{"gene":"BAG4","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Multidimensional NMR structure determination; Hsc70 binding and chaperone activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional binding validation in a single rigorous study","pmids":["12058034"],"is_preprint":false},{"year":2003,"finding":"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.","method":"SODD knockout mouse model; TNF challenge assays; NF-κB and JNK activity measurements in macrophages and embryonic fibroblasts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with multiple orthogonal cellular readouts (NF-κB, JNK, cytokine, apoptosis) in primary cells and in vivo","pmids":["12748303"],"is_preprint":false},{"year":2005,"finding":"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).","method":"Fluorescence-activated cell sorting; two-parameter flow cytometry; immunoprecipitation; BAG4 overexpression in HeLa cells; NK cell cytotoxicity assays; gamma-irradiation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and overexpression with multiple functional readouts in one lab","pmids":["15592361"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Stable cDNA transfection; Western blot; cell viability assays with TNFα and CD95L; receptor quantification","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression model with multiple functional readouts, single lab","pmids":["12706861"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, enzymatic assay, knockout cells, genetic rescue, migration assay) in a single rigorous study","pmids":["21712384"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation; CRISPR/Cas9 knockout; Western blot for phosphoproteins; SODD overexpression; xenograft tumor model","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multiple signaling readouts and in vivo xenograft, single lab","pmids":["37107587"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Phosphoproteomic studies; S-nitrosylation site mapping; in vivo macrophage infection; PknG-knockout M.tb; Caspase-8 activation assays; TNFR1 binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus knockout bacterial model and multiple functional readouts, single lab","pmids":["40035756"],"is_preprint":false},{"year":2025,"finding":"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.","method":"siRNA library screening; co-immunoprecipitation; Western blot; site-specific ubiquitination mapping (K403); mitochondrial protein fractionation; USP14 knockdown; xenograft model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination site identification and functional mitophagy readout, single lab","pmids":["40316942"],"is_preprint":false},{"year":2017,"finding":"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.","method":"SODD overexpression; glucose uptake assays; GLUT1 expression by Western blot; AKT phosphorylation assays; pharmacological inhibition of GLUT1 and AKT","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression and pharmacological inhibition only, single lab, no direct binding/interaction assay","pmids":["29087604"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Luciferase 3'UTR reporter assay; miR-26a mimic transfection; siRNA knockdown; Western blot; apoptosis assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter validation plus siRNA functional rescue in multiple cell lines, single lab","pmids":["23190898"],"is_preprint":false}],"current_model":"BAG4/SODD is a co-chaperone whose short BAG domain binds Hsc70/Hsp70 to modulate chaperone activity; it constitutively associates with the TNFR1 death domain to suppress spontaneous NF-κB signaling and inflammatory cytokine production (but not apoptotic signaling); forms complexes with inositol 5-phosphatases (SKIP, SHIP1, SHIP2) to inhibit their activity and thereby promote PI3K/Akt signaling, actin cytoskeletal remodeling, and cell migration; activates RAF/MEK/ERK signaling through direct interaction with RAF-1; is stabilized by USP14-mediated K48-deubiquitination at K403, which blocks Parkin-dependent mitophagy; and is post-translationally regulated by phosphorylation at Thr405 (by mycobacterial PknG), which drives irreversible TNFR1 binding to prevent Caspase-8-mediated apoptosis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12058034"],"confidence":"High","gaps":["Does not define how chaperone binding couples to BAG4's receptor-adaptor roles","No structure of full-length BAG4 or its complexes"]},{"year":2003,"claim":"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","pmids":["12748303"],"confidence":"High","gaps":["Mechanism by which BAG4 selectively dampens NF-κB but not apoptosis at TNFR1 unresolved","Stoichiometry and dynamics of the BAG4–TNFR1 association not defined"]},{"year":2003,"claim":"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","pmids":["12706861"],"confidence":"Medium","gaps":["Overexpression model only; no