Affinage

BAG4

BAG family molecular chaperone regulator 4 · UniProt O95429

Length
457 aa
Mass
49.6 kDa
Annotated
2026-06-09
23 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAG4 (SODD) is a Hsc70/Hsp70 co-chaperone that integrates death-receptor signaling, PI3K/Akt and RAF/MEK/ERK growth signaling, and chaperone-dependent stress responses (PMID:12058034, PMID:21712384, PMID:37107587). Its defining structural feature is a minimal three-helix BAG domain about one-third shorter than that of BAG1, which binds Hsc70 and modulates its chaperone activity, placing BAG4 in a structural subfamily with BAG3 and BAG5 (PMID:12058034). At the death receptor, BAG4 acts as a negative regulator of TNFR1-driven inflammatory signaling: loss of BAG4 accelerates TNF-induced NF-κB activation and amplifies cytokine responses without sensitizing the apoptotic arm (PMID:12748303). As a signaling adaptor, BAG4 forms complexes with the inositol 5-phosphatases SKIP, SHIP1 and SHIP2 and inhibits SKIP catalytic activity, sustaining PI(3,4,5)P3 levels, Akt activation, actin remodeling, and cell migration (PMID:21712384), and it binds RAF-1 to additionally drive RAF/MEK/ERK signaling (PMID:37107587). BAG4 abundance is set by post-translational control: USP14 stabilizes BAG4 through K48-deubiquitination at K403, and stabilized BAG4 blocks Parkin recruitment to damaged mitochondria to suppress mitophagy (PMID:40316942). BAG4 also associates with Hsp70 at the plasma membrane of tumor cells, where its overexpression confers protection against radiation-induced G2/M arrest (PMID:15592361).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Establishing the structural basis of BAG4 function: it was unknown whether BAG4's BAG domain could engage Hsc70 like BAG1, and the NMR structure defined a minimal three-helix bundle that binds Hsc70 and modulates chaperone activity, founding a distinct BAG subfamily.

    Evidence Multidimensional NMR structure determination with Hsc70 binding and chaperone activity assays

    PMID:12058034

    Open questions at the time
    • Does not define how chaperone binding couples to BAG4's receptor-adaptor roles
    • No structure of full-length BAG4 or its complexes
  2. 2003 High

    Defining BAG4's physiological role at TNFR1: genetic knockout resolved whether BAG4 suppresses inflammatory versus apoptotic signaling, showing it restrains TNF-induced NF-κB and cytokine output but not the apoptotic arm.

    Evidence SODD knockout mouse with TNF challenge and NF-κB/JNK/apoptosis readouts in primary macrophages and MEFs

    PMID:12748303

    Open questions at the time
    • Mechanism by which BAG4 selectively dampens NF-κB but not apoptosis at TNFR1 unresolved
    • Stoichiometry and dynamics of the BAG4–TNFR1 association not defined
  3. 2003 Medium

    Testing the breadth of death-receptor modulation: overexpression showed BAG4 also reduces sensitivity to CD95L and alters receptor levels, extending its influence beyond TNFR1.

    Evidence Stable cDNA overexpression in HeLa with viability assays and receptor quantification

    PMID:12706861

    Open questions at the time
    • Overexpression model only; no direct CD95 binding shown
    • Whether receptor-level changes are direct or secondary unclear
  4. 2005 Medium

    Locating BAG4-Hsp70 at the cell surface: flow cytometry and co-IP showed BAG4 co-localizes with Hsp70 on the tumor plasma membrane and that its overexpression elevates membrane Hsp70 and confers radioprotection.

    Evidence Two-parameter flow cytometry, immunoprecipitation, overexpression, and gamma-irradiation in HeLa cells

    PMID:15592361

    Open questions at the time
    • Mechanism trafficking BAG4/Hsp70 to the membrane unknown
    • Functional consequence of membrane localization beyond radioprotection not defined
  5. 2011 High

    Identifying BAG4 as a phosphoinositide signaling adaptor: it was unclear how BAG4 influences PI3K/Akt, and knockout plus enzymatic assays showed BAG4 binds and inhibits the 5-phosphatase SKIP to sustain PI(3,4,5)P3, Akt activation, actin remodeling, and migration.

