Affinage

BAG6

Large proline-rich protein BAG6 · UniProt P46379

Length
1132 aa
Mass
119.4 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAG6 (BAT3/Scythe) is a multifunctional holdase that recognizes exposed hydrophobicity on newly synthesized, mislocalized, or proteolytically generated polypeptides and triages them between membrane insertion, proteasomal degradation, and aggregate prevention (PMID:20713601, PMID:20516149). As the central scaffold of a heterotrimeric complex with Ubl4A and TRC35, BAG6 uses distinct C-terminal binding sites for each subunit and a large central proline-rich region to capture tail-anchored substrates such as Sec61β, enabling their transfer from SGTA toward the TRC40 targeting pathway (PMID:23533635, PMID:25535373). Substrate selection and fate are domain-partitioned: an N-terminal ubiquitin-like (ULD) domain mediates recognition of hydrophobic and polyubiquitinated clients (PMID:26663859), the UBL domain recruits the E3 ligase RNF126, which preferentially ubiquitinates juxtahydrophobic lysines on BAG6-bound clients to drive degradation (PMID:24981174), and the VCP adaptor UBXN1 then links the unfoldase to ubiquitylated clients prior to ER translocation, with its loss diverting clients into insoluble aggregates (PMID:29685906). BAG6 thereby protects cells from aggregation of orphaned fragments, including C-terminal TDP43 species, by coupling them to RNF126-dependent ubiquitylation (PMID:35542047). SGTA opposes this activity by promoting deubiquitination of BAG6-marked clients, and the SGTA–Ubl4A UBL interaction governs substrate loading (PMID:23246001, PMID:23129660). BAG6 is partitioned between cytosol and nucleus: TRC35 occludes its nuclear localization signal to retain it in the cytosol (PMID:29042515), while nuclear BAG6 scaffolds p300-mediated acetylation of p53 to drive DNA-damage gene expression (PMID:17403783) and supports DOT1L-dependent H3K79 dimethylation required for 53BP1 recruitment and DNA repair (PMID:22373577). Genetic ablation produces developmental defects and altered apoptotic sensitivity in mice (PMID:16287848), and conditional loss in germ cells destabilizes HSPA2 and causes meiotic failure and male infertility (PMID:18678708). BAG6 additionally regulates autophagy through control of p300 localization (PMID:24591579) and engages LC3B via LIR motifs to influence autophagy and PINK1/PARKIN-dependent mitophagy (PMID:33241194, PMID:33522017), and in immune cells it represses Tim-3 and mTORC2 signaling to limit T-cell exhaustion (PMID:22863785, PMID:33931442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Established the founding function of BAG6/Scythe as an essential apoptotic regulator, raising the question of how it controls cell death.

    Evidence Protein purification from Xenopus egg extracts with immunodepletion and N-terminal truncation mutants

    PMID:9799223

    Open questions at the time
    • Molecular identity of the sequestered apoptotic factor not defined
    • Human relevance untested at this stage
  2. 2001 High

    Linked BAG6 to chaperone regulation by showing it inhibits Hsp70 refolding in a Reaper-reversible manner, and defined its nuclear localization signal.

    Evidence In vitro Hsp70 refolding assays and NLS mutagenesis with immunofluorescence

    PMID:11230127 PMID:11587531

    Open questions at the time
    • Cellular substrates of the chaperone-modulating activity unknown
    • Regulation of nucleocytoplasmic partitioning unresolved
  3. 2005 High

    Connected BAG6 to the proteasome and to development, showing a proteasome receptor interaction and severe knockout phenotypes.

    Evidence Xenopus Rpn10c co-IP/deletion mapping and Bat3 knockout mouse histopathology with apoptosis assays

    PMID:16287848 PMID:16336274

    Open questions at the time
    • Direct degradation substrates not yet identified
    • Mechanism connecting proteasome binding to development unclear
  4. 2007 High

    Defined nuclear BAG6 as a p300 cofactor required for p53 acetylation, explaining its role in DNA-damage-induced apoptosis independent of p53 stabilization.

    Evidence Reciprocal Co-IP, p53 acetylation assays, and Bat3-/- thymocyte apoptosis assays

    PMID:17403783

    Open questions at the time
    • How BAG6 enhances p300 catalysis structurally undefined
    • Relationship to cytosolic functions unclear
  5. 2008 High

    Revealed BAG6 as a regulator of client protein stability in germ cells, where its loss triggers ubiquitin-proteasome destruction of HSPA2 and meiotic failure.

    Evidence Conditional Bat3 KO mice with ubiquitination assays and proteasome-inhibitor rescue

    PMID:18678708

    Open questions at the time
    • Whether BAG6 directly shields HSPA2 from ubiquitination not resolved
    • E3 ligase involved not identified
  6. 2010 High

    Defined BAG6's core proteostatic function: capturing nascent/mislocalized chains and routing tail-anchored proteins to the TRC40 membrane-insertion pathway.

    Evidence In vitro/in vivo nascent-chain interaction and degradation assays, plus Sec61β membrane integration assays with depletion

    PMID:20516149 PMID:20713601

    Open questions at the time
    • Identity of the responsible E3 ligase not yet known
    • Substrate-binding domain not yet mapped
  7. 2012 High

    Mapped the SGTA-Ubl4A handoff and extended BAG6 functions to T-cell signaling and chromatin, defining substrate loading, immune regulation, and DNA-repair roles.

