracellular context rather than the main cellular location.
Reason: Keep as non-core localization.
Supporting Evidence:
|
|
GO:0036503
ERAD pathway
|
IDA
PMID:23129660 SGTA antagonizes BAG6-mediated protein triage. |
MODIFY |
Summary: This paper studies SGTA antagonism of BAG6-mediated triage of mislocalized proteins in the cytosol, not canonical ERAD.
Reason: Replace with the narrower protein-quality-control term that better fits cytosolic degradation of mislocalized hydrophobic clients.
Proposed replacements:
protein quality control for misfolded or incompletely synthesized proteins
|
|
GO:0036503
ERAD pathway
|
IDA
PMID:24981174 Cytosolic quality control of mislocalized proteins requires ... |
MODIFY |
Summary: PMID:24981174 defines RNF126-dependent cytosolic quality control of mislocalized proteins rather than general ERAD.
Reason: Replace with the more specific protein-quality-control term rather than the broader ubiquitin-dependent catabolic umbrella term.
Proposed replacements:
protein quality control for misfolded or incompletely synthesized proteins
|
|
GO:1904294
positive regulation of ERAD pathway
|
IMP
PMID:24424410 USP13 antagonizes gp78 to maintain functionality of a chaper... |
MODIFY |
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.
Reason: The direct BAG6 claim is better captured as ERAD pathway participation.
Proposed replacements:
ERAD pathway
|
|
GO:0005737
cytoplasm
|
IDA
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: Whole-cell cytoplasmic localization is fully consistent with the BAG6 complex's proteostasis role.
Reason: This is a defensible localization term.
|
|
GO:0005515
protein binding
|
IPI
PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module... |
REMOVE |
Summary: The structural complex paper supports specific adaptor/complex roles, not generic protein binding.
Reason: Remove generic protein-binding carryover.
|
|
GO:0071818
BAT3 complex
|
IDA
PMID:25535373 Bag6 complex contains a minimal tail-anchor-targeting module... |
ACCEPT |
Summary: This paper directly analyzes the BAG6 heterotrimeric complex architecture.
Reason: BAT3 complex membership is well supported.
|
|
GO:0005515
protein binding
|
IPI
PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... |
REMOVE |
Summary: This ERAD paper supports specific SGTA/BAG6 pathway functions rather than a useful generic binding term.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005829
cytosol
|
IDA
PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... |
ACCEPT |
Summary: The SGTA/BAG6 ERAD paper supports a cytosolic BAG6 pool.
Reason: This matches the core QC role.
|
|
GO:0016020
membrane
|
IDA
PMID:23246001 SGTA recognizes a noncanonical ubiquitin-like domain in the ... |
MODIFY |
Summary: The paper supports regulated ER-membrane association through ERAD machinery rather than a generic membrane localization.
Reason: Use endoplasmic reticulum membrane as the more faithful location.
Proposed replacements:
endoplasmic reticulum membrane
|
|
GO:0005634
nucleus
|
IDA
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: The 2011 ERAD study notes nuclear sequestration when Trc35 is absent, consistent with BAG6's known dynamic localization.
Reason: Nuclear localization is supported.
|
|
GO:0031625
ubiquitin protein ligase binding
|
IPI
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: Bag6 physically associates with ERAD E3 ligases such as gp78/AMFR and SYVN1, which is central to its UPS-adjacent chaperone role.
Reason: This specific binding term is mechanistically informative and supported.
Supporting Evidence:
|
|
GO:0051787
misfolded protein binding
|
IDA
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: This is the key direct evidence for BAG6 recognizing aggregation-prone hydrophobic/misfolded clients.
Reason: The term accurately captures BAG6 holdase specificity.
Supporting Evidence:
|
|
GO:0071818
BAT3 complex
|
IDA
PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... |
ACCEPT |
Summary: The paper directly studies the BAG6/Ubl4A/Trc35 complex.
Reason: Complex membership is well supported.
|
|
GO:1990381
ubiquitin-specific protease binding
|
IPI
PMID:24424410 USP13 antagonizes gp78 to maintain functionality of a chaper... |
KEEP AS NON CORE |
Summary: Direct interaction with USP13 is well supported, but this is a specific partner interaction rather than the best core BAG6 function summary.
Reason: Keep as non-core mechanistic context.
Supporting Evidence:
|
|
GO:0031625
ubiquitin protein ligase binding
|
IPI
PMID:24981174 Cytosolic quality control of mislocalized proteins requires ... |
ACCEPT |
Summary: RNF126 recruitment to the BAG6 UBL domain is a core mechanistic part of mislocalized-protein triage.
Reason: This specific ligase-binding annotation is supported and informative.
Supporting Evidence:
|
|
GO:0005515
protein binding
|
IPI
PMID:18765639 BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H... |
REMOVE |
Summary: The chromatin-regulator interaction paper does not justify retaining a generic protein-binding term.
Reason: Remove generic protein-binding carryover.
|
|
GO:0001822
kidney development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Mouse-based developmental evidence is plausible but not core to human BAG6 proteostasis biology.
Reason: Keep as non-core.
|
|
GO:0005515
protein binding
|
IPI
PMID:17403783 HLA-B-associated transcript 3 (Bat3)/Scythe is essential for... |
REMOVE |
Summary: The p53 acetylation paper supports a specific nuclear scaffold role, not a useful generic protein-binding annotation.
