Affinage

BAG3

BAG family molecular chaperone regulator 3 · UniProt O95817

Length
575 aa
Mass
61.6 kDa
Annotated
2026-06-09
100 papers in source corpus 42 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAG3 is a multidomain co-chaperone that serves as a central organizing hub for protein quality control, coupling the Hsp70/Hsc70 chaperone machinery to selective autophagy, signaling, and cytoskeletal maintenance (PMID:21472004, PMID:18094623). It engages Hsp70/Hsc70 through its C-terminal BAG domain and recruits small heat-shock proteins via IPV motifs in its intermediate domain, with the WW and proline-rich (PXXP) regions mediating contacts with structural and signaling partners (PMID:21472004, PMID:18094623, PMID:21423662). In striated muscle BAG3 localizes to Z-discs and protects myofibrillar integrity under mechanical load: it directs the actin capping protein CapZβ1 and, with Hsc70, sustains sarcomere structure during stretch, with loss causing fulminant myopathy and myofibrillar degeneration (PMID:16936253, PMID:20884878). This protective function operates through chaperone-assisted selective autophagy, in which BAG3 together with HSPB8 and synaptopodin-family scaffolds targets damaged and aggregation-prone clients—including mutant huntingtin, tau, and α-synuclein—to aggresomes and autophagosomes (PMID:18094623, PMID:29405094, PMID:30744518, PMID:35000752). BAG3 spatially coordinates these stress responses by recruiting the TSC complex to actin stress fibers to locally tune mTORC1 during mechanical strain and by gating Hippo-pathway control of YAP/TAZ localization (PMID:27756573, PMID:34761265, PMID:34481290). The Hsp70-BAG3 module also broadly governs proliferative and survival signaling—stabilizing IKKγ to drive NF-κB, restraining BAX mitochondrial translocation, and feeding into Src, ERK, and stress-kinase pathways (PMID:20368414, PMID:21561597, PMID:24994713, PMID:29987014). In cardiomyocytes BAG3 organizes β1-adrenergic receptor and L-type Ca²⁺ channel complexes to support contractile Ca²⁺ handling (PMID:26796036). Dominant disease-causing mutations in the IPV (P209L) and BAG (R477H) regions act through gain-of-function aggregation that sequesters the chaperone machinery and through impaired Hsc70 binding, producing myofibrillar myopathy and dilated/restrictive cardiomyopathy (PMID:30559338, PMID:28724793, PMID:34117258, PMID:31723063). Extracellularly, secreted BAG3 acts as a ligand for the macrophage receptor IFITM-2 to promote tumor progression (PMID:26522614).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Established that BAG3 is physiologically essential in striated muscle, defining its tissue context before its molecular mechanism was known.

    Evidence Bag3 knockout mouse with myofibrillar degeneration plus C2C12 knockdown showing apoptosis on differentiation

    PMID:16936253

    Open questions at the time
    • Did not define the molecular pathway linking BAG3 loss to myofibrillar breakdown
    • Cell-autonomous survival mechanism not resolved at the protein level
  2. 2007 High

    Identified BAG3 as a co-chaperone that routes misfolded clients to macroautophagy, defining its core protein-clearance function and the domain responsible.

    Evidence HspB8 complex characterization and PXXP/BAG deletion mutants in a mutant huntingtin macroautophagy assay

    PMID:18094623

    Open questions at the time
    • Did not establish the downstream autophagy receptor machinery
    • Cargo selectivity rules not defined
  3. 2010 High

    Connected BAG3 chaperone activity to mechanical maintenance of the sarcomere, explaining the muscle phenotype mechanistically.

    Evidence shRNA knockdown with mechanical stretch, reciprocal Co-IP and CapZβ1 rescue in cardiomyocytes

    PMID:20884878

    Open questions at the time
    • How stretch is sensed to trigger CapZβ1 turnover not defined
    • Link to autophagic clearance of damaged sarcomere proteins not yet integrated
  4. 2010 High

    Showed BAG3 promotes survival signaling by reshaping Hsp70 client interactions, extending its role from folding to pro-survival signal control.

    Evidence Co-IP and proteasome inhibition showing BAG3 protects IKKγ to activate NF-κB, with xenograft validation

    PMID:20368414

    Open questions at the time
    • Whether IKKγ stabilization is direct or chaperone-mediated not fully resolved
    • Tissue specificity of NF-κB effect not addressed
  5. 2011 High

    Mapped the structural basis of BAG3's interactions with Hsp70 and small heat-shock proteins, defining its modular architecture.

    Evidence Domain characterization of BAG-domain/Hsp70 binding and IPV-motif mapping to αB-crystallin with rescue of mutant aggregation

    PMID:21423662 PMID:21472004

    Open questions at the time
    • Stoichiometry of the multi-partner complex not determined
    • Structural model of full-length assembly absent
  6. 2016 High

    Revealed how BAG3 spatially partitions protein synthesis and autophagy under mechanical strain via mTORC1, integrating mechanosensing with proteostasis.

    Evidence WW-domain mutants and Co-IP with TSC1, spatial mTORC1 activity assays and human muscle exercise

    PMID:27756573

    Open questions at the time
    • How filamin damage is detected to nucleate TSC recruitment not resolved
    • Quantitative spatial dynamics not defined
  7. 2016 High

    Extended BAG3's reach to cardiomyocyte excitation–contraction coupling, showing it organizes receptor and channel complexes for Ca²⁺ handling.

