Affinage

HSPBP1

Hsp70-binding protein 1 · UniProt Q9NZL4

Length
359 aa
Mass
39.3 kDa
Annotated
2026-04-28
35 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPBP1 is an armadillo-repeat cochaperone that functions as a nucleotide exchange factor (NEF) for Hsp70/Hsc70 and a critical regulator of protein quality control decisions between folding and degradation. Its curved alpha-helical core domain embraces lobe II of the Hsp70 ATPase domain, and steric displacement of lobe I reduces nucleotide affinity — a mechanism structurally distinct from BAG-1 or GrpE — while its flexible N-terminal release domain mimics substrate to ensure efficient client release from Hsp70 (PMID:15694338, PMID:29323280). HSPBP1 inhibits the CHIP ubiquitin ligase in complex with Hsc70, thereby suppressing K48-linked ubiquitination and proteasomal degradation of clients including immature CFTR, inducible HSP70 family members, and RIG-I, and promoting BRCA1-mediated homologous recombination repair (PMID:15215316, PMID:24899640, PMID:33713958, PMID:35387978). Loss of HSPBP1 in mice causes male sterility through spermatocyte apoptosis resulting from destabilization of HSPA2 and failure of synaptonemal complex disassembly (PMID:24899640).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Establishing that HSPBP1 is a nucleotide exchange factor for Hsc70 answered whether this cochaperone directly modulates the Hsp70 ATPase cycle, setting the stage for understanding its role in chaperone regulation.

    Evidence In vitro nucleotide dissociation and luciferase refolding assays with mammalian and yeast Hsp70 proteins

    PMID:12417338

    Open questions at the time
    • No structural basis for NEF activity
    • Inhibition of refolding in vitro not reconciled with in vivo function
  2. 2003 Medium

    Defining the two-domain architecture of HSPBP1 — an unstructured N-terminal domain I and an alpha-helical domain II sufficient for Hsp70 binding — and identifying cooperative reversal of HspBP1 inhibition by Hsp40 plus TPR1 resolved how the cochaperone is structurally organized and dynamically regulated within the chaperone network.

    Evidence Circular dichroism, limited proteolysis, truncation mutagenesis, and in vitro cooperative refolding assays

    PMID:12651857 PMID:14503850

    Open questions at the time
    • No atomic resolution structure of isolated HSPBP1
    • Cooperative mechanism of Hsp40/TPR1 reversal unclear at a structural level
  3. 2004 High

    Demonstrating that HSPBP1 inhibits CHIP ubiquitin ligase activity when complexed with Hsc70, thereby promoting CFTR maturation over degradation, established HSPBP1 as a triage factor that tips protein quality control toward folding.

    Evidence Co-immunoprecipitation, in vitro ubiquitin ligase assays, and cellular CFTR maturation assays with overexpression and knockdown

    PMID:15215316

    Open questions at the time
    • Whether HSPBP1 directly contacts CHIP or acts indirectly through Hsc70 conformation not resolved
    • Range of CHIP substrates affected unknown
  4. 2005 High

    The crystal structure of HSPBP1 in complex with the Hsp70 ATPase domain revealed a novel NEF mechanism in which an armadillo-repeat fold embraces lobe II and sterically displaces lobe I, distinguishing HSPBP1 from all previously characterized NEFs.

    Evidence X-ray crystallography of HspBP1 alone and in complex with Hsp70 ATPase domain; in vitro nucleotide exchange assays; yeast Fes1p deletion complementation

    PMID:15694338

    Open questions at the time
    • No structure of full-length HSPBP1 including the N-terminal domain
    • Dynamics of lobe I displacement not captured
  5. 2007 Medium

    Showing that HSPBP1 antagonizes the prosurvival function of Hsp70 by promoting lysosomal membrane permeabilization and caspase-3 activation broadened its role beyond protein folding to regulation of cell death pathways.

    Evidence RNA interference, overexpression with binding-deficient mutant controls, lysosomal integrity and cathepsin release assays in cancer cell lines

    PMID:17855353

    Open questions at the time
    • Mechanism linking Hsp70 dissociation to lysosomal destabilization not defined
    • Relevance to physiological (non-drug-induced) cell death unclear
  6. 2014 High

    HSPBP1 knockout mice revealed an essential in vivo role: HSPBP1 prevents ubiquitin-dependent degradation of inducible HSP70 proteins (HSPA2), and its loss causes meiotic failure, spermatocyte apoptosis, and male sterility, establishing a physiological client-stabilization function.