Reason: Remove generic protein-binding carryover.
|
|
GO:0005634
nucleus
|
IDA
PMID:17403783 HLA-B-associated transcript 3 (Bat3)/Scythe is essential for... |
ACCEPT |
Summary: This paper supports nuclear BAG6 during DNA-damage signaling.
Reason: Nuclear localization is well supported.
|
|
GO:0005829
cytosol
|
IDA
PMID:17403783 HLA-B-associated transcript 3 (Bat3)/Scythe is essential for... |
ACCEPT |
Summary: This paper also supports the broader nucleo-cytoplasmic distribution of BAG6.
Reason: Cytosolic BAG6 is consistent with its principal proteostasis role.
|
|
GO:0005829
cytosol
|
IDA
PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr... |
ACCEPT |
Summary: The ribosome-associated TA-targeting study places BAG6 complex function in the cytosol.
Reason: Cytosolic localization is central to GET-pathway capture/handoff.
|
|
GO:0006511
ubiquitin-dependent protein catabolic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: The broad catabolic-process inference is directionally consistent with BAG6 QC biology but loses specificity.
Reason: Keep as non-core rather than using it as a core summary term.
|
|
GO:0007130
synaptonemal complex assembly
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Orthology-based reproductive biology is secondary/contextual.
Reason: Keep as non-core.
|
|
GO:0007283
spermatogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Orthology-based reproductive biology is secondary/contextual.
Reason: Keep as non-core.
|
|
GO:0007420
brain development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Orthology-based developmental biology is secondary/contextual.
Reason: Keep as non-core.
|
|
GO:0018393
internal peptidyl-lysine acetylation
|
IDA
PMID:17403783 HLA-B-associated transcript 3 (Bat3)/Scythe is essential for... |
KEEP AS NON CORE |
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.
Reason: Keep as non-core context.
Supporting Evidence:
|
|
GO:0030324
lung development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Orthology-based developmental biology is secondary/contextual.
Reason: Keep as non-core.
|
|
GO:0031593
polyubiquitin modification-dependent protein binding
|
ISS
GO_REF:0000024 |
REMOVE |
Summary: The BAG6 literature reviewed here does not provide a solid basis for a direct polyubiquitin-binding activity.
Reason: Remove this inferred binding term.
|
|
GO:0032435
negative regulation of proteasomal ubiquitin-dependent protein catabolic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: This reflects secondary stabilization biology rather than BAG6's central PN role.
Reason: Keep as non-core.
|
|
GO:0042771
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
|
IMP
PMID:17403783 HLA-B-associated transcript 3 (Bat3)/Scythe is essential for... |
KEEP AS NON CORE |
Summary: This DNA-damage apoptosis role is well supported but context-specific.
Reason: Keep as non-core nuclear stress biology.
Supporting Evidence:
|
|
GO:0043022
ribosome binding
|
IDA
PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr... |
KEEP AS NON CORE |
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.
Reason: Keep as mechanistically informative but non-core.
|
|
GO:0045861
negative regulation of proteolysis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Secondary stabilization/proteolysis control is contextual rather than core.
Reason: Keep as non-core.
|
|
GO:0050821
protein stabilization
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Selected-client stabilization is context-specific and not the main BAG6 role.
Reason: Keep as non-core.
|
|
GO:0070059
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: ER-stress apoptosis is context-dependent and not BAG6's principal conserved function.
Reason: Keep as non-core.
|
|
GO:0070628
proteasome binding
|
ISS
GO_REF:0000024 |
REMOVE |
Summary: Direct proteasome binding is not clearly established by the BAG6 papers reviewed here.
Reason: Remove the inferred binding term.
|
|
GO:0071816
tail-anchored membrane protein insertion into ER membrane
|
IDA
PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr... |
ACCEPT |
Summary: This is the direct GET-pathway core BAG6 process supported by the landmark ribosome-associated TA-targeting paper.
Reason: The evidence specifically fits tail-anchored membrane protein insertion into the ER membrane.
Supporting Evidence:
|
|
GO:0071818
BAT3 complex
|
IDA
PMID:20676083 A ribosome-associating factor chaperones tail-anchored membr... |
ACCEPT |
Summary: The 2010 Nature study defines the Bat3/Trc35/Ubl4A complex as the relevant functional unit.
Reason: BAT3 complex membership is directly supported.
|
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.
The literature synthesized here explicitly refers to human BAG6 using the aliases BAT3 and Scythe, and describes functions/complexes consistent with UniProt P46379 (N-terminal ubiquitin-like domain; BAG6/Bag6_BAGS regions; cytosolic PQC and TA-protein handling). For example, BAG6 is discussed as part of the mammalian TRC/GET tail-anchored pathway and as a cytosolic quality-control holdase and ubiquitin-ligase adaptor in multiple studies (hagiwara2023proteotoxicstressesstimulate pages 1-3, hagiwara2023proteotoxicstressesstimulate pages 3-5, miyauchi2023bag6supportsstress pages 1-2, zhou2024bag6inhibitsinfluenza pages 2-4, guna2018transmembranedomainrecognition pages 4-6).
Tail-anchored proteins are membrane proteins with a single hydrophobic transmembrane domain (TMD) near the C-terminus that typically insert post-translationally into the ER membrane. In mammals, TA protein targeting is carried out by the TRC40 pathway (homologous to the yeast GET pathway). BAG6 is embedded in this pathway as both a substrate-holding factor and a quality-control adaptor (guna2018transmembranedomainrecognition pages 4-6).