    Evidence Co-IP with β1-AR, L-type Ca²⁺ channels and phospholemman, plus patch-clamp and Ca²⁺ imaging after shRNA knockdown in ventricular myocytes

    PMID:26796036

    Open questions at the time
    • Whether scaffolding is chaperone-dependent not established
    • Direct versus indirect channel association unresolved
  8. 2017 High

    Built a human cardiac interactome and tied heterozygous loss-of-function and the R477H mutation to contractile and proteostatic failure, bridging to human cardiomyopathy.

    Evidence Affinity-MS interactome in isogenic iPSC-cardiomyocytes with proteasome challenge and Co-IP of R477H

    PMID:28724793

    Open questions at the time
    • Mechanism by which reduced Hsc70 binding causes myofibril disarray not fully resolved
    • In vivo cardiac penetrance not addressed in this model
  9. 2018 High

    Defined the gain-of-function mechanism of myopathy mutations, showing they stall client processing and aggregate the chaperone machinery rather than simply losing Hsp70 binding.

    Evidence Recombinant protein biochemistry with aggregation assays and genetic/pharmacological Hsp70-interference rescue

    PMID:30559338

    Open questions at the time
    • Why specific mutations stall processing at the structural level not resolved
    • Therapeutic window of Hsp70 interference not defined
  10. 2018 High

    Identified the Hsp70-BAG3 complex as a sensor of stalled translation products linking ribosome quality control to Hippo and stress-kinase signaling and early aggregation control.

    Evidence Co-IP and siRNA of LTN1/VCP/NAC with LATS1/2 activity and oligomer imaging under proteasome inhibition

    PMID:29987014

    Open questions at the time
    • How the complex physically reads stalled polypeptides not resolved
    • Direct LATS1/2 regulation versus indirect not separated
  11. 2019 High

    Established BAG3 as a CNS proteostasis factor whose CDK5-driven loss degrades synaptic proteins and impairs memory, connecting it to Alzheimer's pathology.

    Evidence Phosphoproteomics, in vitro kinase assay, conditional neuronal KO with behavior, and human AD tissue analysis; plus SYNPO-dependent autophagosome–lysosome fusion at post-synapses

    PMID:30744518 PMID:31955914

    Open questions at the time
    • Whether synaptic protein degradation is via CASA or bulk autophagy not fully separated
    • Causality of BAG3 loss in human AD versus correlation not settled
  12. 2021 High

    Demonstrated in vivo that the P209L mutation causes cardiomyopathy and myopathy through reduced solubility and aggregation despite preserved binding, modeling human disease.

    Evidence Humanized transgenic mice and zebrafish bag3-null/P209L models with proteomics, solubility fractionation, and metformin rescue

    PMID:33030392 PMID:34117258

    Open questions at the time
    • Whether autophagy failure is a cause or consequence of aggregation not fully resolved
    • Translatability of metformin rescue to patients not established
  13. 2022 Medium

    Expanded BAG3 into redox and ubiquitin-signaling control, showing it directs PARP1 degradation under acetylation control to limit endothelial oxidative damage.

    Evidence Co-IP, ubiquitination site mapping, CBP/SIRT2 acetylation assays and endothelial-specific KO mice

    PMID:35066290

    Open questions at the time
    • Single lab; how acetylation switches BAG3 activity mechanistically not resolved
    • Relationship to canonical chaperone function unclear
  14. 2023 Medium

    Showed BAG3 mediates astrocytic clearance of aggregation-prone proteins under circadian control, extending its proteostatic role to non-neuronal CNS cells.

    Evidence Astrocyte-specific Bmal1 KO with Bag3-dependent rescue and in vivo α-synuclein spreading assays

