{"gene":"BAG6","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1998,"finding":"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.","method":"Protein purification from Xenopus egg extracts, immunodepletion, truncation mutant expression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein, immunodepletion, and domain-deletion mutagenesis in a single rigorous study","pmids":["9799223"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Cell-free Xenopus egg extract apoptosis assay, pulldown with purified mitochondria, competitive binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified mitochondria, cell-free extract, multiple binding partners tested with controls","pmids":["10523293"],"is_preprint":false},{"year":2001,"finding":"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.","method":"In vitro Hsp70 protein-refolding assay, recombinant protein binding","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro chaperone assay with reconstituted components, mechanistic reversal by Reaper demonstrated","pmids":["11230127"],"is_preprint":false},{"year":2001,"finding":"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.","method":"HA-tagged deletion mutant expression, indirect immunofluorescence, site-directed mutagenesis of NLS","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with NLS mutagenesis, single lab","pmids":["11587531"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Yeast two-hybrid (identification), caspase-3 specific inhibitor zDEVD-fmk, caspase-3-deficient MCF-7 cells, site-directed mutagenesis, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — cleavage site mutagenesis, genetic (caspase-3-deficient cells), inhibitor, and knockdown experiments with multiple orthogonal methods in one study","pmids":["14960581"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Co-immunoprecipitation, deletion mutant analysis, Xenopus embryo overexpression","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with deletion mapping, in vivo embryo validation, single lab","pmids":["16336274"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Gene knockout in mouse, histopathology, apoptosis assays in primary cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mouse KO with defined developmental and apoptosis phenotypes","pmids":["16287848"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation/mass spectrometry, RNAi knockdown, live-cell imaging with histone H2A-YFP","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed interaction, RNAi with live imaging phenotype, single lab","pmids":["16777091"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, siRNA/shRNA knockdown, p53 acetylation assays, Bat3-/- mouse thymocytes, transactivation reporter assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO mice, multiple cell types, orthogonal biochemical and functional readouts","pmids":["17403783"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, immunodepletion from embryonic extracts, ubiquitination assay, overexpression in Xenopus","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunodepletion in embryo extracts, ubiquitination assay, single lab","pmids":["17428197"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, Scythe-/- mouse embryonic cells, AIF protein stability assay, rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus Co-IP plus rescue in multiple conditions","pmids":["18056262"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation with endogenous proteins, transcriptional reporter assay, siRNA knockdown, truncation mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by endogenous Co-IP, functional domain mapping, siRNA; single lab","pmids":["18487607"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Conditional Bat3 KO mice, ubiquitination assay, proteasome inhibitor rescue, immunofluorescence for SYCP3/γ-H2AX/Rad51","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular mechanism (ubiquitination assay) and proteasome inhibitor rescue","pmids":["18678708"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown, proteasome inhibitor treatment, immunoblotting in heat-shock conditions","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with pharmacological inhibition, single lab, two orthogonal approaches","pmids":["19357808"],"is_preprint":false},{"year":2010,"finding":"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.","method":"BAG-6 knockdown, in vivo and in vitro interaction assays with puromycin-labeled nascent chains, proteasomal degradation assays, MHC class I surface staining","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo/in vitro interaction, degradation assay, KD with functional readout) in one study","pmids":["20713601"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, siRNA depletion, in vitro membrane integration assay, heterologous yeast expression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro membrane integration assay with depletion, pathway specificity shown by comparison with TRC40-independent substrate, single lab","pmids":["20516149"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation in vivo, E3 ligase activity assay (SCF complex reconstitution), yeast two-hybrid screen","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP and in vitro E3 ligase assay, single lab","pmids":["20547746"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, Bat3 knockdown in primary T cells, EAE mouse model, flow cytometry","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, KD with defined T cell phenotype, in vivo EAE model; replicated across conditions","pmids":["22863785"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, immunofluorescence (53BP1 foci), comet assay, domain/motif mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including ChIP, Co-IP, mutagenesis, and functional DNA repair readouts","pmids":["22373577"],"is_preprint":false},{"year":2012,"finding":"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.","method":"NMR spectroscopy, biochemical binding assays, ERAD substrate degradation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural determination combined with biochemical validation and functional ERAD assay","pmids":["23246001"],"is_preprint":false},{"year":2012,"finding":"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.","method":"In vitro ubiquitination/deubiquitination assays, SGTA overexpression, MLP stability assays, domain