A key synthesis is that BAG6’s C-terminal region is a structural part of the substrate-loading complex that bridges UBL4A/SGTA to TRC35/TRC40, while the N-terminal ubiquitin-like (UBL) domain recruits ubiquitination machinery (notably RNF126) to route failed clients to proteasomal degradation (guna2018transmembranedomainrecognition pages 4-6).
BAG6 is widely characterized as a chaperone/holdase that binds exposed hydrophobic segments of nascent or mislocalized proteins, preventing aggregation and enabling either productive targeting or degradative routing (abildgaard2020cochaperonesintargeting pages 9-11, abildgaard2020cochaperonesintargeting pages 21-23). Mechanistically, BAG6 links client capture to ubiquitin-mediated proteasomal degradation via recruitment of E3 ligases (e.g., RNF126) and via interactions enabling delivery to the proteasome (guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11).
Recent work emphasizes that BAG6 participates in stress-sensitive triage: allocating capacity between (i) biogenesis of TA proteins via TRC machinery and (ii) elimination of defective/aggregation-prone proteins. Under proteotoxic stress, BAG6 complex composition can shift, consistent with triage between these fates (hagiwara2023proteotoxicstressesstimulate pages 3-5, hagiwara2023proteotoxicstressesstimulate pages 10-12).
Canonical TA targeting / TRC pathway partners: BAG6 forms or participates in assemblies including UBL4A, TRC35, TRC40, and interacts functionally with SGTA and the ER insertase WRB–CAML in TA handover and insertion (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11).
Quality-control and degradation partners: BAG6’s UBL domain can recruit the E3 ligase RNF126 (review-level synthesis), and stress can increase BAG6 association with UBQLN4 in the context of proteasome inhibition (hagiwara2023proteotoxicstressesstimulate pages 3-5, guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11).
A notable quantitative contribution from 2023 is the demonstration that BAG6–UBL4A binding is extremely tight in vitro (Kd ~2.2 nM) and that estimated cellular concentrations in HEK293T are high (~720 nM BAG6; ~700 nM UBL4A), yet proteotoxic stress still induces dissociation in cells—supporting dynamic remodeling rather than a static assembly (hagiwara2023proteotoxicstressesstimulate pages 3-5).
BAG6 is principally discussed as acting in the cytosol at the interface of newly synthesized hydrophobic proteins, TA substrate capture, and proteasomal delivery, with functional coupling to ER insertion machinery (TRC40; WRB–CAML) (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11). It can also appear in ubiquitin-positive inclusions/aggregates under proteotoxic stress conditions, consistent with a PQC role when aggregation risk is high (hagiwara2023proteotoxicstressesstimulate pages 3-5).
Some mechanistic evidence indicates BAG6 is a nucleocytoplasmic shuttling protein, with cytosolic retention promoted by GET4 masking a nuclear localization sequence; disease-linked perturbations of GET4 interactions can alter localization (wang2021analysisofthe pages 80-84).
A high-impact conceptual model is that BAG6 preferentially binds long hydrophobic TMDs with slow off-rate, sequestering clients that fail timely membrane engagement and routing them toward ubiquitination and proteasomal degradation, while still supporting handover to the TRC40 targeting apparatus for productive TA insertion (guna2018transmembranedomainrecognition pages 4-6).
Hagiwara et al. (Biochemical Journal; Oct 2023; https://doi.org/10.1042/BCJ20230267) show that proteotoxic stressors (including polyQ aggregation, proteasome inhibition, mitochondrial depolarization) promote dissociation of UBL4A from BAG6, and propose this as a triage mechanism prioritizing degradation over TA synthesis under stress (hagiwara2023proteotoxicstressesstimulate pages 3-5, hagiwara2023proteotoxicstressesstimulate pages 10-12). The authors explicitly connect disruption of BAG6–UBL4A to impaired TA protein synthesis needed for vesicular trafficking and discuss relevance to aggregate-driven neurodegeneration mechanisms (hagiwara2023proteotoxicstressesstimulate pages 10-12).
Roboti et al. (Journal of Cell Science; May 2022; https://doi.org/10.1242/jcs.259596) identify the mitochondrial TA protein MAVS as an endogenous client of both SGTA and the BAG6 complex, and propose that BAG6 binds a cytosolic pool of MAVS prior to misinsertion and retrieval, with the BAG6-associated fraction responding dynamically to innate immune activation (roboti2022mitochondrialantiviralsignallingprotein pages 1-2).
Miyauchi et al. (Molecular Biology of the Cell; Apr 2023; https://doi.org/10.1091/mbc.e22-08-0355) identify BAG6 as a factor required to stabilize endogenous RhoA and thereby support stress fiber formation, focal adhesion assembly, and cell migration. Mechanistically, BAG6 depletion increases association of GDP-bound RhoA with CUL3-based E3 ligases, increasing RhoA polyubiquitination and degradation (miyauchi2023bag6supportsstress pages 1-2, miyauchi2023bag6supportsstress pages 11-13). The study includes quantitative ubiquitination comparisons with p < 0.05 (miyauchi2023bag6supportsstress pages 11-13).