    PMID:37315555

    Open questions at the time
    • Single lab; mechanism linking Bmal1 to BAG3 induction not resolved
    • Whether astrocytic clearance is CASA-dependent not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BAG3's many context-specific functions—proteostasis, mechanotransduction, Ca²⁺ handling, signaling, and extracellular ligand activity—are integrated and selectively engaged by domain, post-translational modification, or partner availability remains unresolved.
  • No structural model of the assembled multi-domain complex
  • Rules governing client and partner selection across tissues undefined
  • Mechanism of BAG3 secretion and IFITM-2 engagement not detailed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0003723 RNA binding 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005576 extracellular region 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-397014 Muscle contraction 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5357801 Programmed Cell Death 1
Partners
BAXCAPZBCRYABHSPA8HSPB8STK38SYNPOTSC1
Complex memberships
CASA complex (BAG3-HSPB8-Hsc70)Hsp70-BAG3 co-chaperone complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 BAG3 interacts with the ATPase domain of Hsp70 through its BAG domain (110-124 amino acids), functioning as a co-chaperone that regulates Hsp70 activity. BAG3 also contains a WW domain and PXXP repeat mediating interactions with partners other than Hsp70. Biochemical domain characterization, protein interaction studies Cell death & disease High 21472004
2006 BAG3 is prominently expressed in striated muscle and colocalizes with Z-discs. BAG3-deficient mice develop fulminant myopathy with myofibrillar degeneration. Knockdown in C2C12 myoblasts increased apoptosis upon differentiation, establishing a cell-autonomous role in myotube survival. Bag3 gene knockout mouse model, shRNA knockdown in C2C12 cells, immunolocalization, histology The American journal of pathology High 16936253
2007 BAG3 forms a complex with HspB8 that targets misfolded proteins (including mutant huntingtin) to macroautophagy. The proline-rich (PXXP) region of BAG3 is essential for this macroautophagy stimulation, whereas deletion of the BAG domain did not affect this activity. Deletion mutant analysis, macroautophagy assay, co-chaperone complex characterization Autophagy High 18094623
2010 BAG3 and Hsc70 interact with the actin capping protein CapZβ1 to maintain myofibrillar integrity under mechanical stress. BAG3 facilitates correct localization of CapZβ1 and prevents its ubiquitin-proteasome-mediated degradation. Mechanical stretch rapidly disrupts myofibril structure in bag3 knockdown cardiomyocytes. shRNA knockdown, in vitro mechanical stretch experiments in neonatal cardiomyocytes, Co-IP, overexpression rescue experiments Circulation research High 20884878
2010 BAG3 promotes tumor cell survival through the NF-κB pathway by altering the interaction between Hsp70 and IKKγ, increasing availability of IKKγ and protecting it from proteasome-dependent degradation, resulting in increased NF-κB activity. Overexpression and knockdown, Co-IP, proteasome inhibition assays, mouse xenograft model Proceedings of the National Academy of Sciences of the United States of America High 20368414
2007 BAG3 regulates cell motility and adhesion in epithelial cancer cells. BAG3-deficient MEFs show reduced motility and delayed filopodia/focal adhesion formation. BAG3 partially colocalizes with actin at the leading edge of migrating cells. BAG3 knockdown decreased Rac1 activity, linking BAG3 to actin-cytoskeleton dynamics via Rac1. BAG3-deficient MEFs, RNAi knockdown, gene transfer overexpression, motility assays, Rac1 activity assay, immunolocalization Cancer research High 17974966
2011 BAG3 forms a complex with Hsp70 and BAX that prevents BAX translocation to mitochondria, thereby protecting tumor cells from apoptosis in glioblastoma. Co-IP, BAG3 knockdown in vitro and in vivo (rat glioblastoma model), apoptosis assays The American journal of pathology Medium 21561597
2011 BAG3 directly binds wild-type αB-crystallin and the myopathy-causing mutant R120G via two conserved IPV (Ile-Pro-Val) motifs in the intermediate domain of BAG3. BAG3 overexpression increased R120G solubility and inhibited its intracellular aggregation, and suppressed R120G-induced cell death in differentiating myoblasts. In vitro binding assay with inhibitory peptides, Co-IP, overexpression in HEK293 cells and C2C12 cells, aggregation/cell death assays PloS one High 21423662
2014 Bag3 interacts with the SH3 domain of Src kinase, thereby mediating the effects of Hsp70 on Src signaling. The Hsp70-Bag3 module broadly regulates cancer cell signaling including NF-κB, FoxM1, Hif1α, HuR, p21, and survivin. A small-molecule inhibitor YM-1 that disrupts the Hsp70-Bag3 interaction suppresses tumor growth in vivo. Co-IP, small molecule inhibitor (YM-1), multiple signaling pathway assays, mouse xenograft model Cancer research High 24994713
2016 BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1. BAG3 uses its WW domain to contact a proline-rich motif in TSC1, recruiting TSC complexes to actin stress fibers, causing local mTORC1 inhibition to initiate autophagy at sites of filamin damage while relieving mTORC1 inhibition in the remaining cytoplasm to stimulate protein translation. WW domain mutant analysis, Co-IP, mTORC1 activity assays, actin stress fiber fractionation, human muscle exercise experiments Biochimica et biophysica acta. Molecular cell research High 27756573