    Evidence NMR of SGTA-Ubl4A, in vitro deubiquitination assays, Tim-3 Co-IP with T-cell phenotyping, and DOT1L Co-IP/ChIP with 53BP1 readouts

    PMID:22373577 PMID:22863785 PMID:23129660 PMID:23246001

    Open questions at the time
    • Coordination between cytosolic triage and nuclear/immune roles unclear
    • Structural basis of DOT1L interaction not solved
  8. 2014 High

    Identified RNF126 as the BAG6-dependent E3 ligase and resolved the complex architecture, establishing the molecular machinery for client ubiquitination and TA-substrate transfer.

    Evidence Reconstitution with purified RNF126 and domain mapping; crystal structure of BAG6-Ubl4A C-terminal dimer with TA transfer assays; autophagy regulation via p300 in KO MEFs

    PMID:24591579 PMID:24981174 PMID:25535373

    Open questions at the time
    • How ubiquitylated clients are committed to degradation versus insertion not fully resolved
    • BAGS domain functional partners incompletely defined
  9. 2015 High

    Defined the substrate-recognition (ULD) domain and the noncanonical C-terminal BAGS architecture, clarifying how BAG6 discriminates clients and stabilizes its partners.

    Evidence Domain-deletion binding assays and crystallography of BAG6-Ubl4A heterodimer with cellular stability assays

    PMID:25713138 PMID:26663859

    Open questions at the time
    • Structural basis of hydrophobicity sensing not directly visualized
    • Affinity hierarchy among competing clients unknown
  10. 2017 High

    Provided a structural explanation for BAG6 cytosol/nucleus partitioning, showing TRC35 occludes the NLS and shields TRC35 from RNF126.

    Evidence Crystal structure of BAG6-TRC35 with karyopherin-α binding and ubiquitylation assays

    PMID:29042515

    Open questions at the time
    • Signals that release BAG6 for nuclear import not defined
    • Dynamics of partitioning in vivo not measured
  11. 2018 Medium

    Identified UBXN1 as the VCP adaptor coupling ubiquitylated BAG6 clients to the unfoldase, explaining how clients avoid aggregation before ER translocation.

    Evidence Co-IP, siRNA depletion, and solubility/aggregation fractionation with pathway-specificity controls

    PMID:29685906

    Open questions at the time
    • Single lab without structural validation of the VCP-UBXN1-BAG6 assembly
    • Substrate range requiring UBXN1 not delimited
  12. 2021 Medium

    Extended BAG6 to autophagy and mitophagy regulation through direct LC3B engagement and PINK1/PARKIN modulation.

    Evidence NMR of BAG6 LIR1-LC3B, LIR mutagenesis with autophagy flux assays, and BAG6 KO/OE mitophagy assays in null cells

    PMID:32332095 PMID:33241194 PMID:33522017

    Open questions at the time
    • Reconciliation of BAG6 as both autophagy suppressor and mitophagy stimulator unresolved
    • Basal mitochondrial-matrix versus OMM localization mechanism unclear
  13. 2022 Medium

    Established BAG6 as a sensor of aggregation-prone proteolytic fragments and an immunometabolic regulator in dendritic cells.

    Evidence BAG6 KO aggregation/ubiquitylation assays with TDP43 fragments and DC-specific Bat3 KO with metabolomics and paracrine T-cell assays

    PMID:35275752 PMID:35542047

    Open questions at the time
    • Whether fragment sensing is relevant to neurodegenerative disease untested
    • Mechanism linking BAG6 loss to UPR/steroidogenesis incompletely defined
  14. 2024 Medium

    Linked BAG6 control of extracellular vesicle cargo to tumor suppression in cancer microenvironments.

    Evidence Bag6 KO PDAC mouse models with in vivo EV tracking, scRNA-seq, organoids, and patient samples

    PMID:38942797

    Open questions at the time
    • Direct mechanism by which BAG6 selects EV cargo not fully resolved
    • Generality across tumor types untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how BAG6 dynamically coordinates its cytosolic proteostatic triage, nuclear chromatin/p53 functions, autophagy/mitophagy control, and extracellular-vesicle roles within a single cell.
  • No integrated model partitioning BAG6 pools across compartments
  • Regulatory signals switching between degradation, insertion, and aggregate-prevention fates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005576 extracellular region 2 GO:0005739 mitochondrion 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 3 R-HSA-9612973 Autophagy 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
DOT1LEP300HSPA2RNF126SGTATRC35UBL4AUBXN1
Complex memberships
BAG6–Ubl4A–TRC35 (GET/TRC chaperone complex)