direct CD95 binding shown","Whether receptor-level changes are direct or secondary unclear"]},{"year":2005,"claim":"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","pmids":["15592361"],"confidence":"Medium","gaps":["Mechanism trafficking BAG4/Hsp70 to the membrane unknown","Functional consequence of membrane localization beyond radioprotection not defined"]},{"year":2011,"claim":"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","pmids":["21712384"],"confidence":"High","gaps":["Whether SHIP1/SHIP2 are also catalytically inhibited not fully resolved","How BAG4's chaperone function relates to phosphatase inhibition unknown"]},{"year":2017,"claim":"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)","pmids":["29087604"],"confidence":"Low","gaps":["Overexpression and pharmacology only; no direct interaction demonstrated","Causality between BAG4 and GLUT1 not established at the molecular level"]},{"year":2023,"claim":"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","pmids":["37107587"],"confidence":"Medium","gaps":["Direct versus scaffolded nature of the BAG4–RAF-1 interaction unclear","How BAG4 coordinates parallel AKT and ERK activation not defined"]},{"year":2025,"claim":"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","pmids":["40316942"],"confidence":"Medium","gaps":["E3 ligase opposing USP14 on BAG4 not identified","Mechanism by which stabilized BAG4 blocks Parkin recruitment unknown"]},{"year":2025,"claim":"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","pmids":["40035756"],"confidence":"Medium","gaps":["Structural basis of irreversible phospho-BAG4–TNFR1 binding undefined","Whether host kinases phosphorylate Thr405 under physiological conditions unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":[],"partners":["HSPA8","HSPA1A","TNFRSF1A","INPP5K","INPP5D","INPPL1","RAF1","USP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95429","full_name":"BAG family molecular chaperone regulator 4","aliases":["Bcl-2-associated athanogene 4","Silencer of death domains"],"length_aa":457,"mass_kda":49.6,"function":"Inhibits the chaperone activity of HSP70/HSC70 by promoting substrate release (By similarity). Prevents constitutive TNFRSF1A signaling. Negative regulator of PRKN translocation to damaged mitochondria","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O95429/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BAG4","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000156735","cell_line_id":"CID000007","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"nucleolus_fc_dfc","grade":2}],"interactors":[{"gene":"ARHGAP18","stoichiometry":0.2},{"gene":"STIM1","stoichiometry":0.2},{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"AHSA1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DNAJC7","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000007","total_profiled":1310},"omim":[{"mim_id":"615650","title":"REGULATOR OF G PROTEIN SIGNALING 22; RGS22","url":"https://www.omim.org/entry/615650"},{"mim_id":"608309","title":"PTEN-INDUCED KINASE 1; PINK1","url":"https://www.omim.org/entry/608309"},{"mim_id":"607980","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 7; TOMM7","url":"https://www.omim.org/entry/607980"},{"mim_id":"607702","title":"TRANSCRIPTIONAL AND IMMUNE RESPONSE REGULATOR; TCIM","url":"https://www.omim.org/entry/607702"},{"mim_id":"607281","title":"LSM1 HOMOLOG, mRNA DEGRADATION-ASSOCIATED; LSM1","url":"https://www.omim.org/entry/607281"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BAG4"},"hgnc":{"alias_symbol":["SODD"],"prev_symbol":[]},"alphafold":{"accession":"O95429","domains":[{"cath_id":"1.20.58.120","chopping":"377-455","consensus_level":"high","plddt":96.4814,"start":377,"end":455}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95429","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95429-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95429-F1-predicted_aligned_error_v6.png","plddt_mean":54.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BAG4","jax_strain_url":"https://www.jax.org/strain/search?query=BAG4"},"sequence":{"accession":"O95429","fasta_url":"https://rest.uniprot.org/uniprotkb/O95429.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95429/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95429"}},"corpus_meta":[{"pmid":"15592361","id":"PMC_15592361","title":"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.","date":"2005","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/15592361","citation_count":99,"is_preprint":false},{"pmid":"12058034","id":"PMC_12058034","title":"BAG4/SODD protein contains a short BAG domain.