2015 BAG3 secreted by pancreatic ductal adenocarcinoma cells binds to IFITM-2 as a receptor on macrophages and signals through PI3K and p38 MAPK pathways, inducing macrophage activation and secretion of PDAC-supporting factors. An anti-BAG3 antibody reduced tumor growth and prevented metastasis in mouse models. Receptor identification (IFITM-2), signaling pathway assays (PI3K, p38 MAPK), anti-BAG3 antibody treatment in three mouse tumor models Nature communications High 26522614
2016 In adult mouse ventricular myocytes, BAG3 co-localizes with Na+/K+-ATPase and L-type Ca2+ channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitates with the β1-adrenergic receptor, L-type Ca2+ channels, and phospholemman. Reducing BAG3 by shRNA impairs contraction and [Ca2+]i transients in response to isoproterenol, and reduces L-type Ca2+ current and sarcoplasmic reticulum Ca2+ content. Co-immunoprecipitation, immunolocalization, shRNA knockdown, patch-clamp electrophysiology, Ca2+ imaging Journal of molecular and cellular cardiology High 26796036
2017 BAG3 directly stabilizes Hexokinase 2 (HK2) mRNA in pancreatic cancer cells by interacting with the HK2 mRNA. BAG3 alters recruitment of RNA-binding proteins Roquin (destabilizing) and IMP3 (stabilizing) to the HK2 mRNA, thereby promoting aerobic glycolysis. RNA immunoprecipitation, RBP recruitment assays, BAG3 knockdown/overexpression, glycolysis measurements The Journal of cell biology Medium 29114069
2017 BAG3 plays a role in autophagic clearance of α-synuclein via macroautophagy. BAG3 interacts with Hsp70 and sequestosome-1/p62 and colocalizes perinuclearly with these proteins and LC3 in dopaminergic neurons. BAG3 overexpression enhanced autophagy activity; Atg5 knockdown blocked BAG3-mediated SNCA degradation. Co-immunoprecipitation, immunofluorescence, BAG3 overexpression/knockdown, Atg5 knockdown epistasis Neurobiology of aging Medium 28941726
2012 BAG3 is essential for the interaction between ERK and its phosphatase DUSP6 in endothelial cells; BAG3 removal results in reduced DUSP6-ERK binding, sustained ERK phosphorylation, increased p21 and p15 levels, and G1 cell cycle arrest, thereby controlling angiogenesis. BAG3 knockdown, Co-IP of ERK-DUSP6, cell cycle analysis, in vitro angiogenesis assay Oncogene Medium 22310281
2015 BAG3 binds to SNAP-25 and syntaxin-1 (t-SNARE components) and prevents their interaction. Upon glucose stimulation, BAG3 is phosphorylated by FAK and dissociates from SNAP-25, allowing SNARE complex formation, F-actin destabilization, and insulin release in β-cells. Co-IP, BAG3 knockdown, glucose stimulation assays, FAK phosphorylation assay, insulin secretion measurement Cell death & disease Medium 25766323
2015 BAG3 affects the nucleocytoplasmic shuttling of HSF1 during heat stress. BAG3 interacts with HSF1 via its BAG domain and co-translocates to the nucleus upon heat stress. BAG3 overexpression down-regulates nuclear HSF1 by exporting it to the cytoplasm during recovery; BAG3 depletion reduces nuclear HSF1 and decreases Hsp70 promoter activity. Co-immunoprecipitation, domain mapping, immunofluorescence, siRNA knockdown, Hsp70 promoter reporter assay Biochemical and biophysical research communications Medium 26159920
2018 Myopathy-associated BAG3 mutations (IPV or BAG domain) stall Hsp70-dependent client processing without impairing Hsp70 binding per se. Mutant BAG3 proteins cause dominant gain-of-function aggregation of themselves, Hsp70, Hsp70 clients, and tiered interactors. Genetic or pharmacological interference with Hsp70 binding completely reverses stress-induced aggregation for both BAG3 mutations. Recombinant protein biochemistry, Hsp70 binding assays, aggregation assays, genetic rescue (Hsp70 interference), pharmacological rescue Nature communications High 30559338
2018 HSPB8 cooperates with BAG3 to coordinate sequestration of ubiquitinated proteins to the juxtanuclear aggresome. The myopathy-associated P209L mutation (in the HSPB8-binding IPV motif) deregulates the BAG3-p62/SQSTM1 association and the KEAP1-Nrf2 signaling axis. Aggresome targeting can be restored in BAG3-depleted cells by a BAG3 mutant defective in HSPB8 binding, uncoupling HSPB8 from BAG3 for this function. siRNA depletion, dominant mutant rescue, p62/SQSTM1 modification assays, KEAP1-Nrf2 reporter, aggresome formation assay FASEB journal Medium 29405094
2018 The Hsp70-Bag3 complex senses accumulation of defective ribosomal products (stalled polypeptides) upon proteasome suppression, requiring ribosome quality control components LTN1 and VCP and the ribosome-associated chaperone NAC. The complex regulates Hippo pathway effectors LATS1/2 and stress kinases p38 and JNK, and under proteotoxic stress Hsp70-Bag3-LATS1/2 signaling regulates early stages of protein aggregation (oligomer emergence). Co-immunoprecipitation, proteasome inhibition assays, siRNA knockdown (LTN1, VCP, NAC), LATS1/2 activity assay, oligomer formation imaging Proceedings of the National Academy of Sciences of the United States of America High 29987014
2017 BAG3 affinity tagging and mass spectrometry in human iPSC-derived cardiomyocytes defined a cardioprotective chaperone complex. Heterozygous BAG3 loss-of-function mutations in human iPSC-CMs disrupted myofibril structure and compromised contractile function, and increased sensitivity to proteasome inhibitor-induced myofibril disruption. The DCM-associated R477H mutation reduced BAG3-HSC70 binding in co-immunoprecipitation assays. Affinity tagging + mass spectrometry proteomics, isogenic iPSC-CMs, proteasome inhibitor challenge, Co-IP of BAG3-R477H vs WT JCI insight High 28724793