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Scythe (BAG6 ortholog in Xenopus) was purified from Xenopus egg extracts as a 150 kDa reaper-binding protein; immunodepletion of Scythe completely prevented reaper-induced apoptosis, and a truncated Scythe lacking the N-terminal ubiquitin-like domain induced apoptosis even without reaper, establishing Scythe as an essential component in the reaper-induced apoptosis pathway. Protein purification from Xenopus egg extracts, immunodepletion, truncation mutant expression The EMBO journal High 9799223
1999 Reaper binding to Scythe causes Scythe to release a sequestered apoptotic factor sufficient to induce cytochrome c release from purified mitochondria; Scythe also binds Drosophila apoptotic regulators Grim and Hid, but the region of Reaper homologous to Grim/Hid is dispensable for Scythe binding. Cell-free Xenopus egg extract apoptosis assay, pulldown with purified mitochondria, competitive binding assays The EMBO journal High 10523293
2001 Scythe (BAG6) inhibits Hsp70-mediated protein refolding via its BAG-domain-related region; this inhibition is reversed by Reaper, demonstrating regulated, reversible control of chaperone activity. In vitro Hsp70 protein-refolding assay, recombinant protein binding The EMBO journal High 11230127
2001 Human Scythe (BAG6) contains a functional C-terminal nuclear localization sequence (NLS); mutation of the NLS results in complete nuclear exclusion, and Scythe remains in the nucleus during staurosporine-induced apoptosis. HA-tagged deletion mutant expression, indirect immunofluorescence, site-directed mutagenesis of NLS Biochemical and biophysical research communications Medium 11587531
2004 BAT3 (BAG6) is a caspase-3 substrate; ricin activates caspase-3 which cleaves BAT3 at a canonical DEQD site, releasing a C-terminal fragment (CTF-131) that induces phosphatidylserine exposure, cell rounding, and chromatin condensation; BAT3 silencing suppresses ricin-induced apoptosis. Yeast two-hybrid (identification), caspase-3 specific inhibitor zDEVD-fmk, caspase-3-deficient MCF-7 cells, site-directed mutagenesis, siRNA knockdown The Journal of biological chemistry High 14960581
2005 Xenopus Rpn10 isoform Xrpn10c acts as a specific receptor for Scythe (BAG6) at the 26S proteasome; deletional analysis identified at least two Scythe domains required for Xrpn10c binding; forced expression of a Scythe mutant lacking Xrpn10c-binding domains in Xenopus embryos induces inappropriate embryonic death. Co-immunoprecipitation, deletion mutant analysis, Xenopus embryo overexpression The FEBS journal Medium 16336274
2005 Scythe (BAT3) knockout mice die with defects in lung, kidney, and brain development associated with dysregulation of apoptosis and cellular proliferation; Scythe-/- cells are more resistant to menadione- and thapsigargin-induced apoptosis. Gene knockout in mouse, histopathology, apoptosis assays in primary cells Molecular and cellular biology High 16287848
2006 Human SGT (hSGT) interacts with BAG6/BAT3/Scythe and Hsp70/Hsc70 independently; both BAG6 knockdown and hSGT knockdown cause persistence of mislocalized chromosomes near spindle poles and mitotic arrest, implicating hSGT–BAG6 complexes in chromosome congression. Co-immunoprecipitation/mass spectrometry, RNAi knockdown, live-cell imaging with histone H2A-YFP Experimental cell research Medium 16777091
2007 Bat3 (BAG6) forms a complex with p300 acetyltransferase and is essential for p300-mediated acetylation of p53 in response to DNA damage; Bat3 depletion abolishes p53 acetylation and impairs transcriptional activation of Puma and p21 without affecting p53 phosphorylation or stabilization; Bat3-deficient thymocytes are resistant to DNA damage-induced apoptosis in vivo. Co-immunoprecipitation, siRNA/shRNA knockdown, p53 acetylation assays, Bat3-/- mouse thymocytes, transactivation reporter assay Genes & development High 17403783
2007 Scythe (BAG6) N-terminus interacts with XEF1AO (Xenopus EF1A maternal form) and promotes its polyubiquitination and proteasomal degradation; immunodepletion of Scythe from embryonic extracts stabilizes XEF1AO; Scythe overexpression suppresses XEF1AO-induced apoptosis. Co-immunoprecipitation, immunodepletion from embryonic extracts, ubiquitination assay, overexpression in Xenopus The Biochemical journal Medium 17428197
2007 Scythe (BAT3/BAG6) physically interacts with AIF (apoptosis-inducing factor) and regulates its stability; AIF protein levels are markedly reduced in Scythe-/- cells, which show resistance to ER stress-induced apoptosis; reintroduction of Scythe or AIF overexpression restores apoptotic sensitivity. Co-immunoprecipitation, Scythe-/- mouse embryonic cells, AIF protein stability assay, rescue experiments The Journal of biological chemistry High 18056262
2008 BAT3 (BAG6) interacts with both TGF-β receptor type I and type II in renal mesangial cells; full-length BAT3 (but not a C-terminal truncation mutant) enhances TGF-β1-stimulated transcriptional activation and type I collagen expression; BAT3 knockdown suppresses TGF-β1-induced type I collagen. Yeast two-hybrid, co-immunoprecipitation with endogenous proteins, transcriptional reporter assay, siRNA knockdown, truncation mutant analysis The Journal of biological chemistry Medium 18487607
