{"gene":"HSP90AB1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2018,"finding":"HSP90AB1 directly interacts with LRP5 (a Wnt co-receptor) via co-immunoprecipitation and GST pull-down, inhibiting ubiquitin-mediated proteasomal degradation of LRP5 and thereby stabilizing it; this stabilization activates AKT and Wnt/β-catenin signaling to promote epithelial-mesenchymal transition in gastric cancer cells.","method":"Co-immunoprecipitation, GST pull-down, in vitro ubiquitination assay, immunofluorescence, gain/loss-of-function in cell lines and xenograft mouse models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus GST pull-down plus functional ubiquitination assay plus in vivo validation, single lab but multiple orthogonal methods","pmids":["30305727"],"is_preprint":false},{"year":2008,"finding":"HSP90AB1 (HSP90beta) is a direct binding target of gamendazole; the drug binds purified yeast HSP82 (mammalian HSP90AB1 homologue), inhibits its luciferase-refolding (chaperone) activity, causes degradation of HSP90-dependent client proteins AKT1 and ERBB2, and does not compete with geldanamycin or novobiocin for binding, suggesting a distinct binding site.","method":"Biotinylated affinity purification, MALDI-TOF mass spectrometry, Western blot, in vitro luciferase refolding assay with purified HSP82","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of chaperone activity inhibition with purified protein, plus affinity purification identification, single lab","pmids":["18218611"],"is_preprint":false},{"year":2021,"finding":"EEF1A2 physically interacts with HSP90AB1 (confirmed by LC-MS/MS and Co-IP), and this interaction increases TGFβ receptor I and II expression, followed by enhanced SMAD3 phosphorylation and nuclear localization, promoting EMT in lung adenocarcinoma cells.","method":"LC-MS/MS interactome, co-immunoprecipitation, immunofluorescence, in vitro and in vivo functional assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with LC-MS/MS identification plus functional pathway validation, single lab","pmids":["33473168"],"is_preprint":false},{"year":2022,"finding":"HSP90AB1 physically interacts with B7-1 in podocytes via residue K69 in the N-terminal domain of HSP90AB1 (identified by LC-MS/MS and confirmed by molecular docking and mutant analysis), acting as a scaffold to transmit signals from B7-1 to LRP5/β-catenin, thereby mediating podocyte injury and glomerulosclerosis.","method":"LC-MS/MS, molecular docking, site-directed mutagenesis, co-immunoprecipitation, transgenic/adriamycin nephropathy mouse models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — LC-MS/MS identification, mutant-confirmed binding site, Co-IP, and in vivo validation, single lab with multiple orthogonal methods","pmids":["35710882"],"is_preprint":false},{"year":2021,"finding":"HSP90AB1 interacts with the coiled-coil (CC) domain of Bcr-Abl via its N-terminal domain (NTD), retaining Bcr-Abl in the cytoplasm and maintaining Bcr-Abl tyrosine kinase activation; disruption of this interaction (by 17AAG targeting NTD) permits nuclear translocation of Bcr-Abl, which activates p73 and induces apoptosis of CML cells.","method":"Immunoprecipitation-mass spectrometry, immunoprecipitation with domain mapping, immunofluorescence, Western blot, CCK-8, flow cytometry","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS with domain-level binding confirmation plus subcellular localization experiments plus functional assays, single lab","pmids":["34217296"],"is_preprint":false},{"year":2022,"finding":"HSP90AB1 immunoprecipitates latent TGFβ (from osteoblast-secreted proteomes) and inactivates it; extracellular HSP90AB1 also inhibits tumor cell growth and osteoclast maturation in a mouse model of osteolysis.","method":"Immunoprecipitation (from conditioned medium proteomes), whole-genome proteomics, gain/loss-of-function, in vivo mouse osteolysis model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation with proteomic validation plus in vivo functional data, single lab","pmids":["34976221"],"is_preprint":false},{"year":2019,"finding":"USP22 deubiquitylase positively regulates HSP90AB1 expression at the transcriptional level via maintenance of H3K9 acetylation on the HSP90AB1 gene; siRNA knockdown of USP22 reduces H3K9ac at the HSP90AB1 locus and decreases HSP90AB1 mRNA and protein in colorectal and breast cancer cells and in tissue-specific Usp22 knockout mice.","method":"siRNA knockdown, mRNA-seq, Western blot, ChIP (H3K9ac), mouse tissue-specific Usp22 knockout","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-confirmed epigenetic mechanism plus in vivo knockout validation, single lab with two orthogonal methods","pmids":["31801945"],"is_preprint":false},{"year":2022,"finding":"RGNNV capsid protein (CP) binds the NM domain of fish HSP90ab1 (LjHSP90ab1) on the cell surface, competitively blocking AKT interaction with HSP90ab1, thereby inhibiting the AKT-mTOR pathway and inducing incomplete autophagy (impaired autophagosome-lysosome fusion) during early viral infection.","method":"Co-immunoprecipitation, domain mapping, Western blot, autophagy flux assays in fish cell lines","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain-level mapping, competitive binding demonstrated, functional autophagy assays, single lab","pmids":["34904422"],"is_preprint":false},{"year":2023,"finding":"HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV (porcine deltacoronavirus); the C-tail domain of the N protein mediates interaction with HSP90AB1, and HSP90AB1 protects N protein from proteasomal degradation. ATPase activity of HSP90AB1 is required for PDCoV infection (ATPase-inhibiting HSP90 inhibitors suppressed infection, but KW-2478, which does not affect ATPase, had no effect).","method":"Genome-wide CRISPR screen, Co-IP, domain deletion mapping, HSP90 inhibitor treatment, proteasome inhibitor rescue assay, viral titer measurement","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screen plus Co-IP plus domain mapping plus mechanistic rescue assays, multiple orthogonal methods in one study","pmids":["38092149"],"is_preprint":false},{"year":2024,"finding":"SENP1-mediated deSUMOylation of HSP90ab1 at Lys72 suppresses STAT3 activation and fibronectin secretion in cardiomyocytes; loss of SENP1 increases HSP90ab1 SUMOylation, activates STAT3, and drives paracrine fibroblast activation and cardiac fibrosis after myocardial infarction. Mutation of HSP90ab1 Lys72 (SUMOylation site) ameliorates adverse ventricular remodeling.","method":"Cardiomyocyte-specific SENP1 KO and overexpression mice, site-directed mutagenesis (K72 mutation), Western blot, cardiac function measurement, histology","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-directed mutagenesis of PTM site plus in vivo KO/OE mouse models plus functional cardiac phenotype, single lab with multiple orthogonal methods","pmids":["38992961"],"is_preprint":false},{"year":2023,"finding":"DSCC1 interacts with HSP90AB1 (confirmed by co-immunoprecipitation) and promotes ER stress-mediated progression of lung adenocarcinoma; knockdown of either protein reduces LUAD cell proliferation, stemness, EMT, and metastatic potential.