2019 BAG3 interacts with synaptopodin (SYNPO) to facilitate autophagosome-lysosome fusion predominantly in the post-synaptic compartment of mature neurons. Loss of BAG3 or SYNPO impedes autophagic flux in neurites, leading to accumulation of SQSTM1/p62 and phospho-Ser262 MAPT in autophagosomes at post-synaptic densities. Co-immunoprecipitation, shRNA knockdown of BAG3 and SYNPO, live-cell imaging of autophagosome-lysosome fusion, immunofluorescence in mature neurons (DIV 20-24) Autophagy Medium 30744518
2019 CDK5 phosphorylates BAG3 at S297/S291 (mouse/human), destabilizing BAG3. Loss of BAG3 unleashes HSP70 machinery to degrade glutamatergic synaptic proteins. Conditional neuronal Bag3 knockout in vivo impaired learning and memory. Aberrant CDK5-mediated BAG3 loss was found in human AD and related mouse models, and was reversed by ectopic BAG3 reexpression. Quantitative phosphoproteomics, in vitro phosphorylation assay, conditional Bag3 KO mice, shRNA knockdown, behavioral testing, human AD tissue analysis Biological psychiatry High 31955914
2019 BAG3 enhances autophagy via promotion of glutaminolysis by stabilizing glutaminase (GLS). BAG3 interacts with GLS and decreases SIRT5 expression, thereby preventing SIRT5-mediated desuccinylation of GLS at Lys158/Lys164. Succinylation at these sites blocks Lys48-linked ubiquitination, preventing proteasomal GLS degradation. Co-immunoprecipitation, succinylation/ubiquitination site mutagenesis, GLS stability assays, BAG3 knockdown/overexpression, autophagy assays Cell death & disease Medium 30910998
2019 BAG3 interacts with TBC1D10B (a RAB35 GTPase-activating protein) via a BAG3-HSP70-TBC1D10B complex, attenuating TBC1D10B's ability to inactivate RAB35. This supports RAB35 activation and HRS recruitment, initiating ESCRT-dependent endosomal tau clearance. Overexpression of BAG3 in P301S tau mice increased phospho-tau colocalization with ESCRT-III protein CHMP2B and reduced mutant tau levels. Mass spectrometry identification of BAG3 neuronal interactors, Co-IP, live-cell endosomal imaging, immunohistochemistry in human AD brain and P301S mice Biological psychiatry Medium 35000752
2016 BAG3 controls total LC3B protein levels through translational (not transcriptional) regulation of LC3B mRNA in HeLa and HEK293 cells. BAG3 knockdown did not affect LC3B lipidation induced by nutrient deprivation or proteasome inhibition. BAG3 knockdown, LC3B mRNA translation assay, transcriptional reporter, LC3B lipidation assay under starvation and proteasome inhibition Autophagy Medium 26654586
2020 BAG3 Pro209 missense mutations (P209L, P209Q, P209S) acquire a toxic gain-of-function causing accumulation in insoluble HDAC6- and vimentin-positive aggresomes, relocating HSPB8 and Hsp70 (CASA complex components) and trapping ubiquitinated client proteins, preventing their efficient clearance. Overexpression of all three P209 mutants and E455K mutant, detergent solubility fractionation, immunofluorescence for aggresome markers, ubiquitinated protein pulldown Scientific reports Medium 32472079
2021 BAG3 depletion increases cytoplasmic retention of YAP and TAZ, desensitizing myoblasts to matrix stiffness. BAG3 transduces mechanical signals from the extracellular matrix to redistribute YAP/TAZ subcellular localization in muscle progenitor cells, coupling mechanical stimuli to gene expression and muscle progenitor differentiation. BAG3 depletion, dynamically stiffening hydrogels, YAP/TAZ localization imaging, Hippo pathway inhibition rescue experiments Biomaterials Medium 34481290
2019 The Hippo network kinase STK38 is a novel BAG3 interactor that exerts inhibitory activity on BAG3-mediated chaperone-assisted selective autophagy (CASA). STK38 inhibits CASA by disrupting the functional interplay of BAG3 with HSPB8 and SYNPO2, independently of STK38 kinase activity. Co-immunoprecipitation, STK38 overexpression/depletion, CASA assay (filamin degradation), kinase-dead mutant analysis Biochimica et biophysica acta. Molecular cell research Medium 31326538
2021 The Hsp70-Bag3 complex recruits a complex of LATS1, YAP, and the scaffold AmotL2. Upon proteasome inhibition, AmotL2 dissociates from Bag3, preventing LATS1-mediated YAP phosphorylation and leading to nuclear translocation of YAP together with Bag3. Bag3 nuclear localization mutants also facilitated nuclear YAP translocation. Bag3 also controls YAP nuclear localization in response to cell density. Co-immunoprecipitation, Bag3 localization mutants, proteasome inhibition, YAP phosphorylation assays, nuclear fractionation, cell density experiments Journal of cell science Medium 34761265
2022 BAG3 binds to PARP1's BRCT domain and promotes PARP1 ubiquitination at K249 by enhancing the E3 ubiquitin ligase WWP2, leading to proteasome-mediated PARP1 degradation. BAG3 itself is acetylated at K431 by CBP and deacetylated by SIRT2; deacetylated BAG3 promotes PARP1 ubiquitination. Endothelial-specific BAG3 knockout in mice enhances oxidative stress-associated endothelial damage. Co-IP, ubiquitination site mapping (K249), mutagenesis, acetyltransferase/deacetylase assays (CBP, SIRT2), endothelial-specific BAG3 KO mice, ubiquitination assays Redox biology Medium 35066290