Zhou et al. (PLOS Pathogens; Mar 2024; https://doi.org/10.1371/journal.ppat.1012110) identify BAG6 as a host restriction factor for influenza A virus (IAV). Mechanistically, BAG6 binds the N-terminus of PB2, competes with PB1 for RdRp assembly, and promotes K48-linked ubiquitination and degradation of PB2, including mapping PB2 ubiquitination at K189 (zhou2024bag6inhibitsinfluenza pages 1-2).
Effect sizes and in vivo relevance (key statistics):
* In vitro, BAG6 overexpression reduced infectious titers by ~10–15-fold (TCID50), while BAG6 loss increased titers up to ~10-fold (zhou2024bag6inhibitsinfluenza pages 2-4).
* In mice, BAG6 knockdown increased disease severity with ~40% mortality vs 0% in controls (by 8 dpi) and ~10-fold higher lung viral loads at 3 and 5 dpi (zhou2024bag6inhibitsinfluenza pages 4-7).
* Domain requirements: antiviral activity required BAG6 N-terminus including UBL domain (aa 17–92) plus a PB2-binding region (aa 124–186) (zhou2024bag6inhibitsinfluenza pages 1-2). These quantitative/doman-mapping results are also supported by the extracted figure panels (zhou2024bag6inhibitsinfluenza media f7dcee05).
Alhamwe et al. (Cellular & Molecular Immunology; Jun 2024; https://doi.org/10.1038/s41423-024-01195-1) report that Bag6 deficiency accelerates PDAC tumor growth in an EV-dependent and mast-cell–dependent manner, and propose a translational rationale for considering mast-cell depletion (imatinib) in patients stratified by low BAG6 expression and high mast-cell infiltration (alhamwe2024bag6restrictspancreatic pages 1-2). They also discuss pharmacologic inhibition of EV release (GW4869) in vivo as a rescue approach (alhamwe2024bag6restrictspancreatic pages 11-12). The study notes that high BAG6 gene expression and high plasma BAG6 protein are associated with longer overall survival, supporting biomarker relevance (alhamwe2024bag6restrictspancreatic pages 1-2).
Zhou et al. (2024) show that BAG6 manipulation strongly affects viral replication (order-of-magnitude changes in titers) and disease outcomes in mice, implying BAG6-regulated pathways (ubiquitin-dependent PB2 turnover and polymerase assembly) could be explored for host-directed antiviral strategies or as biomarkers of susceptibility/severity (zhou2024bag6inhibitsinfluenza pages 2-4, zhou2024bag6inhibitsinfluenza pages 4-7).
In a cigarette-smoke emphysema model with liver growth factor treatment, Bag6 is upregulated with fold change 2.114 (FDR 3.69E-03) and qRT-PCR validation showing 1.390 ± 0.119 vs 1.061 ± 0.138; p = 0.0087, suggesting Bag6 as part of a repair-associated gene signature in this model (Carretero 2024; Aug 22, 2024; https://doi.org/10.1371/journal.pone.0309166) (carretero2024differentiallunggene pages 8-10).
A widely cited synthesis (Guna & Hegde, Current Biology; Apr 23, 2018; https://doi.org/10.1016/j.cub.2018.02.004) frames BAG6 as a metazoan-specific adaptor that integrates TA targeting with a “fail-safe” degradative arm: BAG6 captures long hydrophobic TMDs with slow off-rate, recruits RNF126 via its UBL domain for ubiquitination, and uses its C-terminus to connect UBL4A/SGTA with TRC35/TRC40 to enable either insertion or disposal (guna2018transmembranedomainrecognition pages 4-6).
Abildgaard et al. (Biomolecules; Aug 2020; https://doi.org/10.3390/biom10081141) emphasize BAG6 as a holdase that can function largely independently of Hsp70, acting as part of a BAG6–UBL4A–TRC35 complex that can recruit ubiquitination machinery (RNF126) and interact with the proteasome to deliver substrates for degradation (abildgaard2020cochaperonesintargeting pages 9-11).
Open Targets reports BAG6 target–disease association evidence for neurodegenerative disease based on CRISPRi neuronal screen studies (PubMed 34031600) (OpenTargets Search: -BAG6). This is hypothesis-generating and should be interpreted as functional-genomics evidence rather than direct causal mechanistic proof.
The table below summarizes BAG6’s best-supported functional modules (partners, locations, mechanisms, and recent quantitative evidence).