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro cell assays, in vivo tumor models","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up on the specific interaction, single lab","pmids":["37742009"],"is_preprint":false},{"year":2016,"finding":"HSP90AB1 knockdown reduces phospho-AKT (Ser473) levels in head and neck squamous cell carcinoma cells, placing HSP90AB1 upstream of AKT activation in HNSCC.","method":"Lentiviral shRNA knockdown, Western blot for phospho-AKT, CCK-8/EdU/colony/transwell/xenograft assays","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Western blot readout for pathway placement, no direct binding assay for AKT, single lab","pmids":["35929142"],"is_preprint":false},{"year":2022,"finding":"HSP90AB1 knockdown in T cells reduces p-AKT, SMARCC1, p-c-Fos, and p-c-Jun expression and increases ROS and apoptosis; overexpression of HSP90AB1 inhibits capecitabine-induced T cell apoptosis by sustaining the AKT/SMARCC1/AP-1 axis and reducing ROS, establishing HSP90AB1 as a pro-survival regulator in T cells via this signaling cascade.","method":"siRNA knockdown, overexpression, quantitative proteomics/phosphoproteomics, Western blot, ROS measurement, flow cytometry apoptosis assay","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional (KD and OE) experiments with proteomic and phosphoproteomic readouts, single lab","pmids":["35368874"],"is_preprint":false},{"year":2023,"finding":"PARP1 interacts with HSP90AB1 (confirmed by Co-IP), and HSP90AB1 counteracts PARP1's repression of BLM promoter activity; HSP90AB1 thus acts as a co-regulator that de-represses BLM transcription in prostate cancer cells.","method":"Co-immunoprecipitation, DNA pull-down with promoter probe, dual luciferase reporter assay, ChIP-qPCR, MS","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus promoter pull-down and luciferase reporter assay confirming transcriptional mechanism, single lab","pmids":["37415147"],"is_preprint":false},{"year":2023,"finding":"CDK1-SRC interaction transcriptionally activates HSP90AB1 expression in hepatocellular carcinoma; manipulation of SRC or HSP90AB1 reverses the effects of CDK1 and SRC on HCC cell proliferation and migration, placing HSP90AB1 downstream of the CDK1-SRC kinase network.","method":"In vitro and in vivo functional assays, transcriptomic/proteomic analysis, siRNA/overexpression experiments","journal":"Journal of proteome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis-type experiments without direct biochemical binding or promoter assay for CDK1-SRC→HSP90AB1 transcriptional activation, single lab","pmids":["37949475"],"is_preprint":false},{"year":2018,"finding":"Calenduloside E (CE) directly binds purified recombinant HSP90AB1 protein, as confirmed by competitive binding assay with CE-P probe and surface plasmon resonance (SPR) kinetic analysis showing dose-dependent binding.","method":"Clickable activity-based probe affinity purification, proteomic identification, competitive binding assay with purified recombinant HSP90AB1, SPR","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding with purified protein confirmed by SPR, but single lab and limited functional follow-up on binding consequence","pmids":["29875664"],"is_preprint":false},{"year":2023,"finding":"HSP90AB1 is required for transmissible gastroenteritis virus (TGEV) infection; knockdown of HSP90AB1 (but not HSP90AA1) and treatment with VER-82576 (an ATPase-inhibiting HSP90 inhibitor) reduce TGEV mRNA, N protein, and virus titers in a dose-dependent manner, with the inhibitory effect occurring mainly at early viral replication.","method":"siRNA knockdown, KO cells, HSP90 inhibitor time-of-addition assay, viral titer measurement, RT-qPCR, Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KD (HSP90AB1 vs HSP90AA1) plus inhibitor with ATPase-dependence control, single lab","pmids":["37958953"],"is_preprint":false},{"year":2025,"finding":"LGR5 directly binds HSP90AB1 (confirmed by GST pull-down and Co-IP), and this interaction promotes phosphorylation of GSK-3β, leading to β-catenin stabilization and nuclear translocation that activates AR transcription, conferring enzalutamide resistance in prostate cancer; reducing HSP90AB1-LGR5 binding restores enzalutamide sensitivity.","method":"GST pull-down, co-immunoprecipitation, immunofluorescence, Western blot, in vitro and in vivo functional assays","journal":"Chinese medical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus GST pull-down plus in vivo validation, single lab","pmids":["40280884"],"is_preprint":false},{"year":2025,"finding":"Polydatin specifically binds HSP90AB1 at the Asp88 residue and disrupts HSP90AB1-mediated stabilization of the client protein ACT1, thereby suppressing the IL-17/MAPK/NF-κB inflammatory pathway in acute lung injury models.","method":"CETSA, thermal proteome profiling, mass spectrometry, site-directed mutagenesis, molecular docking, MST, cell lines overexpressing HSP90AB1, Western blot, in vivo rat ALI model","journal":"Journal of ethnopharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical binding methods (CETSA, TPP, MST) plus mutagenesis of binding site plus client protein functional consequence, single lab but multiple orthogonal methods","pmids":["41707809"],"is_preprint":false},{"year":2025,"finding":"Bruceine A (BRA) binds HSP90AB1 at the Ser-108 residue and inhibits its chaperone function; downstream HSP90AB1 client/partner proteins PIK3CG, EGFR, and KDM5C are destabilized, suppressing HCC cell proliferation and inducing apoptosis.","method":"Chemical proteomics (MST, SPR, CETSA), site-directed mutagenesis, HSP90AB1 knockdown, TMT-based proteomics for downstream clients, patient-derived organoids and xenograft models","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical assays with mutagenesis confirming binding site plus proteomic identification of client proteins, single lab with multiple orthogonal methods","pmids":["40664262"],"is_preprint":false},{"year":2026,"finding":"ACOX1-dependent increase in crotonyl-CoA under hypoxia drives site-specific crotonylation of HSP90AB1 at Lys265; molecular dynamics simulations show K265 crotonylation induces conformational compaction of HSP90AB1, strengthening its interaction with client protein TXN (thioredoxin) and enhancing TXN stability to buffer ROS and confer cisplatin resistance in oral squamous cell carcinoma.","method":"Molecular dynamics simulation, site-directed mutagenesis (K265R), co-immunoprecipitation, Western blot, in vitro and in vivo tumor models, pharmacological inhibition of ACOX1","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of PTM site combined with Co-IP and functional in vivo data, single lab; structural insight from MD not experimentally solved structure","pmids":["41675575"],"is_preprint":false},{"year":2025,"finding":"Chemerin stimulates SUMO2/3 conjugation to HSP90AB1 in monocytes via β2 integrin signaling; this SUMOylation of HSP90AB1 is essential for downstream ERK1/2 phosphorylation and monocyte activation and adhesion, as shown by immunoprecipitation/LC-MS/MS identification and reversal with SUMOylation inhibitor ML-792.","method":"Immunoprecipitation, LC-MS/MS, SUMOylation inhibitor (ML-792), Western blot, monocyte adhesion assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification of SUMO2/3 interaction with HSP90AB1 plus pharmacological inhibition confirming functional role, single lab","pmids":["40744335"],"is_preprint":false},{"year":2026,"finding":"HSP90AB1 interacts with ITGBL1 and mediates its K63-linked ubiquitination and degradation; loss of this HSP90AB1-dependent degradation of ITGBL1 activates ER stress-induced autophagy, suppressing osteosarcoma progression.","method":"Co-IP, domain mapping, ubiquitination assay (K63-linkage), in vitro and in vivo functional assays, virtual screening and Co-IP for inhibitor (ivermectin)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with linkage-specific ubiquitination assay plus in vivo rescue, single lab","pmids":["41697125"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 (m6A reader) binds m6A-tagged HSP90AB1 mRNA and stabilizes it in an m6A-dependent manner, increasing HSP90AB1 protein levels which activate the PI3K/AKT signaling pathway to promote bladder cancer progression.","method":"RNA-seq, m6A-seq, RIP-seq, RIP-qPCR, site-directed mutagenesis of m6A sites, Western blot, in vitro and in vivo assays","journal":"FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-seq/RIP-seq convergence with mutagenesis validation of m6A sites, single lab with multiple orthogonal omics methods","pmids":["40105114"],"is_preprint":false},{"year":2025,"finding":"HNRNPH1 binds HSP90AB1 mRNA and inhibits its protein expression; this suppresses HSP90AB1-mediated inhibition of MAP1LC3B-dependent autophagy, thereby restraining lung adenocarcinoma malignant phenotype.","method":"RIP (RNA binding protein immunoprecipitation), siRNA/overexpression, Western blot, in vivo tumor models, autophagy flux assays","journal":"Respiratory research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP showing mRNA binding with functional consequence, but mechanistic link between HSP90AB1 and MAP1LC3B autophagy is indirect, single lab","pmids":["40468317"],"is_preprint":false},{"year":2024,"finding":"GLCCI1 directly interacts with HSP90AB1 (confirmed by