truncation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitination/deubiquitination cycle, domain mapping; single lab with multiple orthogonal methods","pmids":["23129660"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, domain deletion analysis, ubiquitylation assay, subcellular fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus ubiquitylation assay, single lab","pmids":["22641691"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation (BAT3–BCL-2), caspase inhibitor treatment, macrophage knockdown/overexpression, cytokine assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with functional siRNA KD and inhibitor, single lab","pmids":["22808273"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA depletion, ATM/ATR kinase assay, nuclear fractionation, BRCA1 foci immunofluorescence, clonogenic survival","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATM/ATR phosphorylation assay, BRCA1 foci, nuclear localization, single lab with multiple readouts","pmids":["23723067"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro binding assays, truncation/deletion mutants, heterologous yeast subcellular localization assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with domain mapping and heterologous yeast assay, single lab","pmids":["23533635"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Proteasome assembly assays in TRC pathway-deficient cells, co-immunoprecipitation with precursor regulatory particles","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assembly assay and direct interaction with precursor particles, single lab","pmids":["23900548"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro reconstitution with purified components, fractionation, siRNA depletion, ubiquitination assay, RNF126 domain mapping","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified proteins, domain mapping, siRNA KD with functional readout, multiple methods in one study","pmids":["24981174"],"is_preprint":false},{"year":2014,"finding":"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.","method":"X-ray crystallography, biochemical binding assays, in vitro TA protein transfer assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biochemical reconstitution of TA substrate transfer","pmids":["25535373"],"is_preprint":false},{"year":2014,"finding":"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.","method":"BAT3-/- mouse embryos and MEFs, co-immunoprecipitation, acetylation assays, autophagy flux assays (LC3-II, p62), cytoplasm-restricted BAT3 mutant","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, domain mutant, Co-IP, and multiple acetylation/autophagy readouts in one study","pmids":["24591579"],"is_preprint":false},{"year":2014,"finding":"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.","method":"BAG6 siRNA knockdown, BAG6 overexpression, polyubiquitylation assays, cycloheximide chase","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD and OE with mechanistically distinct outcomes, ubiquitylation assay, single lab","pmids":["24806960"],"is_preprint":false},{"year":2015,"finding":"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.","method":"X-ray crystallography, biochemical interaction assays, cell-based stability assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical and cellular validation","pmids":["25713138"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Deletion mutant analysis, in vitro binding assay, cell-based substrate recognition assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and cell-based domain deletion analysis, single lab","pmids":["26663859"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-localization (immunofluorescence), protein-protein interaction (co-IP/pulldown), human infertility patient samples","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct interaction assay and localization data, patient-cohort correlation; single lab","pmids":["26153132"],"is_preprint":false},{"year":2017,"finding":"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.","method":"X-ray crystallography, biochemical binding assays (karyopherin α interaction), ubiquitylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biochemical mechanism (NLS occlusion and ubiquitylation protection) demonstrated","pmids":["29042515"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, siRNA depletion of UBXN1/VCP, solubility fractionation, aggregation assay, proteasomal degradation assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and siRNA KD with fractionation/aggregation readout, pathway specificity demonstrated, single lab","pmids":["29685906"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation with GTP/GDP-loaded Rab8a mutants, BAG6 siRNA knockdown, Switch I mutagenesis, Golgi/endosomal marker localization","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain/nucleotide-state specificity shown by mutagenesis and Co-IP, functional organelle distribution assay, single lab","pmids":["30804014"],"is_preprint":false},{"year":2019,"finding":"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.","method":"BAG6 knockout (B-16V cells), EV mass spectrometry and RNAseq, in vivo melanoma transplantation model, p53 acetylation assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mass spectrometry cargo profiling and in vivo model; ESCRT motif implicated but mutagenesis not extensively described in abstract","pmids":["31534536"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Subcellular fractionation, co-immunoprecipitation (BAG6-PINK1), BAG6 overexpression/siRNA, half-life assay, neuronal morphology assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA and OE with functional rescue, subcellular localization; single lab","pmids":["32332095"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Bat3 KO mouse T cells, mTORC2/Akt phosphorylation assays, RNA-seq, EAE and tumor models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with pathway-specific kinase assays and transcriptomics, single lab","pmids":["33931442"],"is_preprint":false},{"year":2021,"finding":"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.","method":"NMR spectroscopy, co-immunoprecipitation, LIR site-directed mutagenesis, autophagy flux assay","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural validation plus mutagenesis and functional autophagy assay, single lab","pmids":["33241194"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Mitochondrial