2008 Bat3 (BAG6) deficiency in male germ cells causes polyubiquitylation and proteasomal degradation of testis-specific Hsp70-2/HspA2; inhibition of proteasomal degradation restores Hsp70-2 levels; Bat3 conditional KO results in apoptosis of meiotic germ cells and male infertility with abnormal synaptonemal complex assembly. Conditional Bat3 KO mice, ubiquitination assay, proteasome inhibitor rescue, immunofluorescence for SYCP3/γ-H2AX/Rad51 The Journal of cell biology High 18678708
2009 BAG6 is required for accumulation of HSP70 upon heat shock; conversely, once HSP70 accumulates, it drives CHIP-independent proteasomal degradation of BAG6 via the ubiquitin-proteasome system, suggesting reciprocal regulation. siRNA knockdown, proteasome inhibitor treatment, immunoblotting in heat-shock conditions Cellular and molecular life sciences Medium 19357808
2010 BAG-6 is essential for ubiquitin-mediated degradation of defective proteasomal substrates including the CL1 model degron and puromycin-labeled nascent polypeptides; BAG-6 physically interacts with nascent chain polypeptides in vivo and in vitro; BAG-6 knockdown suppresses MHC class I surface presentation. BAG-6 knockdown, in vivo and in vitro interaction assays with puromycin-labeled nascent chains, proteasomal degradation assays, MHC class I surface staining The Journal of cell biology High 20713601
2010 Bat3 (BAG6) was identified as a cytosolic binding partner of Sec61β (a tail-anchored protein TRC40 substrate); Bat3 depletion inhibits membrane integration of Sec61β but not of the TRC40-independent tail-anchored protein cytochrome b5; in yeast lacking GET pathway, Bat3 associates with cytosolic non-targeted tail-anchored chains and diverts them to the nucleus. Co-immunoprecipitation, siRNA depletion, in vitro membrane integration assay, heterologous yeast expression Journal of cell science High 20516149
2010 The Legionella pneumophila F-box protein LegU1 forms a functional SCF E3 ubiquitin ligase complex and specifically interacts with and directs ubiquitination of the host chaperone BAT3 (BAG6); a second Legionella protein Lpg2160 also independently associates with BAT3. Co-immunoprecipitation in vivo, E3 ligase activity assay (SCF complex reconstitution), yeast two-hybrid screen Infection and immunity Medium 20547746
2012 Bat3 (BAG6) binds to the intracellular tail of Tim-3 and represses Tim-3 function; Bat3-deficient T cells show elevated exhaustion markers (Tim-3, Lag3, Prdm1, Pbx3); Bat3 protects TH1 cells from galectin-9-mediated cell death and promotes proliferation and IFN-γ production. Co-immunoprecipitation, Bat3 knockdown in primary T cells, EAE mouse model, flow cytometry Nature medicine High 22863785
2012 Bat3 (BAG6) co-localizes with DOT1L at histone H3 and is essential for DOT1L-mediated H3K79 dimethylation; Bat3 knockdown reduces DOT1L-H3 interaction and H3K79-2Me, leading to defective IR-induced 53BP1 foci formation at G1/G2 phases, impaired DNA repair, and increased IR sensitivity; a conserved ubiquitin-like motif in Bat3 and a UIM in DOT1L mediate their interaction. Co-immunoprecipitation, ChIP, siRNA knockdown, immunofluorescence (53BP1 foci), comet assay, domain/motif mutagenesis The EMBO journal High 22373577
2012 SGTA contains a noncanonical ubiquitin-like-binding domain that interacts specifically with the unconventional UBL domain of Ubl4A (a BAG6-complex subunit) via electrostatic interactions, thereby recruiting SGTA to the BAG6 complex to enhance substrate loading and prevent nondegradable aggregate formation in ERAD. NMR spectroscopy, biochemical binding assays, ERAD substrate degradation assays Cell reports High 23246001
2012 SGTA actively promotes deubiquitination of mislocalized proteins (MLPs) already ubiquitinated via BAG6, reversing BAG6-dependent ubiquitination and inhibiting substrate degradation; this effect is independent of SGTA tetratricopeptide motifs (not requiring Hsp70/Hsp90); increasing SGTA stabilizes a model MLP derived from amyloid precursor protein. In vitro ubiquitination/deubiquitination assays, SGTA overexpression, MLP stability assays, domain truncation Proceedings of the National Academy of Sciences of the United States of America High 23129660
2012 Bat3 interacts with YWK-II/APLP2 via its proline-rich domain and enhances APLP2 stability by reducing ubiquitylation and proteasomal degradation; nuclear export of Bat3 under apoptotic stimulation elevates APLP2 protein levels, providing a mechanism that inhibits apoptosis. Co-immunoprecipitation, domain deletion analysis, ubiquitylation assay, subcellular fractionation Journal of cell science Medium 22641691
2012 BAT3 modulates macrophage apoptosis triggered by M. tuberculosis ESAT-6 protein; ESAT-6 induces transient BAT3 expression and release; ESAT-6-induced apoptosis depends on caspase-3 cleavage of BAT3 and proteasomal degradation; BAT3 regulates this process by interacting with anti-apoptotic BCL-2. Co-immunoprecipitation (BAT3–BCL-2), caspase inhibitor treatment, macrophage knockdown/overexpression, cytokine assays PloS one Medium 22808273