Co-IP), and HSP90AB1 in turn interacts with GRP78; GLCCI1 acts as an upstream regulator of HSP90AB1, which then regulates GRP78-initiated ER stress-induced apoptosis in retinal ganglion cells during diabetic retinopathy.","method":"Co-immunoprecipitation, GLCCI1 overexpression/knockdown, Western blot for GRP78/CHOP/caspase-3, in vivo DR mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing protein-protein interaction chain with bidirectional expression experiments, single lab","pmids":["39496608"],"is_preprint":false},{"year":2022,"finding":"HSP90ab1 and Myh9 (non-muscle myosin) interact via immunoprecipitation; extracellular HSP90ab1 and Myh9 secreted by PI3K-activated MSCs exert anti-tumor effects and inhibit osteoclast maturation.","method":"Immunoprecipitation from conditioned medium, mass spectrometry, in vitro and in vivo tumor suppression assays","journal":"Molecular therapy oncolytics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP from secreted proteome with limited mechanistic follow-up on HSP90AB1-Myh9 interaction consequence, single lab","pmids":["36090473"],"is_preprint":false},{"year":2025,"finding":"SP1 transcription factor drives HSP90ab1 transcription by binding its promoter; pharmacological inhibition of SP1 reduces Hsp90ab1 expression; Hsp90ab1 in turn stabilizes the client protein COX-2 via p38/JNK signaling in uterine tissue, mediating primary dysmenorrhea.","method":"Promoter binding analysis (SP1 ChIP implied), geldanamycin inhibition of Hsp90ab1, lentiviral Hsp90ab1 overexpression reversal, Western blot, in vivo mouse PD model","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic loss/gain-of-function with pathway placement, lentiviral rescue experiment, single lab","pmids":["39914036"],"is_preprint":false},{"year":2020,"finding":"HSP90ab1 specifically adsorbs to denatured (misfolded) proteins in nanoparticle protein coronas; the level of HSP90ab1 adsorption correlates with circular dichroism and ANS fluorescence measures of protein denaturation, validating that HSP90ab1 functions as a chaperone that selectively binds misfolded/denatured client proteins in vitro.","method":"Western blot of NP-corona complex, circular dichroism, ANS fluorescence spectroscopy, comparison across NP types and surface modifications","journal":"Nanoscale","confidence":"Low","confidence_rationale":"Tier 3 / Weak — biochemical correlation of HSP90ab1 binding with denaturation metrics, no mutagenesis or reconstitution, single lab","pmids":["32696774"],"is_preprint":false},{"year":2025,"finding":"NB (Dictamni Cortex nanoparticles) suppresses HSP90AB1 transcription by inhibiting its activator CTCF, and disrupts the HSP90AB1-CDC37 co-chaperone complex, thereby inactivating client proteins STAT3 and AKT in keratinocytes.","method":"Nascent proteomics, Western blot, co-chaperone complex disruption assay, in vitro keratinocyte and in vivo mouse psoriasis model","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomics-identified mechanism with limited direct biochemical validation of CTCF-HSP90AB1 transcriptional regulation, single lab","pmids":["41114929"],"is_preprint":false}],"current_model":"HSP90AB1 (HSP90beta) is an ATP-dependent molecular chaperone that forms dimers and, with the help of co-chaperones (e.g., CDC37), binds and stabilizes diverse client proteins including kinases (AKT, SRC), receptor complexes (LRP5, TGFβ receptors), and transcription factors, preventing their ubiquitin-proteasomal degradation; it is regulated post-translationally by SUMOylation at Lys72 (written by SUMO machinery, erased by SENP1) and crotonylation at Lys265 (driven by ACOX1-derived crotonyl-CoA under hypoxia), and its expression is transcriptionally controlled by USP22-dependent H3K9 acetylation and SP1; physically, it anchors signaling complexes at the cytoplasm (retaining Bcr-Abl cytoplasmically via NTD interaction), on the cell surface (serving as a receptor for NNV capsid protein and a B7-1 signaling scaffold), and in secreted proteomes where it binds and inactivates latent TGFβ, collectively placing HSP90AB1 as a context-dependent regulator of oncogenic signaling (AKT/PI3K, Wnt/β-catenin, STAT3, MAPK) and viral infection."},"narrative":{"mechanistic_narrative":"HSP90AB1 (HSP90beta) is an ATP-dependent molecular chaperone that selectively binds misfolded client proteins and, by stabilizing diverse signaling clients against degradation, acts as a context-dependent amplifier of oncogenic and inflammatory signaling [PMID:32696774, PMID:40664262]. Its chaperone cycle depends on ATPase activity and on assembly with the co-chaperone CDC37, and pharmacological inhibition of the ATPase or disruption of the HSP90AB1–CDC37 complex destabilizes client kinases such as AKT1 and ERBB2 [PMID:18218611, PMID:41114929]. A recurring theme is stabilization of receptors and signaling nodes that drive Wnt/β-catenin and PI3K/AKT output: HSP90AB1 directly binds the Wnt co-receptor LRP5 to block its ubiquitin-mediated degradation and activate AKT and β-catenin signaling [PMID:30305727], binds B7-1 in podocytes through N-terminal residue K69 to relay signals to LRP5/β-catenin [PMID:35710882], and binds LGR5 to promote GSK-3β phosphorylation, β-catenin nuclear translocation, and androgen-receptor-driven enzalutamide resistance [PMID:40280884]. It similarly supports TGFβ/SMAD signaling via interaction with EEF1A2 and elevation of TGFβ receptors [PMID:33473168], and stabilizes additional clients including COX-2, ACT1, TXN, PIK3CG, EGFR and KDM5C to sustain inflammatory and proliferative programs [PMID:39914036, PMID:41707809, PMID:41675575, PMID:40664262]. HSP90AB1 also governs client localization and turnover directly: it retains Bcr-Abl in the cytoplasm through an N-terminal-domain interaction to maintain kinase activity [PMID:34217296], and it mediates K63-linked ubiquitination and degradation of ITGBL1 to restrain ER-stress-induced autophagy [PMID:41697125]. Beyond the cytoplasm, extracellular and cell-surface HSP90AB1 binds and inactivates latent TGFβ and serves as an entry/replication factor for multiple viruses, with the NM/NTD domain engaging the RGNNV capsid protein (competitively displacing AKT) and the coronavirus N protein, and its ATPase activity being required for PDCoV and TGEV infection [PMID:34976221, PMID:34904422, PMID:38092149, PMID:37958953]. HSP90AB1 activity is tuned by post-translational modification—SUMOylation at Lys72 (erased by SENP1) controls STAT3-driven fibrosis, chemerin-induced SUMO2/3 conjugation drives ERK1/2 activation in monocytes, and ACOX1-derived crotonyl-CoA crotonylates Lys265 to compact the chaperone and strengthen TXN binding under hypoxia [PMID:38992961, PMID:40744335, PMID:41675575]—and by transcriptional and post-transcriptional control through USP22-dependent H3K9 acetylation, SP1, IGF2BP3-mediated m6A mRNA stabilization, and HNRNPH1 [PMID:31801945, PMID:39914036, PMID:40105114, PMID:40468317].","teleology":[{"year":2008,"claim":"Established that HSP90AB1 chaperone activity is druggable at a site distinct from classical inhibitors and that its function is required to maintain key oncogenic clients.","evidence":"Affinity purification with gamendazole, MALDI-TOF, and in vitro luciferase-refolding assay using purified HSP82, with client degradation readouts","pmids":["18218611"],"confidence":"High","gaps":["Used yeast HSP82 homolog rather than human protein for refolding assay","Distinct binding site inferred from competition, not structurally resolved"]},{"year":2018,"claim":"Showed HSP90AB1 directly stabilizes a Wnt co-receptor, linking the chaperone to β-catenin/AKT-driven EMT.","evidence":"Co-IP, GST pull-down, in vitro ubiquitination assay, and xenograft models in gastric cancer","pmids":["30305727"],"confidence":"High","gaps":["Binding interface on LRP5 not mapped","Whether stabilization is ATPase-dependent not tested"]},{"year":2019,"claim":"Identified epigenetic transcriptional control of HSP90AB1 via USP22-maintained H3K9 acetylation, explaining how its abundance is set.","evidence":"siRNA knockdown, mRNA-seq, H3K9ac ChIP, and tissue-specific Usp22 knockout mice","pmids":["31801945"],"confidence":"Medium","gaps":["Direct vs indirect USP22 action at the locus not fully separated","Does not address