| Function/module | Key partners/complex | Cellular location | Mechanism (1 sentence) | Key recent evidence (2023-2024) with effect sizes/statistics when available | Key foundational evidence/reviews |
|---|---|---|---|---|---|
| Tail-anchored (TA) protein capture and handoff | BAG6–UBL4A–TRC35 complex with SGTA, TRC40, WRB–CAML | Cytosol; ER-targeting interface | BAG6 acts as a hydrophobic-client holdase and scaffold that links SGTA-bound TA clients to TRC40-mediated ER insertion while retaining failed clients for triage. (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11) | Proteotoxic stress and polyQ inclusions trigger UBL4A dissociation from BAG6; BAG6–UBL4A affinity is strong in vitro (Kd 2.2 nM), and estimated cellular concentrations are ~720 nM BAG6 and ~700 nM UBL4A, supporting a normally stable TA-recognition complex that is remodeled under stress. (hagiwara2023proteotoxicstressesstimulate pages 1-3, hagiwara2023proteotoxicstressesstimulate pages 3-5) | Reviews place BAG6 as a metazoan quality-control layer in the TRC40 pathway, with its C-terminus bridging UBL4A/SGTA and TRC35/TRC40 during TA targeting. (guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11) |
| Cytosolic PQC and degradation of hydrophobic/mislocalized proteins | RNF126, UBQLN4, SGTA, proteasome | Cytosol; proteasome-associated; aggregate-prone compartments | BAG6 captures hydrophobic or mislocalized clients, keeps them soluble, recruits ubiquitination machinery, and promotes proteasomal delivery/degradation. (guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11, abildgaard2020cochaperonesintargeting pages 21-23) | Under proteasome inhibition, soluble BAG6 loses associated UBL4A but gains UBQLN4, indicating stress-dependent remodeling from TA biogenesis toward degradative PQC; BAG6 also colocalizes with ubiquitin-positive inclusions. (hagiwara2023proteotoxicstressesstimulate pages 3-5) | BAG6’s N-terminal UBL recruits RNF126, and reviews describe BAG6 as a holdase for TA proteins, defective nascent chains, ERAD substrates, and mislocalized membrane proteins. (guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11, abildgaard2020cochaperonesintargeting pages 21-23) |
| ERAD-linked substrate processing | SGTA, p97 pathway components, RNF126 | Cytosol and ER-proximal quality-control interface | BAG6 helps route failed membrane/secretory protein biogenesis products and certain ERAD substrates into ubiquitin-proteasome degradation rather than productive insertion. (abildgaard2020cochaperonesintargeting pages 9-11, roboti2022mitochondrialantiviralsignallingprotein pages 15-15, you2020paqr9modulatesbag6mediated pages 15-16) | 2023 review context continues to position BAG6 in substrate processing and ER-proximal PQC, though BAG6-specific quantitative 2023–2024 ERAD effect sizes were not provided in the retrieved excerpts. (abildgaard2020cochaperonesintargeting pages 9-11, hagiwara2023proteotoxicstressesstimulate pages 14-15) | Reviews summarize BAG6 as coupling client capture, ligase recruitment, and proteasome targeting for ERAD-like outcomes after failed membrane engagement. (guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11) |
| Stress-responsive remodeling of the BAG6 complex | UBL4A, TRC35, TRC40, UBQLN4 | Cytosol; insoluble aggregates under stress | Proteotoxic stress redistributes BAG6 complexes by dissociating UBL4A and favoring aggregate-associated/degradative BAG6 states. (hagiwara2023proteotoxicstressesstimulate pages 1-3, hagiwara2023proteotoxicstressesstimulate pages 3-5) | PolyQ inclusions, proteasome inhibition, and mitochondrial depolarization reduce BAG6–UBL4A association; overexpressed UBL4A suppresses BAG6 translocation into insoluble aggregates. (hagiwara2023proteotoxicstressesstimulate pages 3-5) | Foundational models of BAG6 explain this as a triage switch between TA targeting and degradation of hydrophobic clients. (guna2018transmembranedomainrecognition pages 4-6, abildgaard2020cochaperonesintargeting pages 9-11) |
| Innate immunity-linked TA client control | MAVS with SGTA and BAG6–UBL4A–TRC35 | Cytosolic pool; ER and mitochondrial-signaling membrane interface | BAG6 binds a cytosolic pool of the mitochondrial TA protein MAVS before misinsertion/retrieval, thereby modulating the fraction available for antiviral signaling. (roboti2022mitochondrialantiviralsignallingprotein pages 1-2) | BioID2 proximity labeling identified MAVS as a high-confidence SGTA interactor (BFDR < 0.05), and BAG6-associated MAVS changed dynamically during innate immune activation. (roboti2022mitochondrialantiviralsignallingprotein pages 1-2) | This extends the established BAG6 client-triage model from generic TA proteins to an endogenous immune signaling TA client. (roboti2022mitochondrialantiviralsignallingprotein pages 1-2, guna2018transmembranedomainrecognition pages 4-6) |