2013 Nuclear BAG6-UBL4A-GET4 complex mediates DNA damage response signaling and cell death; BAG6 depletion causes loss of both UBL4A and GET4 proteins; nuclear localization of BAG6 and its phosphorylation by ATM/ATR are required for cell killing; all three subunits regulate BRCA1 recruitment to DNA damage sites. siRNA depletion, ATM/ATR kinase assay, nuclear fractionation, BRCA1 foci immunofluorescence, clonogenic survival The Journal of biological chemistry Medium 23723067
2013 The BAG6 UBL domain is essential for binding to SGTA; a second subunit UBL4A's UBL competes with BAG6-UBL for SGTA binding; the large central proline-rich region of BAG6 (not the UBL or BAG domains) provides the binding site for tail-anchored substrates such as Sec61β. In vitro binding assays, truncation/deletion mutants, heterologous yeast subcellular localization assay PloS one Medium 23533635
2013 Bag6 is required not only for tail-anchored protein targeting but also for efficient 26S proteasome assembly; Bag6 directly associates with precursor regulatory particles (19S) to facilitate regulatory particle assembly. Proteasome assembly assays in TRC pathway-deficient cells, co-immunoprecipitation with precursor regulatory particles Nature communications Medium 23900548
2014 RNF126 is recruited to the N-terminal UBL domain of Bag6 and acts as the primary Bag6-dependent E3 ubiquitin ligase for mislocalized proteins; RNF126 preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients; Bag6-dependent ubiquitination was reconstituted with purified components. In vitro reconstitution with purified components, fractionation, siRNA depletion, ubiquitination assay, RNF126 domain mapping Molecular cell High 24981174
2014 A crystal structure of the BAG6–Ubl4A C-terminal dimer revealed that the BAG6 C-terminal domain is not a canonical BAG domain; both TRC35 and Ubl4A have distinct C-terminal binding sites on BAG6; the minimal BAG6 complex (BAG6+TRC35+Ubl4A) facilitates tail-anchored substrate transfer from SGTα to TRC40. X-ray crystallography, biochemical binding assays, in vitro TA protein transfer assay Proceedings of the National Academy of Sciences of the United States of America High 25535373
2014 BAT3/BAG6 modulates autophagy through regulation of p300 nuclear localization: BAT3 increases p300-dependent p53 acetylation and pro-autophagic target gene expression while limiting p300-dependent acetylation of ATG7 (an autophagy inhibitor); cytosol-restricted BAT3 mutants abrogate autophagy; BAT3 interaction with p300 is stronger in cytoplasm than nucleus. BAT3-/- mouse embryos and MEFs, co-immunoprecipitation, acetylation assays, autophagy flux assays (LC3-II, p62), cytoplasm-restricted BAT3 mutant Proceedings of the National Academy of Sciences of the United States of America High 24591579
2014 BAG6 promotes degradation of the polytopic ERAD substrate OpD; BAG6 knockdown reduces OpD polyubiquitylation while BAG6 overexpression increases polyubiquitylated OpD but paradoxically delays degradation, suggesting BAG6 is needed for delivery to the proteasome after ubiquitination; the UBL and BAG domains are dispensable for OpD stabilisation by overexpressed BAG6. BAG6 siRNA knockdown, BAG6 overexpression, polyubiquitylation assays, cycloheximide chase Journal of cell science Medium 24806960
2015 Crystal structure of BAG6–Ubl4a C-terminal heterodimerization domains revealed that the BAG6 C-terminus (designated BAGS domain) is structurally and functionally distinct from canonical BAG domains; BAG6–Ubl4a interaction modulates Ubl4a protein stability in cells. X-ray crystallography, biochemical interaction assays, cell-based stability assays The Journal of biological chemistry High 25713138
2015 BAG6 contains an evolutionarily conserved N-terminal island designated the BAG6 ubiquitin-linked (ULD) domain; partial deletion of this domain abolishes recognition of polyubiquitinated polypeptides and hydrophobicity-mediated recognition of the CL1 degron both in cells and in vitro. Deletion mutant analysis, in vitro binding assay, cell-based substrate recognition assay The FEBS journal Medium 26663859
2015 BAG6 co-localizes with HSPA2 (HspA2) in human testicular germ cells and spermatozoa; protein-protein interaction assays demonstrate stable BAG6–HSPA2 interaction in mature spermatozoa; BAG6 undergoes capacitation-induced relocation in human sperm; infertile men with zona pellucida binding defects show concomitant deficiency in both BAG6 and HSPA2. Co-localization (immunofluorescence), protein-protein interaction (co-IP/pulldown), human infertility patient samples Molecular human reproduction Medium 26153132
2017 Crystal structure of the BAG6–TRC35 complex revealed that TRC35 occludes the BAG6 nuclear localization sequence from karyopherin α, retaining BAG6 in the cytosol; TRC35 binding also protects TRC35 from RNF126-mediated ubiquitylation and degradation. X-ray crystallography, biochemical binding assays (karyopherin α interaction), ubiquitylation assay Proceedings of the National Academy of Sciences of the United States of America High 29042515