protein-level regulation"]},{"year":2021,"claim":"Defined N-terminal-domain-dependent cytoplasmic retention of Bcr-Abl as a mechanism by which HSP90AB1 sustains oncogenic kinase signaling.","evidence":"IP-MS, domain mapping, immunofluorescence localization, and apoptosis assays in CML cells","pmids":["34217296"],"confidence":"Medium","gaps":["Single-lab domain mapping without structural confirmation","Whether ATPase cycling is needed for retention untested"]},{"year":2021,"claim":"Connected HSP90AB1 to TGFβ/SMAD signaling through an EEF1A2 interaction that upregulates TGFβ receptors.","evidence":"LC-MS/MS interactome, reciprocal Co-IP, and functional assays in lung adenocarcinoma","pmids":["33473168"],"confidence":"Medium","gaps":["Mechanism linking interaction to receptor upregulation unclear","Direct vs scaffolded interaction not resolved"]},{"year":2022,"claim":"Demonstrated a residue-resolved scaffold function (K69) coupling B7-1 to LRP5/β-catenin in podocyte injury.","evidence":"LC-MS/MS, molecular docking, site-directed mutagenesis, Co-IP, and nephropathy mouse models","pmids":["35710882"],"confidence":"High","gaps":["Docking-based interface not crystallographically confirmed","Chaperone-cycle dependence not addressed"]},{"year":2022,"claim":"Revealed an extracellular, anti-tumor role: secreted HSP90AB1 binds and inactivates latent TGFβ and suppresses osteoclast maturation.","evidence":"Immunoprecipitation from conditioned-medium proteomes, whole-genome proteomics, and in vivo osteolysis model","pmids":["34976221"],"confidence":"Medium","gaps":["Direct TGFβ-binding interface not mapped","Secretion mechanism not defined"]},{"year":2022,"claim":"Showed surface HSP90ab1 is hijacked by a viral capsid that competitively displaces AKT, coupling the chaperone to AKT-mTOR and autophagy during infection.","evidence":"Co-IP, domain mapping, and autophagy flux assays in fish cell lines (LjHSP90ab1)","pmids":["34904422"],"confidence":"Medium","gaps":["Fish ortholog; mammalian conservation of mechanism untested","Competition shown biochemically but not structurally"]},{"year":2023,"claim":"Established HSP90AB1 ATPase activity as a host requirement for coronavirus infection through stabilization of the viral N protein.","evidence":"Genome-wide CRISPR screen, Co-IP, domain deletion mapping, and ATPase-selective inhibitor comparison (PDCoV)","pmids":["38092149"],"confidence":"High","gaps":["Whether N stabilization fully accounts for the replication requirement unknown"]},{"year":2023,"claim":"Confirmed isoform-specific (HSP90AB1 over HSP90AA1) ATPase-dependent requirement for another coronavirus, generalizing the host-factor role.","evidence":"Isoform-specific knockdown/KO, time-of-addition inhibitor assay, and viral titering (TGEV)","pmids":["37958953"],"confidence":"Medium","gaps":["Direct viral client interaction not biochemically defined here"]},{"year":2024,"claim":"Identified SUMOylation at Lys72, reversed by SENP1, as a switch controlling STAT3-driven cardiac fibrosis.","evidence":"Cardiomyocyte-specific SENP1 KO/OE mice, K72 mutagenesis, and cardiac phenotyping","pmids":["38992961"],"confidence":"High","gaps":["SUMO ligase writing the K72 mark not identified","Mechanism linking SUMO to STAT3 activation unclear"]},{"year":2025,"claim":"Mapped distinct small-molecule binding residues (Asp88, Ser108) whose engagement disrupts client stabilization, refining the druggable surface.","evidence":"CETSA/TPP/MST/SPR biophysics, site-directed mutagenesis, and client destabilization (ACT1; PIK3CG/EGFR/KDM5C)","pmids":["41707809","40664262"],"confidence":"High","gaps":["Relationship of these residues to the ATPase pocket not defined","Client specificity determinants unresolved"]},{"year":2025,"claim":"Expanded post-transcriptional and transcriptional regulation of HSP90AB1 (SP1, IGF2BP3/m6A, HNRNPH1) and added a chemerin-induced SUMO2/3-ERK1/2 axis.","evidence":"Promoter/ChIP analyses, m6A-seq/RIP-seq with site mutagenesis, RIP, and IP-MS with SUMO inhibitor","pmids":["39914036","40105114","40468317","40744335"],"confidence":"Medium","gaps":["Interplay between competing positive and negative regulators not integrated","Some functional links (HNRNPH1→autophagy) indirect"]},{"year":2026,"claim":"Showed metabolic crotonylation at Lys265 conformationally tunes the chaperone to strengthen TXN binding and confer redox-driven drug resistance, and that HSP90AB1 can also direct K63-ubiquitin-mediated client degradation.","evidence":"Molecular dynamics, K265R mutagenesis, Co-IP, ATPase/ITGBL1 ubiquitination assays, and in vivo tumor models","pmids":["41675575","41697125"],"confidence":"Medium","gaps":["Conformational effect from MD only, not an experimental structure","How HSP90AB1 selects clients for stabilization vs degradation unknown"]},{"year":null,"claim":"It remains unresolved how HSP90AB1's full client repertoire and the combinatorial PTM/regulatory code dictate context-specific outcomes (stabilization vs degradation, intracellular vs secreted/surface roles).","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of PTM effects on the chaperone cycle","Determinants of client fate (stabilize vs K63-degrade) undefined","Mechanism of HSP90AB1 secretion and surface presentation uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,18,19,22]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,28]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,8,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,2]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,26]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,17,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,19,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,16,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,22]}],"complexes":["HSP90AB1-CDC37 co-chaperone complex"],"partners":["LRP5","LGR5","EEF1A2","BCR-ABL","B7-1","ITGBL1","PARP1","CDC37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08238","full_name":"Heat shock protein HSP 90-beta","aliases":["Heat shock 84 kDa","HSP 84","HSP84","Heat shock protein family C member 3"],"length_aa":724,"mass_kda":83.3,"function":"Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (PubMed:16478993, PubMed:19696785). Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle (PubMed:26991466, PubMed:27295069). Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. They first alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression (PubMed:25973397). Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation (PubMed:24613385). Promotes cell differentiation by chaperoning BIRC2 and thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery (PubMed:18239673). Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription (PubMed:20353823). Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10 (PubMed:32272059) (Microbial infection) Binding to N.meningitidis NadA stimulates monocytes (PubMed:21949862). Seems to interfere with N.meningitidis NadA-mediated invasion of human cells (Probable)","subcellular_location":"Cytoplasm; Melanosome; Nucleus; Secreted; Cell membrane; Dynein axonemal particle; Cell surface","url":"https://www.uniprot.org/uniprotkb/P08238/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSP90AB1","classification":"Not Classified","n_dependent_lines":155,"n_total_lines":1208,"dependency_fraction":0.12831125827814568},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000096384","cell_line_id":"CID000042","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"HSP90AA1","stoichiometry":10.0},{"gene":"STIP1","stoichiometry":10.0},{"gene":"PTGES3","stoichiometry":10.0},{"gene":"AHSA1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CSNK2A1","stoichiometry":0.2},{"gene":"CSNK2A2","stoichiometry":0.2},{"gene":"DNAJB6","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"FKBP8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000042","total_profiled":1310},"omim":[{"mim_id":"621316","title":"HSP90AB1-ASSOCIATED LONG NONCODING RNA 1; HSALR1","url":"https://www.omim.org/entry/621316"},{"mim_id":"601231","title":"MECHANISTIC TARGET OF RAPAMYCIN; MTOR","url":"https://www.omim.org/entry/601231"},{"mim_id":"600495","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 4-GAMMA, 1; EIF4G1","url":"https://www.omim.org/entry/600495"},{"mim_id":"140572","title":"HEAT-SHOCK PROTEIN, 90-KD, ALPHA, CLASS B, MEMBER 1; HSP90AB1","url":"https://www.omim.org/entry/140572"},{"mim_id":"140571","title":"HEAT-SHOCK PROTEIN, 90-KD, ALPHA, CLASS A, MEMBER 1; HSP90AA1","url":"https://www.omim.org/entry/140571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HSP90AB1"},"hgnc":{"alias_symbol":[],"prev_symbol":["HSPC2","HSPCB"]},"alphafold":{"accession":"P08238","domains":[{"cath_id":"3.30.565.10","chopping":"20-216","consensus_level":"high","plddt":89.2131,"start":20,"end":216},{"cath_id":"3.30.230.80","chopping":"287-419","consensus_level":"medium","plddt":88.528,"start":287,"end":419},{"cath_id":"1.20.120.790","chopping":"556-687","consensus_level":"high","plddt":88.7586,"start":556,"end":687}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08238","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08238-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08238-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSP90AB1","jax_strain_url":"https://www.jax.org/strain/search?query=HSP90AB1"},"sequence":{"accession":"P08238","fasta_url":"https://rest.uniprot.org/uniprotkb/P08238.