fractionation, BAG6 KO cell lines, BAG6 ectopic expression in BAG6-null LoVo cells, PINK1/PARKIN pathway assays, LIR site-directed mutagenesis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation, KO, OE in null cells, mutagenesis; single lab, two orthogonal approaches","pmids":["33522017"],"is_preprint":false},{"year":2022,"finding":"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.","method":"BAG6 KO cells, aggregation assay (solubility fractionation), Co-immunoprecipitation (BAG6-RNF126), ubiquitylation assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus Co-IP and ubiquitylation assay with aggregation readout; single lab","pmids":["35542047"],"is_preprint":false},{"year":2022,"finding":"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.","method":"DC-specific Bat3 KO mouse models (EAE and tumor), metabolomic analysis (acetyl-CoA/steroid), paracrine T cell suppression assays","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with metabolomic and functional paracrine assays; single lab","pmids":["35275752"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cre/LoxP reporter + scRNA-seq (in vivo EV tracking), Bag6 KO mouse PDAC models (subcutaneous and orthotopic), human organoids, patient samples","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo EV tracking system, scRNA-seq, multiple model systems; single lab","pmids":["38942797"],"is_preprint":false}],"current_model":"BAG6 (also known as BAT3/Scythe) is a multifunctional nuclear-cytoplasmic holdase/chaperone that, as part of a heterotrimeric complex with Ubl4A and TRC35/GET4, captures hydrophobic sequences on newly synthesized, mislocalized, or tail-anchored proteins to triage them toward ER membrane insertion (via TRC40), ubiquitin-proteasome degradation (recruiting E3 ligase RNF126 and the VCP-UBXN1 unfoldase), or aggregate prevention; in the nucleus BAG6 scaffolds p300-mediated acetylation of p53 (promoting DNA-damage responses and autophagy gene expression) and facilitates DOT1L-dependent H3K79 dimethylation required for 53BP1 recruitment; at the plasma membrane and in extracellular vesicles BAG6 serves as a ligand for the NKp30 NK-cell receptor; and as an adaptor it represses Tim-3 signaling in T cells and DCs, regulates PINK1 stability and mitophagy via LIR-domain-dependent LC3 interaction, and controls EV cargo loading through the BAG6/CBP/p300-p53 axis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9799223"],"confidence":"High","gaps":["Molecular identity of the sequestered apoptotic factor not defined","Human relevance untested at this stage"]},{"year":2001,"claim":"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","pmids":["11230127","11587531"],"confidence":"High","gaps":["Cellular substrates of the chaperone-modulating activity unknown","Regulation of nucleocytoplasmic partitioning unresolved"]},{"year":2005,"claim":"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","pmids":["16336274","16287848"],"confidence":"High","gaps":["Direct degradation substrates not yet identified","Mechanism connecting proteasome binding to development unclear"]},{"year":2007,"claim":"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","pmids":["17403783"],"confidence":"High","gaps":["How BAG6 enhances p300 catalysis structurally undefined","Relationship to cytosolic functions unclear"]},{"year":2008,"claim":"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","pmids":["18678708"],"confidence":"High","gaps":["Whether BAG6 directly shields HSPA2 from ubiquitination not resolved","E3 ligase involved not identified"]},{"year":2010,"claim":"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","pmids":["20713601","20516149"],"confidence":"High","gaps":["Identity of the responsible E3 ligase not yet known","Substrate-binding domain not yet mapped"]},{"year":2012,"claim":"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","pmids":["23246001","23129660","22863785","22373577"],"confidence":"High","gaps":["Coordination between cytosolic triage and nuclear/immune roles unclear","Structural basis of DOT1L interaction not solved"]},{"year":2014,"claim":"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","pmids":["24981174","25535373","24591579"],"confidence":"High","gaps":["How ubiquitylated clients are committed to degradation versus insertion not fully resolved","BAGS domain functional partners incompletely defined"]},{"year":2015,"claim":"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","pmids":["26663859","25713138"],"confidence":"High","gaps":["Structural basis of hydrophobicity sensing not directly visualized","Affinity hierarchy among competing clients unknown"]},{"year":2017,"claim":"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","pmids":["29042515"],"confidence":"High","gaps":["Signals that release BAG6 for nuclear import not defined","Dynamics of partitioning in vivo not measured"]},{"year":2018,"claim":"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","pmids":["29685906"],"confidence":"Medium","gaps":["Single lab without structural validation of the VCP-UBXN1-BAG6 assembly","Substrate range requiring UBXN1 not delimited"]},{"year":2021,"claim":"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","pmids":["33241194","33522017","32332095"],"confidence":"Medium","gaps":["Reconciliation of BAG6 as both autophagy suppressor and mitophagy stimulator unresolved","Basal mitochondrial-matrix versus OMM localization mechanism unclear"]},{"year":2022,"claim":"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","pmids":["35542047","35275752"],"confidence":"Medium","gaps":["Whether fragment sensing is relevant to neurodegenerative disease untested","Mechanism linking BAG6 loss to UPR/steroidogenesis incompletely defined"]},{"year":2024,"claim":"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","pmids":["38942797"],"confidence":"Medium","gaps":["Direct mechanism by which BAG6 selects EV cargo not fully resolved","Generality across tumor types untested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model partitioning BAG6 pools across compartments","Regulatory signals switching between degradation, insertion, and aggregate-prevention