2018 UBXN1 is the VCP adaptor that specifically links the VCP unfoldase to ubiquitylated BAG6 clients prior to ER translocation (but not during ERAD); VCP-UBXN1 loss causes inappropriate stabilization of ubiquitylated BAG6 clients and their accumulation in insoluble aggregates. Co-immunoprecipitation, siRNA depletion of UBXN1/VCP, solubility fractionation, aggregation assay, proteasomal degradation assay Molecular and cellular biology Medium 29685906
2019 BAG6 preferentially recognizes GDP-bound (inactive) Rab8a via hydrophobic residues of its Switch I region, promotes ubiquitin-proteasome-mediated degradation of GDP-Rab8a, and prevents excess accumulation of inactive Rab8a that would impair vesicle trafficking; BAG6 also binds other Rab family members and is required for correct Golgi and endosomal marker distribution. Co-immunoprecipitation with GTP/GDP-loaded Rab8a mutants, BAG6 siRNA knockdown, Switch I mutagenesis, Golgi/endosomal marker localization EMBO reports Medium 30804014
2019 BAG6 depletion in melanoma cells switches exosome cargo: BAG6/CBP/p300-dependent p53 acetylation followed by recruitment of ESCRT machinery via a P(S/T)AP double motif in BAG6 is required for anti-tumor EV formation; BAG6 ablation causes release of a distinct EV subtype that fails to suppress metastasis and recruits tumor-promoting neutrophils. BAG6 knockout (B-16V cells), EV mass spectrometry and RNAseq, in vivo melanoma transplantation model, p53 acetylation assay Theranostics Medium 31534536
2020 BAG6 is localized to mitochondria under basal conditions and translocates to the outer mitochondrial membrane upon depolarization; BAG6 interacts with PINK1 and overexpression decreases PINK1 half-life; chronic MPP+ treatment up-regulates BAG6, which accelerates PINK1 degradation; BAG6 knockdown prevents MPP+-induced PINK1 loss and rescues mitochondrial defects. Subcellular fractionation, co-immunoprecipitation (BAG6-PINK1), BAG6 overexpression/siRNA, half-life assay, neuronal morphology assay The Journal of biological chemistry Medium 32332095
2021 Bat3 acts as a mTORC2 inhibitor in T cells; Bat3 deficiency increases Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression and T cell exhaustion; transcriptional analysis of Bat3-/- T cells shows up-regulation of dysfunction-associated and down-regulation of effector genes. Bat3 KO mouse T cells, mTORC2/Akt phosphorylation assays, RNA-seq, EAE and tumor models Science advances Medium 33931442
2021 BAG6 contains two LIR (LC3-interacting Region) domains; cleaved N-terminal BAG6 localizes to the cytosol and interacts with LC3B-I and unprocessed Pro-LC3B through the LIR1 motif to suppress autophagy; NMR verified the direct BAG6 LIR1–LC3B interaction; LIR mutagenesis abolishes BAG6-mediated autophagy suppression. NMR spectroscopy, co-immunoprecipitation, LIR site-directed mutagenesis, autophagy flux assay iScience High 33241194
2021 BAG6 is localized in the mitochondrial matrix under basal conditions and translocates to the outer mitochondrial membrane after mitophagy induction; BAG6 deletion abrogates PINK1 accumulation and mitophagy; ectopic BAG6 expression induces PINK1/PARKIN pathway activation and phospho-ubiquitination of mitochondrial proteins; BAG6 requires wild-type LIR domains for mitophagy stimulation. Mitochondrial fractionation, BAG6 KO cell lines, BAG6 ectopic expression in BAG6-null LoVo cells, PINK1/PARKIN pathway assays, LIR site-directed mutagenesis FASEB journal Medium 33522017
2022 BAG6 functions as a sensor of proteolytic fragments bearing exposed hydrophobicity (including C-terminal TDP43 fragments) and prevents their intracellular aggregation; BAG6 facilitates ubiquitylation of TDP43 fragments by recruiting RNF126; in BAG6-deficient cells, TDP43 fragments form intracellular aggregates. BAG6 KO cells, aggregation assay (solubility fractionation), Co-immunoprecipitation (BAG6-RNF126), ubiquitylation assay iScience Medium 35542047
2022 Bat3 loss in dendritic cells leads to hyperactive unfolded protein response and redirection of acetyl-CoA toward increased steroidogenesis; enhanced DC-intrinsic steroidogenesis suppresses T cell responses in a paracrine manner, establishing Bat3 as an endogenous regulator of DC functional calibration. DC-specific Bat3 KO mouse models (EAE and tumor), metabolomic analysis (acetyl-CoA/steroid), paracrine T cell suppression assays Science immunology Medium 35275752
2024 BAG6 restricts pancreatic cancer progression by suppressing release of IL33-presenting extracellular vesicles; Bag6-deficient PDAC cells release EVs that carry IL33 and activate mast cells via IL33/Il1rl1 signaling; activated mast cells secrete PDGF and CD73, promote tumor proliferation, and shift fibroblasts to an inflammatory CAF phenotype. Cre/LoxP reporter + scRNA-seq (in vivo EV tracking), Bag6 KO mouse PDAC models (subcutaneous and orthotopic), human organoids, patient samples Cellular & molecular immunology Medium 38942797