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12058034","citation_count":55,"is_preprint":false},{"pmid":"11422373","id":"PMC_11422373","title":"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.","date":"2001","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11422373","citation_count":52,"is_preprint":false},{"pmid":"23190898","id":"PMC_23190898","title":"MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD).","date":"2012","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23190898","citation_count":51,"is_preprint":false},{"pmid":"10799310","id":"PMC_10799310","title":"Enhanced expression of Silencer of death domains (SODD/BAG-4) in pancreatic cancer.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10799310","citation_count":48,"is_preprint":false},{"pmid":"12748303","id":"PMC_12748303","title":"Role of SODD in regulation of tumor necrosis factor responses.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12748303","citation_count":42,"is_preprint":false},{"pmid":"18006758","id":"PMC_18006758","title":"BAG-4/SODD and associated antiapoptotic proteins are linked to aggressiveness of epithelial ovarian cancer.","date":"2007","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18006758","citation_count":32,"is_preprint":false},{"pmid":"11225847","id":"PMC_11225847","title":"IkappaB/NF-kappaB mediated cisplatin resistance in HeLa cells after low-dose gamma-irradiation is associated with altered SODD expression.","date":"2000","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/11225847","citation_count":28,"is_preprint":false},{"pmid":"12706861","id":"PMC_12706861","title":"Overexpression of the 'silencer of death domain', SODD/BAG-4, modulates both TNFR1- and CD95-dependent cell death pathways.","date":"2003","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/12706861","citation_count":18,"is_preprint":false},{"pmid":"21712384","id":"PMC_21712384","title":"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.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21712384","citation_count":15,"is_preprint":false},{"pmid":"17641854","id":"PMC_17641854","title":"Expression of SODD and P65 in ALL of children and its relationship with chemotherapeutic drugs.","date":"2007","source":"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","url":"https://pubmed.ncbi.nlm.nih.gov/17641854","citation_count":11,"is_preprint":false},{"pmid":"12017295","id":"PMC_12017295","title":"Altered signaling of TNFalpha-TNFR1 and SODD/BAG4 is responsible for radioresistance in human HT-R15 cells.","date":"2002","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12017295","citation_count":11,"is_preprint":false},{"pmid":"32022644","id":"PMC_32022644","title":"Novel copy number variation of the BAG4 gene is associated with growth traits in three Chinese sheep populations.","date":"2020","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32022644","citation_count":7,"is_preprint":false},{"pmid":"40316942","id":"PMC_40316942","title":"USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer.","date":"2025","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/40316942","citation_count":5,"is_preprint":false},{"pmid":"37107587","id":"PMC_37107587","title":"SODD Promotes Lung Cancer Tumorigenesis by Activating the PDK1/AKT and RAF/MEK/ERK Signaling.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37107587","citation_count":5,"is_preprint":false},{"pmid":"24737427","id":"PMC_24737427","title":"Significance of SODD expression in childhood acute lymphoblastic leukemia and its influence on chemotherapy.","date":"2014","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/24737427","citation_count":5,"is_preprint":false},{"pmid":"40035756","id":"PMC_40035756","title":"S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40035756","citation_count":4,"is_preprint":false},{"pmid":"29087604","id":"PMC_29087604","title":"SODD promotes glucose uptake of colorectal cancer cells via AKT pathway.","date":"2017","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/29087604","citation_count":3,"is_preprint":false},{"pmid":"37386230","id":"PMC_37386230","title":"Downregulation of SODD mediates carnosol-induced reduction in cell proliferation in esophageal adenocarcinoma cells.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37386230","citation_count":2,"is_preprint":false},{"pmid":"25849655","id":"PMC_25849655","title":"The neuronal-specific SGK1.1 (SGK1_v2) kinase as a transcriptional modulator of BAG4, Brox, and PPP1CB genes expression.