fates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[26,41]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2,14,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[27,34,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,17,38]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[14,41]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,33,39]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,8,18,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[37,40]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[36,43]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,26,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,18,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[28,39,40]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,8,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,38,42]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[36,43]}],"complexes":["BAG6–Ubl4A–TRC35 (GET/TRC chaperone complex)"],"partners":["UBL4A","TRC35","SGTA","RNF126","UBXN1","EP300","DOT1L","HSPA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46379","full_name":"Large proline-rich protein BAG6","aliases":["BAG family molecular chaperone regulator 6","BCL2-associated athanogene 6","BAG-6","HLA-B-associated transcript 3","Protein G3","Protein Scythe"],"length_aa":1132,"mass_kda":119.4,"function":"ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins (PubMed:21636303). Functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client proteins in a soluble state and participates in their proper delivery to the endoplasmic reticulum or alternatively can promote their sorting to the proteasome where they undergo degradation (PubMed:20516149, PubMed:21636303, PubMed:21743475, PubMed:28104892). The BAG6/BAT3 complex is involved in the post-translational delivery of tail-anchored/type II transmembrane proteins to the endoplasmic reticulum membrane. Recruited to ribosomes, it interacts with the transmembrane region of newly synthesized tail-anchored proteins and together with SGTA and ASNA1 mediates their delivery to the endoplasmic reticulum (PubMed:20516149, PubMed:20676083, PubMed:25535373, PubMed:28104892). Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated by RNF126, an E3 ubiquitin-protein ligase associated with BAG6 and are sorted to the proteasome (PubMed:24981174, PubMed:27193484, PubMed:28104892). SGTA which prevents the recruitment of RNF126 to BAG6 may negatively regulate the ubiquitination and the proteasomal degradation of client proteins (PubMed:23129660, PubMed:25179605, PubMed:27193484). Similarly, the BAG6/BAT3 complex also functions as a sorting platform for proteins of the secretory pathway that are mislocalized to the cytosol either delivering them to the proteasome for degradation or to the endoplasmic reticulum (PubMed:21743475). The BAG6/BAT3 complex also plays a role in the endoplasmic reticulum-associated degradation (ERAD), a quality control mechanism that eliminates unwanted proteins of the endoplasmic reticulum through their retrotranslocation to the cytosol and their targeting to the proteasome. It maintains these retrotranslocated proteins in an unfolded yet soluble state condition in the cytosol to ensure their proper delivery to the proteasome (PubMed:21636303). BAG6 is also required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, it may participate in the production of antigenic peptides and play a role in antigen presentation in immune response (By similarity). BAG6 is also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation. BAG6 may ensure the proper degradation of these proteins and thereby protects the endoplasmic reticulum from protein overload upon stress (PubMed:26565908). By inhibiting the polyubiquitination and subsequent proteasomal degradation of HSPA2 it may also play a role in the assembly of the synaptonemal complex during spermatogenesis (By similarity). Also positively regulates apoptosis by interacting with and stabilizing the proapoptotic factor AIFM1 (By similarity). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333) Involved in DNA damage-induced apoptosis: following DNA damage, accumulates in the nucleus and forms a complex with p300/EP300, enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase p53/TP53 transcriptional activity (PubMed:17403783). When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 'Lys-4' dimethylation (H3K4me2) (PubMed:18765639) Released extracellularly via exosomes, it is a ligand of the natural killer/NK cells receptor NCR3 and stimulates NK cells cytotoxicity. It may thereby trigger NK cells cytotoxicity against neighboring tumor cells and immature myeloid dendritic cells (DC) Mediates ricin-induced apoptosis","subcellular_location":"Cytoplasm, cytosol; Nucleus; Secreted, extracellular exosome","url":"https://www.uniprot.org/uniprotkb/P46379/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BAG6","classification":"Not Classified","n_dependent_lines":46,"n_total_lines":1208,"dependency_fraction":0.0380794701986755},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000204463","cell_line_id":"CID000009","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"GET4","stoichiometry":10.0},{"gene":"BAG6;BAT3","stoichiometry":10.0},{"gene":"RNF126","stoichiometry":4.0},{"gene":"UBL4A","stoichiometry":4.0},{"gene":"DYNC1H1","stoichiometry":0.2},{"gene":"ERLIN2","stoichiometry":0.2},{"gene":"ERLIN1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000009","total_profiled":1310},"omim":[{"mim_id":"620200","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIy; CDG2Y","url":"https://www.omim.org/entry/620200"},{"mim_id":"612056","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 4; GET4","url":"https://www.omim.org/entry/612056"},{"mim_id":"603419","title":"SMALL GLUTAMINE-RICH TETRATRICOPEPTIDE REPEAT-CONTAINING COCHAPERONE, ALPHA; SGTA","url":"https://www.omim.org/entry/603419"},{"mim_id":"601913","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 3, ATPase; GET3","url":"https://www.omim.org/entry/601913"},{"mim_id":"601118","title":"CALCIUM-MODULATING LIGAND; CAMLG","url":"https://www.omim.org/entry/601118"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BAG6"},"hgnc":{"alias_symbol":["G3","D6S52E","Scythe"],"prev_symbol":["BAT3"]},"alphafold":{"accession":"P46379","domains":[{"cath_id":"3.10.20.90","chopping":"17-87","consensus_level":"high","plddt":90.4731,"start":17,"end":87},{"cath_id":"-","chopping":"164-180_269-364","consensus_level":"high","plddt":87.1659,"start":164,"end":364},{"cath_id":"-","chopping":"774-939","consensus_level":"high","plddt":86.9984,"start":774,"end":939},{"cath_id":"-","chopping":"1078-1132","consensus_level":"medium","plddt":75.9133,"start":1078,"end":1132}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46379","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46379-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46379-F1-predicted_aligned_error_v6.png","plddt_mean":56.