2019 DCM-associated BAG3-R477H mutation reduces HSC70 binding in co-immunoprecipitation assays. Molecular dynamics simulations predicted a partial disengagement of BAG3 from HSC70 with the R477H mutation. R477H and KO iPSC-CMs showed impaired myofibrillar organization upon proteasome inhibition; myofibrillar disarray in R477H cells was mitigated by HSF1 overexpression. Isogenic genome-edited iPSC-CMs, Co-IP, molecular dynamics simulation, RNA-seq, proteasome inhibitor challenge, HSF1 overexpression rescue JCI insight Medium 31723063
2007 BAG3 suppresses transcription of the HIV-1 LTR by suppressing the interaction of NF-κB p65 subunit with the κB DNA motif. This activity was mapped to the C-terminus of BAG3. BAG3 expression is elevated upon HIV-1 infection of lymphocytes and fetal microglial cells. Transcription assays, in vitro and in vivo binding assays (p65 with κB motif), domain mapping (C-terminus), BAG3 overexpression Journal of cellular physiology Medium 17187345
2017 The WW domain of BAG3 interacts with the PPxY motif of both Ebola (EBOV) and Marburg (MARV) VP40 matrix proteins. BAG3 inhibits budding of eVP40 and mVP40 virus-like particles and infectious VSV-EBOV recombinants. BAG3 alters intracellular VP40 localization by sequestering it away from the plasma membrane. WW-domain protein array screen, co-IP, VP40 VLP budding assay, infectious VSV-EBOV rescue assay, immunofluorescence localization PLoS pathogens Medium 28076420
2010 BAG3 WW domain interacts with the PPxY motifs in the N-terminal part of adenovirus penton base protein. BAG3 depletion impairs cell entry of adenovirus and viral progeny production, demonstrating that the BAG3-penton base interaction positively influences viral lifecycle. This interaction is not related to classical BAG3 co-chaperone function. Co-immunoprecipitation, BAG3 depletion, viral infectivity and progeny assays, nuclear co-migration assay Journal of cellular biochemistry Medium 20607728
2023 Astrocyte-specific Bmal1 deletion induces BAG3 expression in astrocytes. Astrocyte Bmal1 deletion enhances phagocytosis of α-synuclein and tau in a Bag3-dependent manner; astrocyte Bag3 overexpression is sufficient to mitigate α-synuclein spreading in vivo. Astrocyte-specific conditional Bmal1 knockout, Bag3-dependent genetic rescue, phagocytosis assay, in vivo α-synuclein spreading model Neuron Medium 37315555
2020 During mitosis, BAG3 depletion inhibits mitotic cell rounding and disrupts the subcortical actin cloud. BAG3 tunes branched actin network assembly by modulating cortactin acetylation/deacetylation dynamics and the spatial association of cortactin with HDAC6. BAG3 depletion hinders the mitotic decrease in cortactin-HDAC6 association, and expression of acetyl-mimic cortactin normalizes mitotic actin organization in BAG3-depleted cells. BAG3 depletion, mitotic cell rounding assay, immunofluorescence of cortactin-HDAC6 interaction, acetyl-mimic cortactin rescue, Arp2/3 and HDAC6 inhibitor pharmacology International journal of molecular sciences Medium 33375626
2016 BAG3 directly interacts with glucose-6-phosphate dehydrogenase (G6PD) and suppresses the pentose phosphate pathway (PPP) flux, de novo DNA synthesis, and hepatocellular carcinoma cell growth. The growth defect caused by BAG3 elevation can be rescued by enforced G6PD expression. BAG3 elevation did not reduce cellular NADPH levels. Co-immunoprecipitation, BAG3 overexpression, G6PD rescue overexpression, PPP flux measurement, DNA synthesis assay Oncotarget Medium 26621836
2013 BAG3 stabilizes JunD mRNA, and serum starvation downregulates BAG3 at the transcriptional level via c-Jun. JunD mRNA stabilization by BAG3 contributes to growth inhibition during serum starvation. mRNA stability assay, BAG3 knockdown/overexpression, transcriptional assay, c-Jun siRNA Biochimica et biophysica acta Low 24140207
2024 USP32 deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. USP32-mediated stabilization of BAG3 increases phosphorylation of the RAF/MEK/ERK signaling pathway in NSCLC cells. BAG3 restoration abrogated the antitumor effects of USP32 silencing. Co-immunoprecipitation, deubiquitination assay (activity-dependent mutant), USP32 knockdown/overexpression, BAG3 restoration rescue, ERK phosphorylation assay Oncogenesis Medium 39030175
2021 BAG3 myofibrillar myopathy modeling in zebrafish: bag3-null fish exhibit impaired autophagic activity (confirmed also in BAG3 patient samples), and the loss of BAG3 due to sequestration in P209L aggregates underlies autophagy failure and muscle weakness. Metformin removes protein aggregates and rescues fiber disintegration and swimming deficits in bag3-null zebrafish. Zebrafish bag3 null and BAG3P209L transgenic models, autophagic flux assay, human patient myoblast analysis, metformin screen Autophagy Medium 33030392
2021 Overexpression of human BAG3P209L in transgenic mice causes Z-disc disintegration, protein aggregate formation, massive fibrosis, and early-onset restrictive cardiomyopathy. The mutation renders BAG3P209L less soluble in vivo but does not abrogate BAG3 binding properties. Proteomics revealed changes in protein quality control system and increased autophagy in mutant hearts. Humanized transgenic mouse model, RNA-seq, proteomics, solubility fractionation, binding assays Nature communications High 34117258
2016 BAG3 regulates YAP and TAZ subcellular localization through mechanotransduction: depletion of BAG3 increases cytoplasmic YAP/TAZ retention. Inhibition of the Hippo pathway partially restored myotube morphology in BAG3-depleted myogenic progenitors, with nuclear YAP/TAZ translocation restored. BAG3 depletion in myoblasts, dynamic hydrogel stiffness assay, YAP/TAZ localization imaging, Hippo pathway inhibitor rescue Biomaterials Medium 34481290