    Evidence Co-IP, SODD-/- MEFs, phosphatase activity assays, F-actin imaging, migration assays, and constitutively active Akt1 rescue

    PMID:21712384

    Open questions at the time
    • Whether SHIP1/SHIP2 are also catalytically inhibited not fully resolved
    • How BAG4's chaperone function relates to phosphatase inhibition unknown
  6. 2017 Low

    Linking BAG4 to tumor metabolism: overexpression studies indicated BAG4 enhances glucose uptake and GLUT1 expression via AKT in colorectal cancer.

    Evidence Overexpression, glucose uptake assays, and pharmacological AKT/GLUT1 inhibition (single lab, no direct binding)

    PMID:29087604

    Open questions at the time
    • Overexpression and pharmacology only; no direct interaction demonstrated
    • Causality between BAG4 and GLUT1 not established at the molecular level
  7. 2023 Medium

    Connecting BAG4 to MAPK signaling: co-IP and knockout showed BAG4 binds RAF-1 and promotes both PI3K/PDK1/AKT and RAF/MEK/ERK activation in lung cancer.

    Evidence Co-IP, CRISPR knockout, phosphoprotein Western blot, overexpression, and xenograft

    PMID:37107587

    Open questions at the time
    • Direct versus scaffolded nature of the BAG4–RAF-1 interaction unclear
    • How BAG4 coordinates parallel AKT and ERK activation not defined
  8. 2025 Medium

    Defining ubiquitin-dependent control of BAG4 abundance: a screen identified USP14 as deubiquitinating BAG4 at K403 (K48-linked), stabilizing it to block Parkin recruitment and suppress mitophagy in MSI-high colorectal cancer.

    Evidence siRNA screen, co-IP, K403 ubiquitination mapping, USP14 knockdown, mitochondrial fractionation, and xenograft

    PMID:40316942

    Open questions at the time
    • E3 ligase opposing USP14 on BAG4 not identified
    • Mechanism by which stabilized BAG4 blocks Parkin recruitment unknown
  9. 2025 Medium

    Revealing pathogen hijacking of BAG4: mycobacterial PknG phosphorylates host BAG4 at Thr405, driving irreversible TNFR1 binding that blocks Caspase-8 activation and apoptosis to promote bacterial survival.

    Evidence Phosphoproteomics, S-nitrosylation site mapping, PknG-knockout M.tb, macrophage infection, and Caspase-8/TNFR1 assays

    PMID:40035756

    Open questions at the time
    • Structural basis of irreversible phospho-BAG4–TNFR1 binding undefined
    • Whether host kinases phosphorylate Thr405 under physiological conditions unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BAG4's core co-chaperone activity mechanistically links its multiple downstream roles—death-receptor regulation, phosphoinositide and MAPK signaling, and mitophagy control—remains unresolved.
  • No unified mechanism connecting Hsc70 binding to receptor/signaling adaptor functions
  • No structure of BAG4 in complex with TNFR1, SKIP, or RAF-1
  • Physiological E3 ligase and kinase regulators of BAG4 not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
HSPA1AHSPA8INPP5DINPP5KINPPL1RAF1TNFRSF1AUSP14