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BAG6","jax_strain_url":"https://www.jax.org/strain/search?query=BAG6"},"sequence":{"accession":"P46379","fasta_url":"https://rest.uniprot.org/uniprotkb/P46379.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46379/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46379"}},"corpus_meta":[{"pmid":"22863785","id":"PMC_22863785","title":"Bat3 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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.\",\n      \"method\": \"Protein purification from Xenopus egg extracts, immunodepletion, truncation mutant expression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein, immunodepletion, and domain-deletion mutagenesis in a single rigorous study\",\n      \"pmids\": [\"9799223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-free Xenopus egg extract apoptosis assay, pulldown with purified mitochondria, competitive binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified mitochondria, cell-free extract, multiple binding partners tested with controls\",\n      \"pmids\": [\"10523293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro Hsp70 protein-refolding assay, recombinant protein binding\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro chaperone assay with reconstituted components, mechanistic reversal by Reaper demonstrated\",\n      \"pmids\": [\"11230127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"HA-tagged deletion mutant expression, indirect immunofluorescence, site-directed mutagenesis of NLS\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with NLS mutagenesis, single lab\",\n      \"pmids\": [\"11587531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid (identification), caspase-3 specific inhibitor zDEVD-fmk, caspase-3-deficient MCF-7 cells, site-directed mutagenesis, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cleavage site mutagenesis, genetic (caspase-3-deficient cells), inhibitor, and knockdown experiments with multiple orthogonal methods in one study\",\n      \"pmids\": [\"14960581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant analysis, Xenopus embryo overexpression\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with deletion mapping, in vivo embryo validation, single lab\",\n      \"pmids\": [\"16336274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Gene knockout in mouse, histopathology, apoptosis assays in primary cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mouse KO with defined developmental and apoptosis phenotypes\",\n      \"pmids\": [\"16287848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry, RNAi knockdown, live-cell imaging with histone H2A-YFP\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed interaction, RNAi with live imaging phenotype, single lab\",\n      \"pmids\": [\"16777091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, p53 acetylation assays, Bat3-/- mouse thymocytes, transactivation reporter assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO mice, multiple cell types, orthogonal biochemical and functional readouts\",\n      \"pmids\": [\"17403783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunodepletion from embryonic extracts, ubiquitination assay, overexpression in Xenopus\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunodepletion in embryo extracts, ubiquitination assay, single lab\",\n      \"pmids\": [\"17428197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Scythe-/- mouse embryonic cells, AIF protein stability assay, rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus Co-IP plus rescue in multiple conditions\",\n      \"pmids\": [\"18056262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation with endogenous proteins, transcriptional reporter assay, siRNA knockdown, truncation mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by endogenous Co-IP, functional domain mapping, siRNA; single lab\",\n      \"pmids\": [\"18487607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Bat3 KO mice, ubiquitination assay, proteasome inhibitor rescue, immunofluorescence for SYCP3/γ-H2AX/Rad51\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular mechanism (ubiquitination assay) and proteasome inhibitor rescue\",\n      \"pmids\": [\"18678708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, proteasome inhibitor treatment, immunoblotting in heat-shock conditions\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with pharmacological inhibition, single lab, two orthogonal approaches\",\n      \"pmids\": [\"19357808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"BAG-6 knockdown, in vivo and in vitro interaction assays with puromycin-labeled nascent chains, proteasomal degradation assays, MHC class I surface staining\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo/in vitro interaction, degradation assay, KD with functional readout) in one study\",\n      \"pmids\": [\"20713601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, in vitro membrane integration assay, heterologous yeast expression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro membrane integration assay with depletion, pathway specificity shown by comparison with TRC40-independent substrate, single lab\",\n      \"pmids\": [\"20516149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation in vivo, E3 ligase activity assay (SCF complex reconstitution), yeast two-hybrid screen\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP and in vitro E3 ligase assay, single lab\",\n      \"pmids\": [\"20547746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Bat3 knockdown in primary T cells, EAE mouse model, flow cytometry\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, KD with defined T cell phenotype, in vivo EAE model; replicated across conditions\",\n      \"pmids\": [\"22863785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, immunofluorescence (53BP1 foci), comet assay, domain/motif mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including ChIP, Co-IP, mutagenesis, and functional DNA repair readouts\",\n      \"pmids\": [\"22373577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"NMR spectroscopy, biochemical binding assays, ERAD substrate degradation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural determination combined with biochemical validation and functional ERAD assay\",\n      \"pmids\": [\"23246001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ubiquitination/deubiquitination assays, SGTA overexpression, MLP stability assays, domain truncation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitination/deubiquitination cycle, domain mapping; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23129660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, ubiquitylation assay, subcellular fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus ubiquitylation assay, single lab\",\n      \"pmids\": [\"22641691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (BAT3–BCL-2), caspase inhibitor treatment, macrophage knockdown/overexpression, cytokine assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with functional siRNA KD and inhibitor, single lab\",\n      \"pmids\": [\"22808273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA depletion, ATM/ATR kinase assay, nuclear fractionation, BRCA1 foci immunofluorescence, clonogenic survival\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATM/ATR phosphorylation assay, BRCA1 foci, nuclear localization, single lab with multiple readouts\",\n      \"pmids\": [\"23723067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays, truncation/deletion mutants, heterologous yeast subcellular localization assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with domain mapping and heterologous yeast assay, single lab\",\n      \"pmids\": [\"23533635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Proteasome assembly assays in TRC pathway-deficient cells, co-immunoprecipitation with precursor regulatory particles\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assembly assay and direct interaction with precursor particles, single lab\",\n      \"pmids\": [\"23900548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro reconstitution with purified components, fractionation, siRNA depletion, ubiquitination assay, RNF126 domain mapping\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified proteins, domain mapping, siRNA KD with functional readout, multiple methods in one study\",\n      \"pmids\": [\"24981174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, in vitro TA protein transfer assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biochemical reconstitution of TA substrate transfer\",\n      \"pmids\": [\"25535373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"BAT3-/- mouse embryos and MEFs, co-immunoprecipitation, acetylation assays, autophagy flux assays (LC3-II, p62), cytoplasm-restricted BAT3 mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, domain mutant, Co-IP, and multiple acetylation/autophagy readouts in one study\",\n      \"pmids\": [\"24591579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"BAG6 siRNA knockdown, BAG6 overexpression, polyubiquitylation assays, cycloheximide chase\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD and OE with mechanistically distinct outcomes, ubiquitylation assay, single lab\",\n      \"pmids\": [\"24806960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, biochemical interaction assays, cell-based stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical and cellular validation\",\n      \"pmids\": [\"25713138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Deletion mutant analysis, in vitro binding assay, cell-based substrate recognition assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and cell-based domain deletion analysis, single lab\",\n      \"pmids\": [\"26663859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-localization (immunofluorescence), protein-protein interaction (co-IP/pulldown), human infertility patient samples\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct interaction assay and localization data, patient-cohort correlation; single lab\",\n      \"pmids\": [\"26153132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays (karyopherin α interaction), ubiquitylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biochemical mechanism (NLS occlusion and ubiquitylation protection) demonstrated\",\n      \"pmids\": [\"29042515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion of UBXN1/VCP, solubility fractionation, aggregation assay, proteasomal degradation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and siRNA KD with fractionation/aggregation readout, pathway specificity demonstrated, single lab\",\n      \"pmids\": [\"29685906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation with GTP/GDP-loaded Rab8a mutants, BAG6 siRNA knockdown, Switch I mutagenesis, Golgi/endosomal marker localization\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain/nucleotide-state specificity shown by mutagenesis and Co-IP, functional organelle distribution assay, single lab\",\n      \"pmids\": [\"30804014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"BAG6 knockout (B-16V cells), EV mass spectrometry and RNAseq, in vivo melanoma transplantation model, p53 acetylation assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mass spectrometry cargo profiling and in vivo model; ESCRT motif implicated but mutagenesis not extensively described in abstract\",\n      \"pmids\": [\"31534536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation (BAG6-PINK1), BAG6 overexpression/siRNA, half-life assay, neuronal morphology assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA and OE with functional rescue, subcellular localization; single lab\",\n      \"pmids\": [\"32332095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Bat3 KO mouse T cells, mTORC2/Akt phosphorylation assays, RNA-seq, EAE and tumor models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with pathway-specific kinase assays and transcriptomics, single lab\",\n      \"pmids\": [\"33931442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"NMR spectroscopy, co-immunoprecipitation, LIR site-directed mutagenesis, autophagy flux assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural validation plus mutagenesis and functional autophagy assay, single lab\",\n      \"pmids\": [\"33241194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Mitochondrial