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 BAG3: a multifaceted protein that regulates major cell pathways. Cell death & disease 267 21472004
2006 BAG3 deficiency results in fulminant myopathy and early lethality. The American journal of pathology 219 16936253
2016 Breaking BAG: The Co-Chaperone BAG3 in Health and Disease. Trends in pharmacological sciences 213 27162137
2007 HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy. Autophagy 206 18094623
2017 The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease. Frontiers in molecular neuroscience 164 28680391
2014 Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer research 149 24994713
2018 Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations. Journal of the American College of Cardiology 134 30442290
2010 BAG3 and Hsc70 interact with actin capping protein CapZ to maintain myofibrillar integrity under mechanical stress. Circulation research 122 20884878
2007 Apoptosis inhibition in cancer cells: a novel molecular pathway that involves BAG3 protein. The international journal of biochemistry & cell biology 118 17493862
2015 Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer. Molecular cancer therapeutics 113 25564440
2011 BAG3 protein is overexpressed in human glioblastoma and is a potential target for therapy. The American journal of pathology 108 21561597
2010 IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth. Proceedings of the National Academy of Sciences of the United States of America 107 20368414
2011 BAG3 and friends: co-chaperones in selective autophagy during aging and disease. Autophagy 106 21681022
2007 BAG3 regulates motility and adhesion of epithelial cancer cells. Cancer research 101 17974966
2015 BAG3: a new player in the heart failure paradigm. Heart failure reviews 91 25925243
2015 BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages. Nature communications 88 26522614
2023 An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology. Neuron 82 37315555
2018 BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells. Neoplasia (New York, N.Y.) 82 29462756
2017 A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress. JCI insight 79 28724793
2019 BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes. Autophagy 77 30744518
2017 BAG3-mediated proteostasis at a glance. Journal of cell science 72 28808089
2018 Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nature communications 70 30559338
2017 Role of BAG3 in cancer progression: A therapeutic opportunity. Seminars in cell & developmental biology 70 28864347
2016 Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis. Molecular cancer therapeutics 68 27777286
2021 Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease. The Journal of clinical investigation 65 34396980
2023 BAG3 Overexpression Attenuates Ischemic Stroke Injury by Activating Autophagy and Inhibiting Apoptosis. Stroke 63 37377010
2018 Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation. Proceedings of the National Academy of Sciences of the United States of America 62 29987014
2011 BAG3 directly interacts with mutated alphaB-crystallin to suppress its aggregation and toxicity. PloS one 61 21423662
2007 Evidence for BAG3 modulation of HIV-1 gene transcription. Journal of cellular physiology 61 17187345
2016 BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes. Journal of molecular and cellular cardiology 60 26796036
2016 The cochaperone BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1. Biochimica et biophysica acta. Molecular cell research 59 27756573
2020 At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer. Cells 57 32121220
2019 BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase. Cell death & disease 56 30910998
2018 The Multifunctional Protein BAG3: A Novel Therapeutic Target in Cardiovascular Disease. JACC. Basic to translational science 52 29938246
2017 A role of BAG3 in regulating SNCA/α-synuclein clearance via selective macroautophagy. Neurobiology of aging 52 28941726
2017 BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells. The Journal of cell biology 52 29114069
2018 HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 50 29405094
2017 Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress. PLoS pathogens 45 28076420
2013 BAG3 regulates epithelial-mesenchymal transition and angiogenesis in human hepatocellular carcinoma. Laboratory investigation; a journal of technical methods and pathology 42 24365746
2012 BAG3 controls angiogenesis through regulation of ERK phosphorylation. Oncogene 42 22310281
2015 BAG3 affects the nucleocytoplasmic shuttling of HSF1 upon heat stress. Biochemical and biophysical research communications 40 26159920
2014 HIV-1 Tat protein induces glial cell autophagy through enhancement of BAG3 protein levels. Cell cycle (Georgetown, Tex.) 40 25483098
2009 Caught in the middle: the role of Bag3 in disease. The Biochemical journal 40 20001957
2020 BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes. Scientific reports 39 32472079
2015 BAG3-mediated miRNA let-7g and let-7i inhibit proliferation and enhance apoptosis of human esophageal carcinoma cells by targeting the drug transporter ABCC10. Cancer letters 39 26655271
2008 Activation of BAG3 by Egr-1 in response to FGF-2 in neuroblastoma cells. Oncogene 39 18469860
2019 Investigation of a dilated cardiomyopathy-associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytes. JCI insight 38 31723063
2016 Overexpression of BAG3 Attenuates Hypoxia-Induced Cardiomyocyte Apoptosis by Inducing Autophagy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 38 27383426
2018 miR-206 Inhibits Cell Proliferation, Migration, and Invasion by Targeting BAG3 in Human Cervical Cancer. Oncology research 37 29295729
2010 BAG3 protein delocalisation in prostate carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 20535599
2022 An unexpected role for BAG3 in regulating PARP1 ubiquitination in oxidative stress-related endothelial damage. Redox biology 35 35066290
2021 The role of BAG3 in health and disease: A "Magic BAG of Tricks". Journal of cellular biochemistry 35 33987872