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25849655","citation_count":2,"is_preprint":false},{"pmid":"35818199","id":"PMC_35818199","title":"Expression Characteristics of SODD and ALG-2 as Possible Biomarkers for Evaluating Lymphatic Metastasis Potential of Hepatocarcinoma in a Mouse Model.","date":"2022","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/35818199","citation_count":1,"is_preprint":false},{"pmid":"40870378","id":"PMC_40870378","title":"Expression Analysis, Diagnostic Significance and Biological Functions of BAG4 in Acute Myeloid Leukemia.","date":"2025","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/40870378","citation_count":1,"is_preprint":false},{"pmid":"17605853","id":"PMC_17605853","title":"[Effects of SODD and survivin on leukemia cell apoptosis induced by chemotherapeutic drugs].","date":"2007","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/17605853","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14386,"output_tokens":2824,"usd":0.042759,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10070,"output_tokens":3571,"usd":0.069812,"stage2_stop_reason":"end_turn"},"total_usd":0.112571,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Multidimensional NMR structure determination; Hsc70 binding and chaperone activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional binding validation in a single rigorous study\",\n      \"pmids\": [\"12058034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"SODD knockout mouse model; TNF challenge assays; NF-κB and JNK activity measurements in macrophages and embryonic fibroblasts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with multiple orthogonal cellular readouts (NF-κB, JNK, cytokine, apoptosis) in primary cells and in vivo\",\n      \"pmids\": [\"12748303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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).\",\n      \"method\": \"Fluorescence-activated cell sorting; two-parameter flow cytometry; immunoprecipitation; BAG4 overexpression in HeLa cells; NK cell cytotoxicity assays; gamma-irradiation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and overexpression with multiple functional readouts in one lab\",\n      \"pmids\": [\"15592361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Stable cDNA transfection; Western blot; cell viability assays with TNFα and CD95L; receptor quantification\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression model with multiple functional readouts, single lab\",\n      \"pmids\": [\"12706861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, enzymatic assay, knockout cells, genetic rescue, migration assay) in a single rigorous study\",\n      \"pmids\": [\"21712384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; CRISPR/Cas9 knockout; Western blot for phosphoproteins; SODD overexpression; xenograft tumor model\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multiple signaling readouts and in vivo xenograft, single lab\",\n      \"pmids\": [\"37107587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphoproteomic studies; S-nitrosylation site mapping; in vivo macrophage infection; PknG-knockout M.tb; Caspase-8 activation assays; TNFR1 binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus knockout bacterial model and multiple functional readouts, single lab\",\n      \"pmids\": [\"40035756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA library screening; co-immunoprecipitation; Western blot; site-specific ubiquitination mapping (K403); mitochondrial protein fractionation; USP14 knockdown; xenograft model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination site identification and functional mitophagy readout, single lab\",\n      \"pmids\": [\"40316942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"SODD overexpression; glucose uptake assays; GLUT1 expression by Western blot; AKT phosphorylation assays; pharmacological inhibition of GLUT1 and AKT\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression and pharmacological inhibition only, single lab, no direct binding/interaction assay\",\n      \"pmids\": [\"29087604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase 3'UTR reporter assay; miR-26a mimic transfection; siRNA knockdown; Western blot; apoptosis assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter validation plus siRNA functional rescue in multiple cell lines, single lab\",\n      \"pmids\": [\"23190898\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAG4/SODD is a co-chaperone whose short BAG domain binds Hsc70/Hsp70 to modulate chaperone activity; it constitutively associates with the TNFR1 death domain to suppress spontaneous NF-κB signaling and inflammatory cytokine production (but not apoptotic signaling); forms complexes with inositol 5-phosphatases (SKIP, SHIP1, SHIP2) to inhibit their activity and thereby promote PI3K/Akt signaling, actin cytoskeletal remodeling, and cell migration; activates RAF/MEK/ERK signaling through direct interaction with RAF-1; is stabilized by USP14-mediated K48-deubiquitination at K403, which blocks Parkin-dependent mitophagy; and is post-translationally regulated by phosphorylation at Thr405 (by mycobacterial PknG), which drives irreversible TNFR1 binding to prevent Caspase-8-mediated apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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 [#0, #4, #5]. 