fractionation, BAG6 KO cell lines, BAG6 ectopic expression in BAG6-null LoVo cells, PINK1/PARKIN pathway assays, LIR site-directed mutagenesis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation, KO, OE in null cells, mutagenesis; single lab, two orthogonal approaches\",\n      \"pmids\": [\"33522017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"BAG6 KO cells, aggregation assay (solubility fractionation), Co-immunoprecipitation (BAG6-RNF126), ubiquitylation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus Co-IP and ubiquitylation assay with aggregation readout; single lab\",\n      \"pmids\": [\"35542047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"DC-specific Bat3 KO mouse models (EAE and tumor), metabolomic analysis (acetyl-CoA/steroid), paracrine T cell suppression assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with metabolomic and functional paracrine assays; single lab\",\n      \"pmids\": [\"35275752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cre/LoxP reporter + scRNA-seq (in vivo EV tracking), Bag6 KO mouse PDAC models (subcutaneous and orthotopic), human organoids, patient samples\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo EV tracking system, scRNA-seq, multiple model systems; single lab\",\n      \"pmids\": [\"38942797\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAG6 (also known as BAT3/Scythe) is a multifunctional nuclear-cytoplasmic holdase/chaperone that, as part of a heterotrimeric complex with Ubl4A and TRC35/GET4, captures hydrophobic sequences on newly synthesized, mislocalized, or tail-anchored proteins to triage them toward ER membrane insertion (via TRC40), ubiquitin-proteasome degradation (recruiting E3 ligase RNF126 and the VCP-UBXN1 unfoldase), or aggregate prevention; in the nucleus BAG6 scaffolds p300-mediated acetylation of p53 (promoting DNA-damage responses and autophagy gene expression) and facilitates DOT1L-dependent H3K79 dimethylation required for 53BP1 recruitment; at the plasma membrane and in extracellular vesicles BAG6 serves as a ligand for the NKp30 NK-cell receptor; and as an adaptor it represses Tim-3 signaling in T cells and DCs, regulates PINK1 stability and mitophagy via LIR-domain-dependent LC3 interaction, and controls EV cargo loading through the BAG6/CBP/p300-p53 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#14, #15]. 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 Sec61\\u03b2, enabling their transfer from SGTA toward the TRC40 targeting pathway [#24, #27]. Substrate selection and fate are domain-partitioned: an N-terminal ubiquitin-like (ULD) domain mediates recognition of hydrophobic and polyubiquitinated clients [#31], the UBL domain recruits the E3 ligase RNF126, which preferentially ubiquitinates juxtahydrophobic lysines on BAG6-bound clients to drive degradation [#26], and the VCP adaptor UBXN1 then links the unfoldase to ubiquitylated clients prior to ER translocation, with its loss diverting clients into insoluble aggregates [#34]. BAG6 thereby protects cells from aggregation of orphaned fragments, including C-terminal TDP43 species, by coupling them to RNF126-dependent ubiquitylation [#41]. SGTA opposes this activity by promoting deubiquitination of BAG6-marked clients, and the SGTA\\u2013Ubl4A UBL interaction governs substrate loading [#19, #20]. BAG6 is partitioned between cytosol and nucleus: TRC35 occludes its nuclear localization signal to retain it in the cytosol [#33], while nuclear BAG6 scaffolds p300-mediated acetylation of p53 to drive DNA-damage gene expression [#8] and supports DOT1L-dependent H3K79 dimethylation required for 53BP1 recruitment and DNA repair [#18]. Genetic ablation produces developmental defects and altered apoptotic sensitivity in mice [#6], and conditional loss in germ cells destabilizes HSPA2 and causes meiotic failure and male infertility [#12]. BAG6 additionally regulates autophagy through control of p300 localization [#28] and engages LC3B via LIR motifs to influence autophagy and PINK1/PARKIN-dependent mitophagy [#39, #40], and in immune cells it represses Tim-3 and mTORC2 signaling to limit T-cell exhaustion [#17, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the founding function of BAG6/Scythe as an essential apoptotic regulator, raising the question of how it controls cell death.\",\n      \"evidence\": \"Protein purification from Xenopus egg extracts with immunodepletion and N-terminal truncation mutants\",\n      \"pmids\": [\"9799223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the sequestered apoptotic factor not defined\", \"Human relevance untested at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked BAG6 to chaperone regulation by showing it inhibits Hsp70 refolding in a Reaper-reversible manner, and defined its nuclear localization signal.\",\n      \"evidence\": \"In vitro Hsp70 refolding assays and NLS mutagenesis with immunofluorescence\",\n      \"pmids\": [\"11230127\", \"11587531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular substrates of the chaperone-modulating activity unknown\", \"Regulation of nucleocytoplasmic partitioning unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected BAG6 to the proteasome and to development, showing a proteasome receptor interaction and severe knockout phenotypes.\",\n      \"evidence\": \"Xenopus Rpn10c co-IP/deletion mapping and Bat3 knockout mouse histopathology with apoptosis assays\",\n      \"pmids\": [\"16336274\", \"16287848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct degradation substrates not yet identified\", \"Mechanism connecting proteasome binding to development unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined nuclear BAG6 as a p300 cofactor required for p53 acetylation, explaining its role in DNA-damage-induced apoptosis independent of p53 stabilization.\",\n      \"evidence\": \"Reciprocal Co-IP, p53 acetylation assays, and Bat3-/- thymocyte apoptosis assays\",\n      \"pmids\": [\"17403783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BAG6 enhances p300 catalysis structurally undefined\", \"Relationship to cytosolic functions unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed BAG6 as a regulator of client protein stability in germ cells, where its loss triggers ubiquitin-proteasome destruction of HSPA2 and meiotic failure.