| Direct antiviral restriction of influenza A virus | Viral PB2, PB1/RdRp complex | Predominantly cytosolic/nuclear viral polymerase context | BAG6 binds PB2, competes with PB1 for polymerase assembly, and promotes K48-linked ubiquitination-dependent PB2 degradation to suppress IAV replication. (zhou2024bag6inhibitsinfluenza pages 2-4, zhou2024bag6inhibitsinfluenza pages 1-2) | Overexpression decreased IAV titers by ~10–15-fold across H1N1, H7N9, H9N2, and H5N1; BAG6 loss increased titers up to ~10-fold; in mice, BAG6 knockdown caused ~40% mortality by 8 dpi versus 0% in controls and ~10-fold higher lung viral loads. Figure review also mapped required BAG6 regions to the UBL domain (aa 17–92) plus a PB2-binding region (aa 124–186). (zhou2024bag6inhibitsinfluenza pages 2-4, zhou2024bag6inhibitsinfluenza pages 4-7, zhou2024bag6inhibitsinfluenza media f7dcee05) | Recent primary work builds on broader BAG6 chaperone/PQC functions rather than a separate foundational antiviral literature in the retrieved corpus. (abildgaard2020cochaperonesintargeting pages 9-11, abildgaard2020cochaperonesintargeting pages 21-23) |
| Cytoskeletal regulation via small GTPase stabilization | RhoA, CUL3-based ubiquitin ligases | Cytosol; stress fibers/focal adhesions | BAG6 acts as a holdase for GDP-bound RhoA, limiting its association with CUL3 ligases and thereby preserving RhoA-dependent actin assembly. (miyauchi2023bag6supportsstress pages 1-2) | BAG6 depletion increased RhoA polyubiquitination and degradation, impairing stress fibers, focal adhesion assembly, and cell migration; RhoA re-expression rescued the phenotype. (miyauchi2023bag6supportsstress pages 1-2) | This expands BAG6 client selectivity beyond membrane-hydrophobic clients to a soluble signaling protein stabilized through a related anti-degradation holdase mechanism. (miyauchi2023bag6supportsstress pages 1-2, abildgaard2020cochaperonesintargeting pages 21-23) |
| Tumor microenvironment and extracellular vesicle regulation | p53, CBP/p300, ESCRT machinery, IL33-positive EVs, mast cells | Cytosol/nucleus-linked vesicle biogenesis pathway; extracellular vesicles; tumor microenvironment | BAG6 restrains pancreatic tumor progression by promoting EV biogenesis programs that prevent release of IL33-presenting EVs that activate mast cells and remodel the TME. (alhamwe2024bag6restrictspancreatic pages 1-2) | In PDAC models, Bag6 deficiency accelerated subcutaneous and orthotopic tumor growth in an EV-dependent manner; high BAG6 gene expression and plasma BAG6 associated with longer overall survival, and imatinib-mediated mast-cell depletion reduced tumor growth in BAG6-low contexts. (alhamwe2024bag6restrictspancreatic pages 1-2) | The study leverages prior evidence that BAG6 regulates membrane vesicle trafficking, EV cargo sorting, and immune-cell activation. (alhamwe2024bag6restrictspancreatic pages 1-2) |
| Nuclear-cytoplasmic shuttling and localization control | GET4, UBL4A, FBXO7 | Cytosol and nucleus | BAG6 is a nucleocytoplasmic shuttling protein whose retention in the cytosol is promoted by GET4 masking its nuclear localization sequence. (wang2021analysisofthe pages 80-84) | Dissertation-level mechanistic evidence reports that FBXO7-enhanced GET4 ubiquitination increases GET4–BAG6 binding and shifts BAG6 cytoplasmic localization; disease-associated FBXO7 variants weaken this control. (wang2021analysisofthe pages 80-84) | This localization logic fits BAG6’s established need to remain cytosolic for TA targeting/PQC while retaining the capacity for alternative signaling roles. (wang2021analysisofthe pages 80-84, guna2018transmembranedomainrecognition pages 4-6) |
Table: This table summarizes the best-supported functional modules of human BAG6 (UniProt P46379), integrating core mechanistic roles, partners, locations, and recent 2023-2024 evidence with quantitative findings where available. It is useful for quickly distinguishing BAG6’s foundational tail-anchored protein/PQC functions from newer roles in antiviral defense, cytoskeletal regulation, and tumor biology.
Some frequently discussed BAG6 roles (e.g., antigen presentation, apoptosis regulation, mitophagy/autophagy) are mentioned in the retrieved PDAC/virology papers as contextual background but were not comprehensively supported with primary mechanistic excerpts within the currently retrieved text segments. Accordingly, the report emphasizes roles with direct mechanistic and/or quantitative support in the available evidence corpus.
References
(hagiwara2023proteotoxicstressesstimulate pages 1-3): Takumi Hagiwara, Ryosuke Minami, Chizuru Ushio, Naoto Yokota, and Hiroyuki Kawahara. Proteotoxic stresses stimulate dissociation of ubl4a from the tail-anchored protein recognition complex. Biochemical Journal, 480:1583-1598, Oct 2023. URL: https://doi.org/10.1042/bcj20230267, doi:10.1042/bcj20230267. This article has 0 citations and is from a domain leading peer-reviewed journal.
(hagiwara2023proteotoxicstressesstimulate pages 3-5): Takumi Hagiwara, Ryosuke Minami, Chizuru Ushio, Naoto Yokota, and Hiroyuki Kawahara. Proteotoxic stresses stimulate dissociation of ubl4a from the tail-anchored protein recognition complex. Biochemical Journal, 480:1583-1598, Oct 2023. URL: https://doi.org/10.1042/bcj20230267, doi:10.1042/bcj20230267. This article has 0 citations and is from a domain leading peer-reviewed journal.
(miyauchi2023bag6supportsstress pages 1-2): Maho Miyauchi, Reina Matsumura, and Hiroyuki Kawahara. Bag6 supports stress fiber formation by preventing the ubiquitin-mediated degradation of rhoa. Molecular Biology of the Cell, Apr 2023. URL: https://doi.org/10.1091/mbc.e22-08-0355, doi:10.1091/mbc.e22-08-0355. This article has 7 citations and is from a domain leading peer-reviewed journal.