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08238/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08238"}},"corpus_meta":[{"pmid":"26358502","id":"PMC_26358502","title":"HSP90AB1: 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\"HSP90AB1 directly interacts with LRP5 (a Wnt co-receptor) via co-immunoprecipitation and GST pull-down, inhibiting ubiquitin-mediated proteasomal degradation of LRP5 and thereby stabilizing it; this stabilization activates AKT and Wnt/β-catenin signaling to promote epithelial-mesenchymal transition in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, in vitro ubiquitination assay, immunofluorescence, gain/loss-of-function in cell lines and xenograft mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus GST pull-down plus functional ubiquitination assay plus in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30305727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HSP90AB1 (HSP90beta) is a direct binding target of gamendazole; the drug binds purified yeast HSP82 (mammalian HSP90AB1 homologue), inhibits its luciferase-refolding (chaperone) activity, causes degradation of HSP90-dependent client proteins AKT1 and ERBB2, and does not compete with geldanamycin or novobiocin for binding, suggesting a distinct binding site.\",\n      \"method\": \"Biotinylated affinity purification, MALDI-TOF mass spectrometry, Western blot, in vitro luciferase refolding assay with purified HSP82\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of chaperone activity inhibition with purified protein, plus affinity purification identification, single lab\",\n      \"pmids\": [\"18218611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EEF1A2 physically interacts with HSP90AB1 (confirmed by LC-MS/MS and Co-IP), and this interaction increases TGFβ receptor I and II expression, followed by enhanced SMAD3 phosphorylation and nuclear localization, promoting EMT in lung adenocarcinoma cells.\",\n      \"method\": \"LC-MS/MS interactome, co-immunoprecipitation, immunofluorescence, in vitro and in vivo functional assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with LC-MS/MS identification plus functional pathway validation, single lab\",\n      \"pmids\": [\"33473168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSP90AB1 physically interacts with B7-1 in podocytes via residue K69 in the N-terminal domain of HSP90AB1 (identified by LC-MS/MS and confirmed by molecular docking and mutant analysis), acting as a scaffold to transmit signals from B7-1 to LRP5/β-catenin, thereby mediating podocyte injury and glomerulosclerosis.\",\n      \"method\": \"LC-MS/MS, molecular docking, site-directed mutagenesis, co-immunoprecipitation, transgenic/adriamycin nephropathy mouse models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — LC-MS/MS identification, mutant-confirmed binding site, Co-IP, and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35710882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSP90AB1 interacts with the coiled-coil (CC) domain of Bcr-Abl via its N-terminal domain (NTD), retaining Bcr-Abl in the cytoplasm and maintaining Bcr-Abl tyrosine kinase activation; disruption of this interaction (by 17AAG targeting NTD) permits nuclear translocation of Bcr-Abl, which activates p73 and induces apoptosis of CML cells.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, immunoprecipitation with domain mapping, immunofluorescence, Western blot, CCK-8, flow cytometry\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS with domain-level binding confirmation plus subcellular localization experiments plus functional assays, single lab\",\n      \"pmids\": [\"34217296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSP90AB1 immunoprecipitates latent TGFβ (from osteoblast-secreted proteomes) and inactivates it; extracellular HSP90AB1 also inhibits tumor cell growth and osteoclast maturation in a mouse model of osteolysis.\",\n      \"method\": \"Immunoprecipitation (from conditioned medium proteomes), whole-genome proteomics, gain/loss-of-function, in vivo mouse osteolysis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation with proteomic validation plus in vivo functional data, single lab\",\n      \"pmids\": [\"34976221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP22 deubiquitylase positively regulates HSP90AB1 expression at the transcriptional level via maintenance of H3K9 acetylation on the HSP90AB1 gene; siRNA knockdown of USP22 reduces H3K9ac at the HSP90AB1 locus and decreases HSP90AB1 mRNA and protein in colorectal and breast cancer cells and in tissue-specific Usp22 knockout mice.\",\n      \"method\": \"siRNA knockdown, mRNA-seq, Western blot, ChIP (H3K9ac), mouse tissue-specific Usp22 knockout\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-confirmed epigenetic mechanism plus in vivo knockout validation, single lab with two orthogonal methods\",\n      \"pmids\": [\"31801945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGNNV capsid protein (CP) binds the NM domain of fish HSP90ab1 (LjHSP90ab1) on the cell surface, competitively blocking AKT interaction with HSP90ab1, thereby inhibiting the AKT-mTOR pathway and inducing incomplete autophagy (impaired autophagosome-lysosome fusion) during early viral infection.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, Western blot, autophagy flux assays in fish cell lines\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain-level mapping, competitive binding demonstrated, functional autophagy assays, single lab\",\n      \"pmids\": [\"34904422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV (porcine deltacoronavirus); the C-tail domain of the N protein mediates interaction with HSP90AB1, and HSP90AB1 protects N protein from proteasomal degradation. ATPase activity of HSP90AB1 is required for PDCoV infection (ATPase-inhibiting HSP90 inhibitors suppressed infection, but KW-2478, which does not affect ATPase, had no effect).\",\n      \"method\": \"Genome-wide CRISPR screen, Co-IP, domain deletion mapping, HSP90 inhibitor treatment, proteasome inhibitor rescue assay, viral titer measurement\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screen plus Co-IP plus domain mapping plus mechanistic rescue assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38092149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1-mediated deSUMOylation of HSP90ab1 at Lys72 suppresses STAT3 activation and fibronectin secretion in cardiomyocytes; loss of SENP1 increases HSP90ab1 SUMOylation, activates STAT3, and drives paracrine fibroblast activation and cardiac fibrosis after myocardial infarction. Mutation of HSP90ab1 Lys72 (SUMOylation site) ameliorates adverse ventricular remodeling.\",\n      \"method\": \"Cardiomyocyte-specific SENP1 KO and overexpression mice, site-directed mutagenesis (K72 mutation), Western blot, cardiac function measurement, histology\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-directed mutagenesis of PTM site plus in vivo KO/OE mouse models plus functional cardiac phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38992961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DSCC1 interacts with HSP90AB1 (confirmed by co-immunoprecipitation) and promotes ER stress-mediated progression of lung adenocarcinoma; knockdown of either protein reduces LUAD cell proliferation, stemness, EMT, and metastatic potential.