2021 In silico structure evaluation of BAG3 and elucidating its association with bacterial infections through protein-protein and host-pathogen interaction analysis. Journal of cellular biochemistry 34 33998043
2020 The multiple activities of BAG3 protein: Mechanisms. Biochimica et biophysica acta. General subjects 34 32360144
2019 Cyclin-Dependent Kinase 5-Dependent BAG3 Degradation Modulates Synaptic Protein Turnover. Biological psychiatry 34 31955914
2020 Metformin rescues muscle function in BAG3 myofibrillar myopathy models. Autophagy 33 33030392
2022 Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies. Journal of the American Heart Association 31 36382946
2021 Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy. Nature communications 31 34117258
2021 Advances in the role and mechanism of BAG3 in dilated cardiomyopathy. Heart failure reviews 29 31808029
2016 BAG3 regulates total MAP1LC3B protein levels through a translational but not transcriptional mechanism. Autophagy 29 26654586
2012 BAG3: a new therapeutic target of human cancers? Histology and histopathology 28 22237703
2012 Role of BAG3 protein in leukemia cell survival and response to therapy. Biochimica et biophysica acta 28 22710027
2020 BAG3 Proteomic Signature under Proteostasis Stress. Cells 27 33158300
2019 The BAG3-dependent and -independent roles of cardiac small heat shock proteins. JCI insight 27 30830872
2009 Autoregulation of co-chaperone BAG3 gene transcription. Journal of cellular biochemistry 27 19777443
2021 Myoblast mechanotransduction and myotube morphology is dependent on BAG3 regulation of YAP and TAZ. Biomaterials 26 34481290
2020 Drosophila NUAK functions with Starvin/BAG3 in autophagic protein turnover. PLoS genetics 26 32320396
2016 BAG3 elevation inhibits cell proliferation via direct interaction with G6PD in hepatocellular carcinomas. Oncotarget 26 26621836
2013 BAG3 is upregulated by c-Jun and stabilizes JunD. Biochimica et biophysica acta 26 24140207
2019 The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy. Biochimica et biophysica acta. Molecular cell research 25 31326538
2022 BAG3 promotes autophagy and suppresses NLRP3 inflammasome activation in Parkinson's disease. Annals of translational medicine 24 36544667
2021 BAG3 Regulation of RAB35 Mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome Pathway and Tau Clearance. Biological psychiatry 24 35000752
2015 BAG3 regulates cell proliferation, migration, and invasion in human colorectal cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 26577854
2014 BAG3 promoted starvation-induced apoptosis of thyroid cancer cells via attenuation of autophagy. The Journal of clinical endocrinology and metabolism 23 25062457
2010 Co-chaperone BAG3 and adenovirus penton base protein partnership. Journal of cellular biochemistry 23 20607728
2021 BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease. American journal of physiology. Heart and circulatory physiology 21 33989081
2020 BAG3 in Tumor Resistance to Therapy. Trends in cancer 21 32718905
2015 BAG3 regulates formation of the SNARE complex and insulin secretion. Cell death & disease 21 25766323
2021 The role of Bag3 in cell signaling. Journal of cellular biochemistry 20 34297413
2021 BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients. Journal of cellular biochemistry 20 34741483
2017 BAG3 promotes proliferation of ovarian cancer cells via post-transcriptional regulation of Skp2 expression. Biochimica et biophysica acta. Molecular cell research 20 28624440
2024 Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway. Acta neuropathologica 19 39394356
2023 BAG3: Nature's Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue. Cells 19 36980278
2018 P209L mutation in Bag3 does not cause cardiomyopathy in mice. American journal of physiology. Heart and circulatory physiology 19 30499714
2023 Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart. JACC. Basic to translational science 18 37547075
2021 An emerging role for BAG3 in gynaecological malignancies. British journal of cancer 18 34099896
2021 Pharmacological inhibition of BAG3-HSP70 with the proposed cancer therapeutic JG-98 is toxic for cardiomyocytes. Journal of cellular biochemistry 18 34487557
2019 BAG3-positive pancreatic stellate cells promote migration and invasion of pancreatic ductal adenocarcinoma. Journal of cellular and molecular medicine 18 31119886
2018 BAG3 mutation in a patient with atypical phenotypes of myofibrillar myopathy and Charcot-Marie-Tooth disease. Genes & genomics 18 30145633
2016 BAG3 Protein Is Over-Expressed in Endometrioid Endometrial Adenocarcinomas. Journal of cellular physiology 18 27414463
2016 The prosurvival protein BAG3: a new participant in vascular homeostasis. Cell death & disease 18 27763645
2015 Analysis of BAG3 plasma concentrations in patients with acutely decompensated heart failure. Clinica chimica acta; international journal of clinical chemistry 17 25753466
2023 Critical Role of Viral Protein Hexon in Hypervirulent Fowl Adenovirus Serotype-4-Induced Autophagy by Interaction with BAG3 and Promotion of Viral Replication in LMH Cells. Journal of virology 16 37255472
2021 The Hsp70-Bag3 complex modulates the phosphorylation and nuclear translocation of Hippo pathway protein Yap. Journal of cell science 16 34761265
2020 Chaperone-Assisted Mitotic Actin Remodeling by BAG3 and HSPB8 Involves the Deacetylase HDAC6 and Its Substrate Cortactin. International journal of molecular sciences 16 33375626
2019 BAG3 deletion suppresses stem cell-like features of pancreatic ductal adenocarcinoma via translational suppression of ISG15. Biochimica et biophysica acta. Molecular cell research 16 30771383
2018 BAG3 Protein Is Involved in Endothelial Cell Response to Phenethyl Isothiocyanate. Oxidative medicine and cellular longevity 16 29955247
2024 USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway. Oncogenesis 15 39030175
2021 BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells. Journal of cellular biochemistry 15 34180073
2016 2'-Hydroxycinnamaldehyde induces apoptosis through HSF1-mediated BAG3 expression. International journal of oncology 15 27922674

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