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion. Nature medicine 335 22863785
2001 HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis. Journal of immunology (Baltimore, Md. : 1950) 287 11290782
2013 Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocrine-related cancer 262 23845449
2014 Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Molecular cell 153 24981174
2004 Versican/PG-M G3 domain promotes tumor growth and angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 151 14766798
2016 Aspartyl Protease-Mediated Cleavage of BAG6 Is Necessary for Autophagy and Fungal Resistance in Plants. The Plant cell 144 26739014
2018 Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC. Cell death & disease 137 29706626
2010 BAG-6 is essential for selective elimination of defective proteasomal substrates. The Journal of cell biology 124 20713601
2019 Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocrine-related cancer 122 30540557
1998 Scythe: a novel reaper-binding apoptotic regulator. The EMBO journal 113 9799223
2007 HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. Genes & development 111 17403783
2010 Bat3 promotes the membrane integration of tail-anchored proteins. Journal of cell science 107 20516149
2010 E3 ubiquitin ligase activity and targeting of BAT3 by multiple Legionella pneumophila translocated substrates. Infection and immunity 104 20547746
2004 HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy? European journal of cancer (Oxford, England : 1990) 97 14687790
2012 Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases. The EMBO journal 95 22373577
2020 PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Endocrine-related cancer 87 31846429
2001 Reversible inhibition of Hsp70 chaperone function by Scythe and Reaper. The EMBO journal 87 11230127
2012 SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation. Cell reports 80 23246001
2014 Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain. Proceedings of the National Academy of Sciences of the United States of America 79 25535373
2005 The reaper-binding protein scythe modulates apoptosis and proliferation during mammalian development. Molecular and cellular biology 78 16287848
2014 BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy. Proceedings of the National Academy of Sciences of the United States of America 76 24591579
2012 BAG6/BAT3: emerging roles in quality control for nascent polypeptides. Journal of biochemistry 75 23275523
2012 SGTA antagonizes BAG6-mediated protein triage. Proceedings of the National Academy of Sciences of the United States of America 73 23129660
2010 G3.5 PAMAM dendrimers enhance transepithelial transport of SN38 while minimizing gastrointestinal toxicity. Journal of controlled release : official journal of the Controlled Release Society 68 21115079
2018 Distinguishing Echinococcus granulosus sensu stricto genotypes G1 and G3 with confidence: A practical guide. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 66 29936039
2007 Scythe regulates apoptosis-inducing factor stability during endoplasmic reticulum stress-induced apoptosis. The Journal of biological chemistry 66 18056262
1999 Reaper-induced dissociation of a Scythe-sequestered cytochrome c-releasing activity. The EMBO journal 65 10523293
2013 Bag6/Bat3/Scythe: a novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation. BioEssays : news and reviews in molecular, cellular and developmental biology 63 23417671
2004 Ricin triggers apoptotic morphological changes through caspase-3 cleavage of BAT3. The Journal of biological chemistry 61 14960581
2019 Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53. Theranostics 59 31534536
2010 Versican G3 promotes mouse mammary tumor cell growth, migration, and metastasis by influencing EGF receptor signaling. PloS one 58 21079779
2006 Human SGT interacts with Bag-6/Bat-3/Scythe and cells with reduced levels of either protein display persistence of few misaligned chromosomes and mitotic arrest. Experimental cell research 58 16777091
2017 Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers. Digestion 56 28161703
2013 BAG-6, a jack of all trades in health and disease. Cellular and molecular life sciences : CMLS 55 24305946
2017 Everolimus in Pancreatic Neuroendocrine Carcinomas G3. Pancreas 48 28099254
2008 Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis. The Journal of cell biology 47 18678708
2022 Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function. Science immunology 46 35275752
2021 An analysis of 130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis, and diagnostic features. Virchows Archiv : an international journal of pathology 45 34499237
2012 Effect of polyamidoamine dendrimer G3 and G4 on skin permeation of 8-methoxypsoralene--in vivo study. International journal of pharmaceutics 45 22310461
2001 Human Scythe contains a functional nuclear localization sequence and remains in the nucleus during staurosporine-induced apoptosis. Biochemical and biophysical research communications 44 11587531
2015 Novel characterization of the HSPA2-stabilizing protein BAG6 in human spermatozoa. Molecular human reproduction 42 26153132
2008 Scythe/BAT3 regulates apoptotic cell death induced by papillomavirus binding factor in human osteosarcoma. Cancer science 42 19018758
2005 Unique proteasome subunit Xrpn10c is a specific receptor for the antiapoptotic ubiquitin-like protein Scythe. The FEBS journal 41 16336274
2001 The possible use of HLA-G1 and G3 in the inhibition of NK cell-mediated swine endothelial cell lysis. Clinical and experimental immunology 41 11678914
1994 M12 protein from Streptococcus pyogenes is a receptor for immunoglobulin G3 and human albumin. Infection and immunity 41 8188363
2019 Whole-gene analysis of inter-genogroup reassortant rotaviruses from the Dominican Republic: Emergence of equine-like G3 strains and evidence of their reassortment with locally-circulating strains. Virology 40 31228725
2021 Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion. Science advances 39 33931442
2013 The association of BAG6 with SGTA and tail-anchored proteins. PloS one 39 23533635
2008 BAT3 interacts with transforming growth factor-beta (TGF-beta) receptors and enhances TGF-beta1-induced type I collagen expression in mesangial cells. The Journal of biological chemistry 38 18487607
2014 BAG6/BAT3 modulates autophagy by affecting EP300/p300 intracellular localization. Autophagy 37 24852146
2012 BAT3 regulates Mycobacterium tuberculosis protein ESAT-6-mediated apoptosis of macrophages. PloS one 37 22808273
2020 Echinococcus granulosus (sensu stricto) (G1, G3) and E. ortleppi (G5) in Pakistan: phylogeny, genetic diversity and population structural analysis based on mitochondrial DNA. Parasites & vectors 35 32660553