(zhou2024bag6inhibitsinfluenza pages 2-4): Yong Zhou, Tian Li, Yunfan Zhang, Nianzhi Zhang, Yuxin Guo, Xiaoyi Gao, Wenjing Peng, Sicheng Shu, Chuankuo Zhao, Di Cui, Honglei Sun, Yipeng Sun, Jinhua Liu, Jun Tang, Rui Zhang, and Juan Pu. Bag6 inhibits influenza a virus replication by inducing viral polymerase subunit pb2 degradation and perturbing rdrp complex assembly. PLOS Pathogens, 20:e1012110, Mar 2024. URL: https://doi.org/10.1371/journal.ppat.1012110, doi:10.1371/journal.ppat.1012110. This article has 13 citations and is from a highest quality peer-reviewed journal.
(guna2018transmembranedomainrecognition pages 4-6): Alina Guna and Ramanujan S. Hegde. Transmembrane domain recognition during membrane protein biogenesis and quality control. Current Biology, 28:R498-R511, Apr 2018. URL: https://doi.org/10.1016/j.cub.2018.02.004, doi:10.1016/j.cub.2018.02.004. This article has 151 citations and is from a highest quality peer-reviewed journal.
(abildgaard2020cochaperonesintargeting pages 9-11): Amanda B. Abildgaard, Sarah K. Gersing, Sven Larsen-Ledet, Sofie V. Nielsen, Amelie Stein, Kresten Lindorff-Larsen, and Rasmus Hartmann-Petersen. Co-chaperones in targeting and delivery of misfolded proteins to the 26s proteasome. Biomolecules, 10:1141, Aug 2020. URL: https://doi.org/10.3390/biom10081141, doi:10.3390/biom10081141. This article has 54 citations.
(abildgaard2020cochaperonesintargeting pages 21-23): Amanda B. Abildgaard, Sarah K. Gersing, Sven Larsen-Ledet, Sofie V. Nielsen, Amelie Stein, Kresten Lindorff-Larsen, and Rasmus Hartmann-Petersen. Co-chaperones in targeting and delivery of misfolded proteins to the 26s proteasome. Biomolecules, 10:1141, Aug 2020. URL: https://doi.org/10.3390/biom10081141, doi:10.3390/biom10081141. This article has 54 citations.
(hagiwara2023proteotoxicstressesstimulate pages 10-12): Takumi Hagiwara, Ryosuke Minami, Chizuru Ushio, Naoto Yokota, and Hiroyuki Kawahara. Proteotoxic stresses stimulate dissociation of ubl4a from the tail-anchored protein recognition complex. Biochemical Journal, 480:1583-1598, Oct 2023. URL: https://doi.org/10.1042/bcj20230267, doi:10.1042/bcj20230267. This article has 0 citations and is from a domain leading peer-reviewed journal.
(roboti2022mitochondrialantiviralsignallingprotein pages 1-2): Peristera Roboti, Craig Lawless, and Stephen High. Mitochondrial antiviral-signalling protein is a client of the bag6 protein quality control complex. Journal of Cell Science, May 2022. URL: https://doi.org/10.1242/jcs.259596, doi:10.1242/jcs.259596. This article has 1 citations and is from a domain leading peer-reviewed journal.
(wang2021analysisofthe pages 80-84): Quan Wang. Analysis of the interaction of the parkinsonism-associated protein fbxo7 with the bag6 complex. Dissertation, Jan 2021. URL: https://doi.org/10.18154/rwth-2022-00532, doi:10.18154/rwth-2022-00532. This article has 0 citations.
(miyauchi2023bag6supportsstress pages 11-13): Maho Miyauchi, Reina Matsumura, and Hiroyuki Kawahara. Bag6 supports stress fiber formation by preventing the ubiquitin-mediated degradation of rhoa. Molecular Biology of the Cell, Apr 2023. URL: https://doi.org/10.1091/mbc.e22-08-0355, doi:10.1091/mbc.e22-08-0355. This article has 7 citations and is from a domain leading peer-reviewed journal.
(zhou2024bag6inhibitsinfluenza pages 1-2): Yong Zhou, Tian Li, Yunfan Zhang, Nianzhi Zhang, Yuxin Guo, Xiaoyi Gao, Wenjing Peng, Sicheng Shu, Chuankuo Zhao, Di Cui, Honglei Sun, Yipeng Sun, Jinhua Liu, Jun Tang, Rui Zhang, and Juan Pu. Bag6 inhibits influenza a virus replication by inducing viral polymerase subunit pb2 degradation and perturbing rdrp complex assembly. PLOS Pathogens, 20:e1012110, Mar 2024. URL: https://doi.org/10.1371/journal.ppat.1012110, doi:10.1371/journal.ppat.1012110. This article has 13 citations and is from a highest quality peer-reviewed journal.
(zhou2024bag6inhibitsinfluenza pages 4-7): Yong Zhou, Tian Li, Yunfan Zhang, Nianzhi Zhang, Yuxin Guo, Xiaoyi Gao, Wenjing Peng, Sicheng Shu, Chuankuo Zhao, Di Cui, Honglei Sun, Yipeng Sun, Jinhua Liu, Jun Tang, Rui Zhang, and Juan Pu. Bag6 inhibits influenza a virus replication by inducing viral polymerase subunit pb2 degradation and perturbing rdrp complex assembly. PLOS Pathogens, 20:e1012110, Mar 2024. URL: https://doi.org/10.1371/journal.ppat.1012110, doi:10.1371/journal.ppat.1012110. This article has 13 citations and is from a highest quality peer-reviewed journal.