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 [#0]. At the death receptor, BAG4 acts as a negative regulator of TNFR1-driven inflammatory signaling: loss of BAG4 accelerates TNF-induced NF-\\u03baB activation and amplifies cytokine responses without sensitizing the apoptotic arm [#1]. 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 [#4], and it binds RAF-1 to additionally drive RAF/MEK/ERK signaling [#5]. 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 [#7]. BAG4 also associates with Hsp70 at the plasma membrane of tumor cells, where its overexpression confers protection against radiation-induced G2/M arrest [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Multidimensional NMR structure determination with Hsc70 binding and chaperone activity assays\",\n      \"pmids\": [\"12058034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how chaperone binding couples to BAG4's receptor-adaptor roles\", \"No structure of full-length BAG4 or its complexes\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining BAG4's physiological role at TNFR1: genetic knockout resolved whether BAG4 suppresses inflammatory versus apoptotic signaling, showing it restrains TNF-induced NF-\\u03baB and cytokine output but not the apoptotic arm.\",\n      \"evidence\": \"SODD knockout mouse with TNF challenge and NF-\\u03baB/JNK/apoptosis readouts in primary macrophages and MEFs\",\n      \"pmids\": [\"12748303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BAG4 selectively dampens NF-\\u03baB but not apoptosis at TNFR1 unresolved\", \"Stoichiometry and dynamics of the BAG4\\u2013TNFR1 association not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Testing the breadth of death-receptor modulation: overexpression showed BAG4 also reduces sensitivity to CD95L and alters receptor levels, extending its influence beyond TNFR1.\",\n      \"evidence\": \"Stable cDNA overexpression in HeLa with viability assays and receptor quantification\",\n      \"pmids\": [\"12706861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression model only; no direct CD95 binding shown\", \"Whether receptor-level changes are direct or secondary unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Two-parameter flow cytometry, immunoprecipitation, overexpression, and gamma-irradiation in HeLa cells\",\n      \"pmids\": [\"15592361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism trafficking BAG4/Hsp70 to the membrane unknown\", \"Functional consequence of membrane localization beyond radioprotection not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, SODD-/- MEFs, phosphatase activity assays, F-actin imaging, migration assays, and constitutively active Akt1 rescue\",\n      \"pmids\": [\"21712384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHIP1/SHIP2 are also catalytically inhibited not fully resolved\", \"How BAG4's chaperone function relates to phosphatase inhibition unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking BAG4 to tumor metabolism: overexpression studies indicated BAG4 enhances glucose uptake and GLUT1 expression via AKT in colorectal cancer.\",\n      \"evidence\": \"Overexpression, glucose uptake assays, and pharmacological AKT/GLUT1 inhibition (single lab, no direct binding)\",\n      \"pmids\": [\"29087604\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Overexpression and pharmacology only; no direct interaction demonstrated\", \"Causality between BAG4 and GLUT1 not established at the molecular level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, CRISPR knockout, phosphoprotein Western blot, overexpression, and xenograft\",\n      \"pmids\": [\"37107587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus scaffolded nature of the BAG4\\u2013RAF-1 interaction unclear\", \"How BAG4 coordinates parallel AKT and ERK activation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA screen, co-IP, K403 ubiquitination mapping, USP14 knockdown, mitochondrial fractionation, and xenograft\",\n      \"pmids\": [\"40316942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP14 on BAG4 not identified\", \"Mechanism by which stabilized BAG4 blocks Parkin recruitment unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phosphoproteomics, S-nitrosylation site mapping, PknG-knockout M.tb, macrophage infection, and Caspase-8/TNFR1 assays\",\n      \"pmids\": [\"40035756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of irreversible phospho-BAG4\\u2013TNFR1 binding undefined\", \"Whether host kinases phosphorylate Thr405 under physiological conditions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BAG4's core co-chaperone activity mechanistically links its multiple downstream roles\\u2014death-receptor regulation, phosphoinositide and MAPK signaling, and mitophagy control\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA8\", \"HSPA1A\", \"TNFRSF1A\", \"INPP5K\", \"INPP5D\", \"INPPL1\", \"RAF1\", \"USP14\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}