\",\n      \"evidence\": \"Conditional Bat3 KO mice with ubiquitination assays and proteasome-inhibitor rescue\",\n      \"pmids\": [\"18678708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BAG6 directly shields HSPA2 from ubiquitination not resolved\", \"E3 ligase involved not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined BAG6's core proteostatic function: capturing nascent/mislocalized chains and routing tail-anchored proteins to the TRC40 membrane-insertion pathway.\",\n      \"evidence\": \"In vitro/in vivo nascent-chain interaction and degradation assays, plus Sec61\\u03b2 membrane integration assays with depletion\",\n      \"pmids\": [\"20713601\", \"20516149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible E3 ligase not yet known\", \"Substrate-binding domain not yet mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the SGTA-Ubl4A handoff and extended BAG6 functions to T-cell signaling and chromatin, defining substrate loading, immune regulation, and DNA-repair roles.\",\n      \"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\",\n      \"pmids\": [\"23246001\", \"23129660\", \"22863785\", \"22373577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between cytosolic triage and nuclear/immune roles unclear\", \"Structural basis of DOT1L interaction not solved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified RNF126 as the BAG6-dependent E3 ligase and resolved the complex architecture, establishing the molecular machinery for client ubiquitination and TA-substrate transfer.\",\n      \"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\",\n      \"pmids\": [\"24981174\", \"25535373\", \"24591579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ubiquitylated clients are committed to degradation versus insertion not fully resolved\", \"BAGS domain functional partners incompletely defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the substrate-recognition (ULD) domain and the noncanonical C-terminal BAGS architecture, clarifying how BAG6 discriminates clients and stabilizes its partners.\",\n      \"evidence\": \"Domain-deletion binding assays and crystallography of BAG6-Ubl4A heterodimer with cellular stability assays\",\n      \"pmids\": [\"26663859\", \"25713138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of hydrophobicity sensing not directly visualized\", \"Affinity hierarchy among competing clients unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a structural explanation for BAG6 cytosol/nucleus partitioning, showing TRC35 occludes the NLS and shields TRC35 from RNF126.\",\n      \"evidence\": \"Crystal structure of BAG6-TRC35 with karyopherin-\\u03b1 binding and ubiquitylation assays\",\n      \"pmids\": [\"29042515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that release BAG6 for nuclear import not defined\", \"Dynamics of partitioning in vivo not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified UBXN1 as the VCP adaptor coupling ubiquitylated BAG6 clients to the unfoldase, explaining how clients avoid aggregation before ER translocation.\",\n      \"evidence\": \"Co-IP, siRNA depletion, and solubility/aggregation fractionation with pathway-specificity controls\",\n      \"pmids\": [\"29685906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without structural validation of the VCP-UBXN1-BAG6 assembly\", \"Substrate range requiring UBXN1 not delimited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended BAG6 to autophagy and mitophagy regulation through direct LC3B engagement and PINK1/PARKIN modulation.\",\n      \"evidence\": \"NMR of BAG6 LIR1-LC3B, LIR mutagenesis with autophagy flux assays, and BAG6 KO/OE mitophagy assays in null cells\",\n      \"pmids\": [\"33241194\", \"33522017\", \"32332095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of BAG6 as both autophagy suppressor and mitophagy stimulator unresolved\", \"Basal mitochondrial-matrix versus OMM localization mechanism unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established BAG6 as a sensor of aggregation-prone proteolytic fragments and an immunometabolic regulator in dendritic cells.\",\n      \"evidence\": \"BAG6 KO aggregation/ubiquitylation assays with TDP43 fragments and DC-specific Bat3 KO with metabolomics and paracrine T-cell assays\",\n      \"pmids\": [\"35542047\", \"35275752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether fragment sensing is relevant to neurodegenerative disease untested\", \"Mechanism linking BAG6 loss to UPR/steroidogenesis incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked BAG6 control of extracellular vesicle cargo to tumor suppression in cancer microenvironments.\",\n      \"evidence\": \"Bag6 KO PDAC mouse models with in vivo EV tracking, scRNA-seq, organoids, and patient samples\",\n      \"pmids\": [\"38942797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which BAG6 selects EV cargo not fully resolved\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model partitioning BAG6 pools across compartments\", \"Regulatory signals switching between degradation, insertion, and aggregate-prevention fates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [26, 41]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2, 14, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [27, 34, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 17, 38]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [14, 41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 33, 39]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 8, 18, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [37, 40]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [36, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0392499\", \"supporting_discovery_ids\": [14, 26, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 26, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 18, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [28, 39, 40]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 8, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 38, 42]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [36, 43]}\n    ],\n    \"complexes\": [\n      \"BAG6\\u2013Ubl4A\\u2013TRC35 (GET/TRC chaperone complex)\"\n    ],\n    \"partners\": [\n      \"UBL4A\",\n      \"TRC35\",\n      \"SGTA\",\n      \"RNF126\",\n      \"UBXN1\",\n      \"EP300\",\n      \"DOT1L\",\n      \"HSPA2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}