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 The BAG domain (BD) of BAG4/SODD was structurally determined by multidimensional NMR to be a three-helix bundle approximately one-third shorter than the BAG1 BD, representing a minimal functional fragment capable of binding Hsc70 and modulating its chaperone activity. This defines BAG4/SODD as founding a structural subfamily with BAG3 and BAG5, distinct from BAG1. Multidimensional NMR structure determination; Hsc70 binding and chaperone activity assays The Journal of biological chemistry High 12058034
2003 SODD-deficient mice and cells show accelerated TNF-induced NF-κB activation and larger cytokine responses to TNF challenge, while TNF-induced JNK activity is slightly repressed and apoptotic signaling is not hyperresponsive, establishing SODD as a negative regulator of the TNFR1 inflammatory signaling pathway but not of the apoptotic arm. SODD knockout mouse model; TNF challenge assays; NF-κB and JNK activity measurements in macrophages and embryonic fibroblasts Molecular and cellular biology High 12748303
2005 BAG4/SODD co-localizes with Hsp70 not only in the cytosol but also on the plasma membrane of tumor cells, as confirmed by two-parameter flow cytometry and immunoprecipitation. Overexpression of BAG4 elevates membrane Hsp70 levels and protects cells against radiation-induced G2/M arrest and growth inhibition, but membrane BAG4 itself is not a recognition target for NK cell cytotoxicity (Hsp70 is). Fluorescence-activated cell sorting; two-parameter flow cytometry; immunoprecipitation; BAG4 overexpression in HeLa cells; NK cell cytotoxicity assays; gamma-irradiation Cell death and differentiation Medium 15592361
2003 Stable overexpression of SODD/BAG4 in HeLa cells reduces cellular sensitivity not only to TNFα (via TNFR1) but also to CD95 ligand, indicating that SODD modulates the CD95 apoptotic pathway in addition to TNFR1. Overexpression also elevated protein levels of both TNFR1 and CD95 receptors and altered BAG1 expression. Stable cDNA transfection; Western blot; cell viability assays with TNFα and CD95L; receptor quantification Cancer letters Medium 12706861
2011 SODD/BAG4 forms a complex with inositol 5-phosphatases SKIP, SHIP1, and SHIP2; interaction with SKIP inhibits its PI(3,4,5)P3 5-phosphatase catalytic activity, thereby enhancing PI(3,4,5)P3-effector recruitment to the plasma membrane and Akt activation. SODD-deficient MEFs show reduced Akt phosphorylation (Ser473 and Thr308) after EGF stimulation with increased SKIP activity, decreased F-actin stress fibers, lamellipodia, and focal adhesion complexity, rescued by constitutively active Akt1. SODD-deficient macrophages show reduced cell migration. Co-immunoprecipitation; SODD-/- mouse embryonic fibroblasts; phosphoinositide 5-phosphatase activity assays; Akt phosphorylation assays; F-actin/lamellipodia imaging; cell migration assays; constitutively active Akt1 rescue The Journal of biological chemistry High 21712384
2023 SODD/BAG4 binds RAF-1 (confirmed by co-immunoprecipitation) in lung cancer cells, and SODD knockout reduces phosphorylation of AKT, RAF-1, and ERK-1, while SODD overexpression increases AKT phosphorylation, placing SODD as an activator of both the PI3K/PDK1/AKT and RAF/MEK/ERK signaling pathways. SODD knockout also reduces PDK1 protein expression. Co-immunoprecipitation; CRISPR/Cas9 knockout; Western blot for phosphoproteins; SODD overexpression; xenograft tumor model Genes Medium 37107587
2025 Mycobacterial PknG, secreted into macrophages upon S-nitrosylation at Cys109, phosphorylates host SODD at Thr405. Phosphorylated SODD irreversibly binds the TNFR1 death domain, preventing Caspase-8 activation and extrinsic apoptosis in infected macrophages, thereby promoting mycobacterial survival. Phosphoproteomic studies; S-nitrosylation site mapping; in vivo macrophage infection; PknG-knockout M.tb; Caspase-8 activation assays; TNFR1 binding assays Proceedings of the National Academy of Sciences of the United States of America Medium 40035756
2025 USP14 deubiquitinates BAG4 at K403 via K48-linked deubiquitination, stabilizing BAG4 protein levels. Stabilized BAG4 prevents Parkin recruitment to damaged mitochondria, thereby inhibiting mitophagy in microsatellite instability-high colorectal cancer cells. siRNA library screening; co-immunoprecipitation; Western blot; site-specific ubiquitination mapping (K403); mitochondrial protein fractionation; USP14 knockdown; xenograft model Molecular medicine Medium 40316942
2017 SODD overexpression in colorectal cancer cells enhances glucose uptake and GLUT1 expression via AKT phosphorylation upregulation, and inhibition of either GLUT1 or AKT reverses SODD-induced glucose uptake enhancement. SODD overexpression; glucose uptake assays; GLUT1 expression by Western blot; AKT phosphorylation assays; pharmacological inhibition of GLUT1 and AKT Cell biology international Low 29087604
2012 miR-26a directly represses BAG4/SODD expression through a binding site in the SODD 3'UTR (luciferase reporter assay), and siRNA knockdown of SODD induces apoptosis in most miR-26a-sensitive melanoma cell lines, establishing SODD as a functionally important anti-apoptotic target of miR-26a in melanoma. Luciferase 3'UTR reporter assay; miR-26a mimic transfection; siRNA knockdown; Western blot; apoptosis assays The Journal of investigative dermatology Medium 23190898