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro cell assays, in vivo tumor models\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up on the specific interaction, single lab\",\n      \"pmids\": [\"37742009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HSP90AB1 knockdown reduces phospho-AKT (Ser473) levels in head and neck squamous cell carcinoma cells, placing HSP90AB1 upstream of AKT activation in HNSCC.\",\n      \"method\": \"Lentiviral shRNA knockdown, Western blot for phospho-AKT, CCK-8/EdU/colony/transwell/xenograft assays\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Western blot readout for pathway placement, no direct binding assay for AKT, single lab\",\n      \"pmids\": [\"35929142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSP90AB1 knockdown in T cells reduces p-AKT, SMARCC1, p-c-Fos, and p-c-Jun expression and increases ROS and apoptosis; overexpression of HSP90AB1 inhibits capecitabine-induced T cell apoptosis by sustaining the AKT/SMARCC1/AP-1 axis and reducing ROS, establishing HSP90AB1 as a pro-survival regulator in T cells via this signaling cascade.\",\n      \"method\": \"siRNA knockdown, overexpression, quantitative proteomics/phosphoproteomics, Western blot, ROS measurement, flow cytometry apoptosis assay\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional (KD and OE) experiments with proteomic and phosphoproteomic readouts, single lab\",\n      \"pmids\": [\"35368874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP1 interacts with HSP90AB1 (confirmed by Co-IP), and HSP90AB1 counteracts PARP1's repression of BLM promoter activity; HSP90AB1 thus acts as a co-regulator that de-represses BLM transcription in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, DNA pull-down with promoter probe, dual luciferase reporter assay, ChIP-qPCR, MS\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus promoter pull-down and luciferase reporter assay confirming transcriptional mechanism, single lab\",\n      \"pmids\": [\"37415147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK1-SRC interaction transcriptionally activates HSP90AB1 expression in hepatocellular carcinoma; manipulation of SRC or HSP90AB1 reverses the effects of CDK1 and SRC on HCC cell proliferation and migration, placing HSP90AB1 downstream of the CDK1-SRC kinase network.\",\n      \"method\": \"In vitro and in vivo functional assays, transcriptomic/proteomic analysis, siRNA/overexpression experiments\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis-type experiments without direct biochemical binding or promoter assay for CDK1-SRC→HSP90AB1 transcriptional activation, single lab\",\n      \"pmids\": [\"37949475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Calenduloside E (CE) directly binds purified recombinant HSP90AB1 protein, as confirmed by competitive binding assay with CE-P probe and surface plasmon resonance (SPR) kinetic analysis showing dose-dependent binding.\",\n      \"method\": \"Clickable activity-based probe affinity purification, proteomic identification, competitive binding assay with purified recombinant HSP90AB1, SPR\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding with purified protein confirmed by SPR, but single lab and limited functional follow-up on binding consequence\",\n      \"pmids\": [\"29875664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSP90AB1 is required for transmissible gastroenteritis virus (TGEV) infection; knockdown of HSP90AB1 (but not HSP90AA1) and treatment with VER-82576 (an ATPase-inhibiting HSP90 inhibitor) reduce TGEV mRNA, N protein, and virus titers in a dose-dependent manner, with the inhibitory effect occurring mainly at early viral replication.\",\n      \"method\": \"siRNA knockdown, KO cells, HSP90 inhibitor time-of-addition assay, viral titer measurement, RT-qPCR, Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KD (HSP90AB1 vs HSP90AA1) plus inhibitor with ATPase-dependence control, single lab\",\n      \"pmids\": [\"37958953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LGR5 directly binds HSP90AB1 (confirmed by GST pull-down and Co-IP), and this interaction promotes phosphorylation of GSK-3β, leading to β-catenin stabilization and nuclear translocation that activates AR transcription, conferring enzalutamide resistance in prostate cancer; reducing HSP90AB1-LGR5 binding restores enzalutamide sensitivity.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, immunofluorescence, Western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus GST pull-down plus in vivo validation, single lab\",\n      \"pmids\": [\"40280884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Polydatin specifically binds HSP90AB1 at the Asp88 residue and disrupts HSP90AB1-mediated stabilization of the client protein ACT1, thereby suppressing the IL-17/MAPK/NF-κB inflammatory pathway in acute lung injury models.\",\n      \"method\": \"CETSA, thermal proteome profiling, mass spectrometry, site-directed mutagenesis, molecular docking, MST, cell lines overexpressing HSP90AB1, Western blot, in vivo rat ALI model\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical binding methods (CETSA, TPP, MST) plus mutagenesis of binding site plus client protein functional consequence, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41707809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Bruceine A (BRA) binds HSP90AB1 at the Ser-108 residue and inhibits its chaperone function; downstream HSP90AB1 client/partner proteins PIK3CG, EGFR, and KDM5C are destabilized, suppressing HCC cell proliferation and inducing apoptosis.\",\n      \"method\": \"Chemical proteomics (MST, SPR, CETSA), site-directed mutagenesis, HSP90AB1 knockdown, TMT-based proteomics for downstream clients, patient-derived organoids and xenograft models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical assays with mutagenesis confirming binding site plus proteomic identification of client proteins, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40664262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ACOX1-dependent increase in crotonyl-CoA under hypoxia drives site-specific crotonylation of HSP90AB1 at Lys265; molecular dynamics simulations show K265 crotonylation induces conformational compaction of HSP90AB1, strengthening its interaction with client protein TXN (thioredoxin) and enhancing TXN stability to buffer ROS and confer cisplatin resistance in oral squamous cell carcinoma.\",\n      \"method\": \"Molecular dynamics simulation, site-directed mutagenesis (K265R), co-immunoprecipitation, Western blot, in vitro and in vivo tumor models, pharmacological inhibition of ACOX1\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of PTM site combined with Co-IP and functional in vivo data, single lab; structural insight from MD not experimentally solved structure\",\n      \"pmids\": [\"41675575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Chemerin stimulates SUMO2/3 conjugation to HSP90AB1 in monocytes via β2 integrin signaling; this SUMOylation of HSP90AB1 is essential for downstream ERK1/2 phosphorylation and monocyte activation and adhesion, as shown by immunoprecipitation/LC-MS/MS identification and reversal with SUMOylation inhibitor ML-792.\",\n      \"method\": \"Immunoprecipitation, LC-MS/MS, SUMOylation inhibitor (ML-792), Western blot, monocyte adhesion assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification of SUMO2/3 interaction with HSP90AB1 plus pharmacological inhibition confirming functional role, single lab\",\n      \"pmids\": [\"40744335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HSP90AB1 interacts with ITGBL1 and mediates its K63-linked ubiquitination and degradation; loss of this HSP90AB1-dependent degradation of ITGBL1 activates ER stress-induced autophagy, suppressing osteosarcoma progression.