2013 Nuclear BAG6-UBL4A-GET4 complex mediates DNA damage signaling and cell death. The Journal of biological chemistry 35 23723067
2009 Sequential interplay between BAG6 and HSP70 upon heat shock. Cellular and molecular life sciences : CMLS 34 19357808
2014 A role for the TIM-3/GAL-9/BAT3 pathway in determining the clinical phenotype of multiple sclerosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 25091272
2012 The role of versican G3 domain in regulating breast cancer cell motility including effects on osteoblast cell growth and differentiation in vitro - evaluation towards understanding breast cancer cell bone metastasis. BMC cancer 33 22862967
2011 A novel interaction between CCaMK and a protein containing the Scythe_N ubiquitin-like domain in Lotus japonicus. Plant physiology 33 21209278
2015 G3-C12 Peptide Reverses Galectin-3 from Foe to Friend for Active Targeting Cancer Treatment. Molecular pharmaceutics 31 26393405
2014 BAG6 regulates the quality control of a polytopic ERAD substrate. Journal of cell science 31 24806960
2011 Versican G3 domain modulates breast cancer cell apoptosis: a mechanism for breast cancer cell response to chemotherapy and EGFR therapy. PloS one 31 22096483
2000 Role of the C-terminal G3 domain in sorting and secretion of aggrecan core protein and ubiquitin-mediated degradation of accumulated mutant precursors. The Journal of biological chemistry 31 11063750
2021 Gastroenteropancreatic neuroendocrine neoplasms G3: Novel insights and unmet needs. Biochimica et biophysica acta. Reviews on cancer 30 34678439
2016 Management of neuroendocrine carcinomas of the pancreas (WHO G3): A tailored approach between proliferation and morphology. World journal of gastroenterology 30 28018101
2019 Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3. Scientific reports 29 31253840
2019 Cytoplasmic control of Rab family small GTPases through BAG6. EMBO reports 28 30804014
2015 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. The Journal of biological chemistry 28 25713138
2012 Frequency of group A rotavirus with mixed G and P genotypes in bovines: predominance of G3 genotype and its emergence in combination with G8/G10 types. Journal of veterinary science 28 23006956
2007 Scythe regulates apoptosis through modulating ubiquitin-mediated proteolysis of the Xenopus elongation factor XEF1AO. The Biochemical journal 28 17428197
2023 SlERF.G3-Like mediates a hierarchical transcriptional cascade to regulate ripening and metabolic changes in tomato fruit. Plant biotechnology journal 27 37750661
2018 The VCP-UBXN1 Complex Mediates Triage of Ubiquitylated Cytosolic Proteins Bound to the BAG6 Complex. Molecular and cellular biology 27 29685906
2015 A conserved island of BAG6/Scythe is related to ubiquitin domains and participates in short hydrophobicity recognition. The FEBS journal 27 26663859
2024 Rapid Evolution of Metastases in Patients with Treated G3 Neuroendocrine Tumors Associated with NEC-Like Transformation and TP53 Mutation. Endocrine pathology 26 39382626
2023 Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review. Journal of clinical medicine 26 36675645
2019 The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase. Nucleic acids research 26 30952159
2016 The Ep152R ORF of African swine fever virus strain Georgia encodes for an essential gene that interacts with host protein BAG6. Virus research 26 27497620
2013 Involvement of Bag6 and the TRC pathway in proteasome assembly. Nature communications 26 23900548
2011 Interaction between the G3 and L5 proteins of the vaccinia virus entry-fusion complex. Virology 26 21295816
2023 G3'MTMD3 in the insect GABA receptor subunit, RDL, confers resistance to broflanilide and fluralaner. PLoS genetics 25 37384781
2019 Comparison of tumor‑targeting properties of directly and indirectly radioiodinated designed ankyrin repeat protein (DARPin) G3 variants for molecular imaging of HER2. International journal of oncology 25 30968147
2013 The C-type lectin of the aggrecan G3 domain activates complement. PloS one 25 23596522
2003 Versican G3 domain enhances cellular adhesion and proliferation of bovine intervertebral disc cells cultured in vitro. Life sciences 25 14572881
2015 Association of the FAM46A gene VNTRs and BAG6 rs3117582 SNP with non small cell lung cancer (NSCLC) in Croatian and Norwegian populations. PloS one 24 25884493
2012 Fibroblasts prepared from different types of malignant tumors stimulate expression of luminal marker keratin 8 in the EM-G3 breast cancer cell line. Histochemistry and cell biology 24 22270320
2022 BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43. iScience 23 35542047
2021 Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles. International journal of molecular sciences 23 33671836
2021 Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort. Scientific reports 23 34504148
2020 Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2-associated athanogene 6 (BAG6). The Journal of biological chemistry 23 32332095
2018 The roles of cytosolic quality control proteins, SGTA and the BAG6 complex, in disease. Advances in protein chemistry and structural biology 23 30635083
2019 Indirect Radioiodination of DARPin G3 Using N-succinimidyl-Para-Iodobenzoate Improves the Contrast of HER2 Molecular Imaging. International journal of molecular sciences 22 31234471
2012 Regulation of apoptosis by Bat3-enhanced YWK-II/APLP2 protein stability. Journal of cell science 22 22641691
2024 Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion. International journal of molecular sciences 21 38673831
2021 BAG6 promotes PINK1 signaling pathway and is essential for mitophagy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 33522017
2014 Susceptibility to large-joint osteoarthritis (hip and knee) is associated with BAG6 rs3117582 SNP and the VNTR polymorphism in the second exon of the FAM46A gene on chromosome 6. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 21 25231575
2011 Versican G1 and G3 domains are upregulated and latent transforming growth factor-β binding protein-4 is downregulated in breast cancer stroma. Breast cancer (Tokyo, Japan) 21 21505857
2009 Components and properties of the G3 ganglion cell circuit in the rabbit retina. The Journal of comparative neurology 21 19107780
2024 BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells. Cellular & molecular immunology 20 38942797
2020 Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 20 32891532
2020 The Chaperone BAG6 Regulates Cellular Homeostasis between Autophagy and Apoptosis by Holding LC3B. iScience 19 33241194
2017 Structural basis for regulation of the nucleo-cytoplasmic distribution of Bag6 by TRC35. Proceedings of the National Academy of Sciences of the United States of America 19 29042515
1999 Cloning and characterization of rat BAT3 cDNA. DNA and cell biology 19 10390159

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