(zhou2024bag6inhibitsinfluenza media f7dcee05): Yong Zhou, Tian Li, Yunfan Zhang, Nianzhi Zhang, Yuxin Guo, Xiaoyi Gao, Wenjing Peng, Sicheng Shu, Chuankuo Zhao, Di Cui, Honglei Sun, Yipeng Sun, Jinhua Liu, Jun Tang, Rui Zhang, and Juan Pu. Bag6 inhibits influenza a virus replication by inducing viral polymerase subunit pb2 degradation and perturbing rdrp complex assembly. PLOS Pathogens, 20:e1012110, Mar 2024. URL: https://doi.org/10.1371/journal.ppat.1012110, doi:10.1371/journal.ppat.1012110. This article has 13 citations and is from a highest quality peer-reviewed journal.
(alhamwe2024bag6restrictspancreatic pages 1-2): Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, and Elke Pogge von Strandmann. Bag6 restricts pancreatic cancer progression by suppressing the release of il33-presenting extracellular vesicles and the activation of mast cells. Cellular and Molecular Immunology, 21:918-931, Jun 2024. URL: https://doi.org/10.1038/s41423-024-01195-1, doi:10.1038/s41423-024-01195-1. This article has 28 citations and is from a peer-reviewed journal.
(alhamwe2024bag6restrictspancreatic pages 8-10): Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, and Elke Pogge von Strandmann. Bag6 restricts pancreatic cancer progression by suppressing the release of il33-presenting extracellular vesicles and the activation of mast cells. Cellular and Molecular Immunology, 21:918-931, Jun 2024. URL: https://doi.org/10.1038/s41423-024-01195-1, doi:10.1038/s41423-024-01195-1. This article has 28 citations and is from a peer-reviewed journal.
(carretero2024differentiallunggene pages 8-10): Laura Sánchez Carretero, Adele Chloe Cardeñosa Pérez, Germán Peces-Barba, and Sandra Pérez-Rial. Differential lung gene expression identified zscan2 and bag6 as novel tissue repair players in an experimental copd model. PLOS ONE, 19:e0309166, Aug 2024. URL: https://doi.org/10.1371/journal.pone.0309166, doi:10.1371/journal.pone.0309166. This article has 2 citations and is from a peer-reviewed journal.
(alhamwe2024bag6restrictspancreatic pages 11-12): Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, and Elke Pogge von Strandmann. Bag6 restricts pancreatic cancer progression by suppressing the release of il33-presenting extracellular vesicles and the activation of mast cells. Cellular and Molecular Immunology, 21:918-931, Jun 2024. URL: https://doi.org/10.1038/s41423-024-01195-1, doi:10.1038/s41423-024-01195-1. This article has 28 citations and is from a peer-reviewed journal.
(OpenTargets Search: -BAG6): Open Targets Query (-BAG6, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(roboti2022mitochondrialantiviralsignallingprotein pages 15-15): Peristera Roboti, Craig Lawless, and Stephen High. Mitochondrial antiviral-signalling protein is a client of the bag6 protein quality control complex. Journal of Cell Science, May 2022. URL: https://doi.org/10.1242/jcs.259596, doi:10.1242/jcs.259596. This article has 1 citations and is from a domain leading peer-reviewed journal.
(you2020paqr9modulatesbag6mediated pages 15-16): Xue You, Yijun Lin, Yongfan Hou, Lijiao Xu, Qianqian Cao, and Yan Chen. Paqr9 modulates bag6-mediated protein quality control of mislocalized membrane proteins. Biochemical Journal, 477:477-489, Jan 2020. URL: https://doi.org/10.1042/bcj20190620, doi:10.1042/bcj20190620. This article has 10 citations and is from a domain leading peer-reviewed journal.
(hagiwara2023proteotoxicstressesstimulate pages 14-15): Takumi Hagiwara, Ryosuke Minami, Chizuru Ushio, Naoto Yokota, and Hiroyuki Kawahara. Proteotoxic stresses stimulate dissociation of ubl4a from the tail-anchored protein recognition complex. Biochemical Journal, 480:1583-1598, Oct 2023. URL: https://doi.org/10.1042/bcj20230267, doi:10.1042/bcj20230267. This article has 0 citations and is from a domain leading peer-reviewed journal.
ER proteostasis > Protein transport > GET pathway component. The narrow GET-pathway mapping to GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane is appropriate and is already represented in the local review/GOA.ER proteostasis > Protein transport mapping would additionally propagate broad GO:0015031 protein transport to BAG6. This is directionally related but less informative than the reviewed BAG6 terms, especially GO:0071816 tail-anchored membrane protein insertion into ER membrane and GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane [PMID:20676083 "facilitates TA protein capture by TRC40"; PMID:25535373 "facilitates tail-anchored substrate transfer"].GO:0015031 protein transport candidate.local_review_complete_not_phase1. PN placement: ER proteostasis > GET pathway component; UPS > associated non-Ub enzyme chaperone; UPS > UBL domain > chaperones and related. Main issue: Review supports specific GET, ERAD, and holdase roles but not broad parent protein-transport propagationNo phase-1 dossier exists for this priority-only gene. This note preserves the current PROTEOSTASIS boundary or exception decision and should be superseded by a dossier section if the gene is promoted into a full phase-1 batch.
This file is generated from the current PROTEOSTASIS priority table, PN projection outputs, and local gene-review artifacts. Edit those source records rather than this generated note when correcting the underlying curation.
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