\",\n      \"method\": \"Co-IP, domain mapping, ubiquitination assay (K63-linkage), in vitro and in vivo functional assays, virtual screening and Co-IP for inhibitor (ivermectin)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with linkage-specific ubiquitination assay plus in vivo rescue, single lab\",\n      \"pmids\": [\"41697125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 (m6A reader) binds m6A-tagged HSP90AB1 mRNA and stabilizes it in an m6A-dependent manner, increasing HSP90AB1 protein levels which activate the PI3K/AKT signaling pathway to promote bladder cancer progression.\",\n      \"method\": \"RNA-seq, m6A-seq, RIP-seq, RIP-qPCR, site-directed mutagenesis of m6A sites, Western blot, in vitro and in vivo assays\",\n      \"journal\": \"FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-seq/RIP-seq convergence with mutagenesis validation of m6A sites, single lab with multiple orthogonal omics methods\",\n      \"pmids\": [\"40105114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPH1 binds HSP90AB1 mRNA and inhibits its protein expression; this suppresses HSP90AB1-mediated inhibition of MAP1LC3B-dependent autophagy, thereby restraining lung adenocarcinoma malignant phenotype.\",\n      \"method\": \"RIP (RNA binding protein immunoprecipitation), siRNA/overexpression, Western blot, in vivo tumor models, autophagy flux assays\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP showing mRNA binding with functional consequence, but mechanistic link between HSP90AB1 and MAP1LC3B autophagy is indirect, single lab\",\n      \"pmids\": [\"40468317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLCCI1 directly interacts with HSP90AB1 (confirmed by Co-IP), and HSP90AB1 in turn interacts with GRP78; GLCCI1 acts as an upstream regulator of HSP90AB1, which then regulates GRP78-initiated ER stress-induced apoptosis in retinal ganglion cells during diabetic retinopathy.\",\n      \"method\": \"Co-immunoprecipitation, GLCCI1 overexpression/knockdown, Western blot for GRP78/CHOP/caspase-3, in vivo DR mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing protein-protein interaction chain with bidirectional expression experiments, single lab\",\n      \"pmids\": [\"39496608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSP90ab1 and Myh9 (non-muscle myosin) interact via immunoprecipitation; extracellular HSP90ab1 and Myh9 secreted by PI3K-activated MSCs exert anti-tumor effects and inhibit osteoclast maturation.\",\n      \"method\": \"Immunoprecipitation from conditioned medium, mass spectrometry, in vitro and in vivo tumor suppression assays\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP from secreted proteome with limited mechanistic follow-up on HSP90AB1-Myh9 interaction consequence, single lab\",\n      \"pmids\": [\"36090473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SP1 transcription factor drives HSP90ab1 transcription by binding its promoter; pharmacological inhibition of SP1 reduces Hsp90ab1 expression; Hsp90ab1 in turn stabilizes the client protein COX-2 via p38/JNK signaling in uterine tissue, mediating primary dysmenorrhea.\",\n      \"method\": \"Promoter binding analysis (SP1 ChIP implied), geldanamycin inhibition of Hsp90ab1, lentiviral Hsp90ab1 overexpression reversal, Western blot, in vivo mouse PD model\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic loss/gain-of-function with pathway placement, lentiviral rescue experiment, single lab\",\n      \"pmids\": [\"39914036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSP90ab1 specifically adsorbs to denatured (misfolded) proteins in nanoparticle protein coronas; the level of HSP90ab1 adsorption correlates with circular dichroism and ANS fluorescence measures of protein denaturation, validating that HSP90ab1 functions as a chaperone that selectively binds misfolded/denatured client proteins in vitro.\",\n      \"method\": \"Western blot of NP-corona complex, circular dichroism, ANS fluorescence spectroscopy, comparison across NP types and surface modifications\",\n      \"journal\": \"Nanoscale\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — biochemical correlation of HSP90ab1 binding with denaturation metrics, no mutagenesis or reconstitution, single lab\",\n      \"pmids\": [\"32696774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NB (Dictamni Cortex nanoparticles) suppresses HSP90AB1 transcription by inhibiting its activator CTCF, and disrupts the HSP90AB1-CDC37 co-chaperone complex, thereby inactivating client proteins STAT3 and AKT in keratinocytes.\",\n      \"method\": \"Nascent proteomics, Western blot, co-chaperone complex disruption assay, in vitro keratinocyte and in vivo mouse psoriasis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomics-identified mechanism with limited direct biochemical validation of CTCF-HSP90AB1 transcriptional regulation, single lab\",\n      \"pmids\": [\"41114929\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSP90AB1 (HSP90beta) is an ATP-dependent molecular chaperone that forms dimers and, with the help of co-chaperones (e.g., CDC37), binds and stabilizes diverse client proteins including kinases (AKT, SRC), receptor complexes (LRP5, TGFβ receptors), and transcription factors, preventing their ubiquitin-proteasomal degradation; it is regulated post-translationally by SUMOylation at Lys72 (written by SUMO machinery, erased by SENP1) and crotonylation at Lys265 (driven by ACOX1-derived crotonyl-CoA under hypoxia), and its expression is transcriptionally controlled by USP22-dependent H3K9 acetylation and SP1; physically, it anchors signaling complexes at the cytoplasm (retaining Bcr-Abl cytoplasmically via NTD interaction), on the cell surface (serving as a receptor for NNV capsid protein and a B7-1 signaling scaffold), and in secreted proteomes where it binds and inactivates latent TGFβ, collectively placing HSP90AB1 as a context-dependent regulator of oncogenic signaling (AKT/PI3K, Wnt/β-catenin, STAT3, MAPK) and viral infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HSP90AB1 (HSP90beta) is an ATP-dependent molecular chaperone that selectively binds misfolded client proteins and, by stabilizing diverse signaling clients against degradation, acts as a context-dependent amplifier of oncogenic and inflammatory signaling [#28, #19]. Its chaperone cycle depends on ATPase activity and on assembly with the co-chaperone CDC37, and pharmacological inhibition of the ATPase or disruption of the HSP90AB1–CDC37 complex destabilizes client kinases such as AKT1 and ERBB2 [#1, #29]. A recurring theme is stabilization of receptors and signaling nodes that drive Wnt/\\u03b2-catenin and PI3K/AKT output: HSP90AB1 directly binds the Wnt co-receptor LRP5 to block its ubiquitin-mediated degradation and activate AKT and \\u03b2-catenin signaling [#0], binds B7-1 in podocytes through N-terminal residue K69 to relay signals to LRP5/\\u03b2-catenin [#3], and binds LGR5 to promote GSK-3\\u03b2 phosphorylation, \\u03b2-catenin nuclear translocation, and androgen-receptor-driven enzalutamide resistance [#17]. It similarly supports TGF\\u03b2/SMAD signaling via interaction with EEF1A2 and elevation of TGF\\u03b2 receptors [#2], and stabilizes additional clients including COX-2, ACT1, TXN, PIK3CG, EGFR and KDM5C to sustain inflammatory and proliferative programs [#27, #18, #20, #19]. HSP90AB1 also governs client localization and turnover directly: it retains Bcr-Abl in the cytoplasm through an N-terminal-domain interaction to maintain kinase activity [#4], and it mediates K63-linked ubiquitination and degradation of ITGBL1 to restrain ER-stress-induced autophagy [#22]. Beyond the cytoplasm, extracellular and cell-surface HSP90AB1 binds and inactivates latent TGF\\u03b2 and serves as an entry/replication factor for multiple viruses, with the NM/NTD domain engaging the RGNNV capsid protein (competitively displacing AKT) and the coronavirus N protein, and its ATPase activity being required for PDCoV and TGEV infection [#5, #7, #8, #16]. HSP90AB1 activity is tuned by post-translational modification—SUMOylation at Lys72 (erased by SENP1) controls STAT3-driven fibrosis, chemerin-induced SUMO2/3 conjugation drives ERK1/2 activation in monocytes, and ACOX1-derived crotonyl-CoA crotonylates Lys265 to compact the chaperone and strengthen TXN binding under hypoxia [#9, #21, #20]—and by transcriptional and post-transcriptional control through USP22-dependent H3K9 acetylation, SP1, IGF2BP3-mediated m6A mRNA stabilization, and HNRNPH1 [#6, #27, #23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that HSP90AB1 chaperone activity is druggable at a site distinct from classical inhibitors and that its function is required to maintain key oncogenic clients.