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells. Cell death and differentiation 99 15592361
2002 BAG4/SODD protein contains a short BAG domain. The Journal of biological chemistry 55 12058034
2001 Samui, a novel cold-inducible gene, encoding a protein with a BAG domain similar to silencer of death domains (SODD/BAG-4), isolated from Bombyx diapause eggs. European journal of biochemistry 52 11422373
2012 MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD). The Journal of investigative dermatology 51 23190898
2000 Enhanced expression of Silencer of death domains (SODD/BAG-4) in pancreatic cancer. Biochemical and biophysical research communications 48 10799310
2003 Role of SODD in regulation of tumor necrosis factor responses. Molecular and cellular biology 42 12748303
2007 BAG-4/SODD and associated antiapoptotic proteins are linked to aggressiveness of epithelial ovarian cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 32 18006758
2000 IkappaB/NF-kappaB mediated cisplatin resistance in HeLa cells after low-dose gamma-irradiation is associated with altered SODD expression. Apoptosis : an international journal on programmed cell death 28 11225847
2003 Overexpression of the 'silencer of death domain', SODD/BAG-4, modulates both TNFR1- and CD95-dependent cell death pathways. Cancer letters 18 12706861
2011 Silencer of death domains (SODD) inhibits skeletal muscle and kidney enriched inositol 5-phosphatase (SKIP) and regulates phosphoinositide 3-kinase (PI3K)/Akt signaling to the actin cytoskeleton. The Journal of biological chemistry 15 21712384
2007 Expression of SODD and P65 in ALL of children and its relationship with chemotherapeutic drugs. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 11 17641854
2002 Altered signaling of TNFalpha-TNFR1 and SODD/BAG4 is responsible for radioresistance in human HT-R15 cells. Anticancer research 11 12017295
2020 Novel copy number variation of the BAG4 gene is associated with growth traits in three Chinese sheep populations. Animal biotechnology 7 32022644
2025 USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer. Molecular medicine (Cambridge, Mass.) 5 40316942
2023 SODD Promotes Lung Cancer Tumorigenesis by Activating the PDK1/AKT and RAF/MEK/ERK Signaling. Genes 5 37107587
2014 Significance of SODD expression in childhood acute lymphoblastic leukemia and its influence on chemotherapy. Genetics and molecular research : GMR 5 24737427
2025 S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages. Proceedings of the National Academy of Sciences of the United States of America 4 40035756
2017 SODD promotes glucose uptake of colorectal cancer cells via AKT pathway. Cell biology international 3 29087604
2023 Downregulation of SODD mediates carnosol-induced reduction in cell proliferation in esophageal adenocarcinoma cells. Scientific reports 2 37386230
2015 The neuronal-specific SGK1.1 (SGK1_v2) kinase as a transcriptional modulator of BAG4, Brox, and PPP1CB genes expression. International journal of molecular sciences 2 25849655
2025 Expression Analysis, Diagnostic Significance and Biological Functions of BAG4 in Acute Myeloid Leukemia. Medicina (Kaunas, Lithuania) 1 40870378
2022 Expression Characteristics of SODD and ALG-2 as Possible Biomarkers for Evaluating Lymphatic Metastasis Potential of Hepatocarcinoma in a Mouse Model. Cellular and molecular biology (Noisy-le-Grand, France) 1 35818199
2007 [Effects of SODD and survivin on leukemia cell apoptosis induced by chemotherapeutic drugs]. Zhongguo shi yan xue ye xue za zhi 0 17605853

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