\",\n      \"evidence\": \"Affinity purification with gamendazole, MALDI-TOF, and in vitro luciferase-refolding assay using purified HSP82, with client degradation readouts\",\n      \"pmids\": [\"18218611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Used yeast HSP82 homolog rather than human protein for refolding assay\", \"Distinct binding site inferred from competition, not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed HSP90AB1 directly stabilizes a Wnt co-receptor, linking the chaperone to \\u03b2-catenin/AKT-driven EMT.\",\n      \"evidence\": \"Co-IP, GST pull-down, in vitro ubiquitination assay, and xenograft models in gastric cancer\",\n      \"pmids\": [\"30305727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on LRP5 not mapped\", \"Whether stabilization is ATPase-dependent not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified epigenetic transcriptional control of HSP90AB1 via USP22-maintained H3K9 acetylation, explaining how its abundance is set.\",\n      \"evidence\": \"siRNA knockdown, mRNA-seq, H3K9ac ChIP, and tissue-specific Usp22 knockout mice\",\n      \"pmids\": [\"31801945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect USP22 action at the locus not fully separated\", \"Does not address protein-level regulation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined N-terminal-domain-dependent cytoplasmic retention of Bcr-Abl as a mechanism by which HSP90AB1 sustains oncogenic kinase signaling.\",\n      \"evidence\": \"IP-MS, domain mapping, immunofluorescence localization, and apoptosis assays in CML cells\",\n      \"pmids\": [\"34217296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab domain mapping without structural confirmation\", \"Whether ATPase cycling is needed for retention untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected HSP90AB1 to TGF\\u03b2/SMAD signaling through an EEF1A2 interaction that upregulates TGF\\u03b2 receptors.\",\n      \"evidence\": \"LC-MS/MS interactome, reciprocal Co-IP, and functional assays in lung adenocarcinoma\",\n      \"pmids\": [\"33473168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking interaction to receptor upregulation unclear\", \"Direct vs scaffolded interaction not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a residue-resolved scaffold function (K69) coupling B7-1 to LRP5/\\u03b2-catenin in podocyte injury.\",\n      \"evidence\": \"LC-MS/MS, molecular docking, site-directed mutagenesis, Co-IP, and nephropathy mouse models\",\n      \"pmids\": [\"35710882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Docking-based interface not crystallographically confirmed\", \"Chaperone-cycle dependence not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an extracellular, anti-tumor role: secreted HSP90AB1 binds and inactivates latent TGF\\u03b2 and suppresses osteoclast maturation.\",\n      \"evidence\": \"Immunoprecipitation from conditioned-medium proteomes, whole-genome proteomics, and in vivo osteolysis model\",\n      \"pmids\": [\"34976221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TGF\\u03b2-binding interface not mapped\", \"Secretion mechanism not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed surface HSP90ab1 is hijacked by a viral capsid that competitively displaces AKT, coupling the chaperone to AKT-mTOR and autophagy during infection.\",\n      \"evidence\": \"Co-IP, domain mapping, and autophagy flux assays in fish cell lines (LjHSP90ab1)\",\n      \"pmids\": [\"34904422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fish ortholog; mammalian conservation of mechanism untested\", \"Competition shown biochemically but not structurally\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established HSP90AB1 ATPase activity as a host requirement for coronavirus infection through stabilization of the viral N protein.\",\n      \"evidence\": \"Genome-wide CRISPR screen, Co-IP, domain deletion mapping, and ATPase-selective inhibitor comparison (PDCoV)\",\n      \"pmids\": [\"38092149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether N stabilization fully accounts for the replication requirement unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed isoform-specific (HSP90AB1 over HSP90AA1) ATPase-dependent requirement for another coronavirus, generalizing the host-factor role.\",\n      \"evidence\": \"Isoform-specific knockdown/KO, time-of-addition inhibitor assay, and viral titering (TGEV)\",\n      \"pmids\": [\"37958953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct viral client interaction not biochemically defined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SUMOylation at Lys72, reversed by SENP1, as a switch controlling STAT3-driven cardiac fibrosis.\",\n      \"evidence\": \"Cardiomyocyte-specific SENP1 KO/OE mice, K72 mutagenesis, and cardiac phenotyping\",\n      \"pmids\": [\"38992961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase writing the K72 mark not identified\", \"Mechanism linking SUMO to STAT3 activation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped distinct small-molecule binding residues (Asp88, Ser108) whose engagement disrupts client stabilization, refining the druggable surface.\",\n      \"evidence\": \"CETSA/TPP/MST/SPR biophysics, site-directed mutagenesis, and client destabilization (ACT1; PIK3CG/EGFR/KDM5C)\",\n      \"pmids\": [\"41707809\", \"40664262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of these residues to the ATPase pocket not defined\", \"Client specificity determinants unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded post-transcriptional and transcriptional regulation of HSP90AB1 (SP1, IGF2BP3/m6A, HNRNPH1) and added a chemerin-induced SUMO2/3-ERK1/2 axis.\",\n      \"evidence\": \"Promoter/ChIP analyses, m6A-seq/RIP-seq with site mutagenesis, RIP, and IP-MS with SUMO inhibitor\",\n      \"pmids\": [\"39914036\", \"40105114\", \"40468317\", \"40744335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between competing positive and negative regulators not integrated\", \"Some functional links (HNRNPH1\\u2192autophagy) indirect\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed metabolic crotonylation at Lys265 conformationally tunes the chaperone to strengthen TXN binding and confer redox-driven drug resistance, and that HSP90AB1 can also direct K63-ubiquitin-mediated client degradation.\",\n      \"evidence\": \"Molecular dynamics, K265R mutagenesis, Co-IP, ATPase/ITGBL1 ubiquitination assays, and in vivo tumor models\",\n      \"pmids\": [\"41675575\", \"41697125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational effect from MD only, not an experimental structure\", \"How HSP90AB1 selects clients for stabilization vs degradation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how HSP90AB1's full client repertoire and the combinatorial PTM/regulatory code dictate context-specific outcomes (stabilization vs degradation, intracellular vs secreted/surface roles).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of PTM effects on the chaperone cycle\", \"Determinants of client fate (stabilize vs K63-degrade) undefined\", \"Mechanism of HSP90AB1 secretion and surface presentation uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 18, 19, 22]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 28]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 8, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 2]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 17, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 19, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 16, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 22]}\n    ],\n    \"complexes\": [\"HSP90AB1-CDC37 co-chaperone complex\"],\n    \"partners\": [\"LRP5\", \"LGR5\", \"EEF1A2\", \"Bcr-Abl\", \"B7-1\", \"ITGBL1\", \"PARP1\", \"CDC37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}