    Evidence HSPBP1 knockout mouse; Western blot and ubiquitination assays; testis histology

    PMID:24899640

    Open questions at the time
    • Whether HSPBP1 loss affects female fertility or other tissues not explored
    • Identity of the E3 ligase degrading HSPA2 in the absence of HSPBP1 not established
  7. 2014 Medium

    HSPBP1 modulates steroid receptor signaling by reducing Hsp70 binding to the ligand-binding domain of glucocorticoid, mineralocorticoid, and androgen receptors, revealing a nuclear-receptor-specific regulatory axis distinct from BAG-1M.

    Evidence Co-immunoprecipitation, GST pull-down, and reporter gene assays in cell lines

    PMID:24454860

    Open questions at the time
    • Physiological relevance in endocrine tissues not tested in vivo
    • Structural basis for differential effects versus BAG-1M unknown
  8. 2017 High

    In neurons, abundant HSPBP1 suppresses CHIP-mediated K48-polyubiquitination of misfolded proteins including mutant huntingtin; CRISPR-Cas9 silencing of HSPBP1 in a Huntington's disease mouse model reduced mHtt aggregation and neuropathology, establishing HSPBP1 as a potential therapeutic target in neurodegeneration.

    Evidence Co-immunoprecipitation; CHIP ubiquitination assays; CRISPR-Cas9 knockdown in primary neurons; HD knockin mouse model

    PMID:28847953

    Open questions at the time
    • Long-term safety of HSPBP1 depletion in neurons not assessed
    • Whether HSPBP1 inhibition affects other neurodegenerative disease proteins not tested
  9. 2018 High

    Discovery of the N-terminal release domain (RD) that mimics substrate and competes for the Hsp70 substrate-binding domain resolved a longstanding question: how HSPBP1 ensures substrate release after nucleotide exchange, showing a dual-domain mechanism — armadillo for NEF, RD for substrate eviction.

    Evidence In vitro binding and competition assays with recombinant proteins; release domain mutagenesis; functional assays in yeast and mammalian cells

    PMID:29323280

    Open questions at the time
    • Atomic structure of the RD in complex with Hsp70 SBD not available
    • Whether RD competes equally with all substrate types not tested
  10. 2020 Medium

    Identification of HSPBP1 as a stress granule component that directly binds polyA-RNA and regulates stress granule assembly expanded its function beyond the Hsp70 chaperone cycle into RNA granule biology.

    Evidence Immunofluorescence colocalization with G3BP1/TIA-1; co-immunoprecipitation; in vitro RNA binding; siRNA knockdown and overexpression

    PMID:32235396

    Open questions at the time
    • Whether stress granule role is Hsp70-dependent or independent not resolved
    • RNA targets of HSPBP1 not identified transcriptome-wide
  11. 2021 Medium

    HSPBP1 stabilizes RIG-I by inhibiting its K48-linked ubiquitination, thereby promoting innate antiviral IFN-β signaling, extending the anti-degradation paradigm to innate immunity.

    Evidence Overexpression and knockout; ubiquitination and IRF3 phosphorylation assays; IFN-β reporter and ELISA upon Sendai virus infection

    PMID:33713958

    Open questions at the time
    • The E3 ligase targeting RIG-I that HSPBP1 antagonizes not identified
    • In vivo antiviral phenotype in HSPBP1 KO mice not tested
  12. 2022 Medium

    HSPBP1 promotes BRCA1-dependent homologous recombination repair and separately disrupts the Hsp70–Apaf-1 interaction to suppress apoptosis after DNA damage, adding a DNA repair dimension to its functions.

    Evidence Co-immunoprecipitation with BRCA1; HR reporter assays; knockdown/overexpression; xenograft tumor models

    PMID:35387978

    Open questions at the time
    • Direct versus Hsp70-mediated mechanism of BRCA1 interaction not distinguished
    • Whether HSPBP1 affects other DNA repair pathways untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: (1) the full-length HSPBP1 structure with the release domain bound to Hsp70 SBD, (2) whether the stress granule and DNA repair functions are Hsp70-dependent or represent independent activities, and (3) the identity of the E3 ligase(s) antagonized by HSPBP1 beyond CHIP in different physiological contexts.
  • No full-length structure including the N-terminal release domain in complex
  • Hsp70 dependence of stress granule and HR functions not resolved
  • E3 ligases antagonized in innate immunity and spermatogenesis not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0044183 protein folding chaperone 3 GO:0003723 RNA binding 1
Localization
GO:0005829 cytosol 3 GO:0005576 extracellular region 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1 R-HSA-73894 DNA Repair 1
Partners
BRCA1DDX58G3BP1HSPA1AHSPA2HSPA8STUB1

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 HspBP1 acts as a nucleotide exchange factor (NEF) for Hsp70 via a mechanism distinct from BAG-1 or GrpE: its curved, all alpha-helical armadillo-repeat fold embraces lobe II of the Hsp70 ATPase domain, and steric conflict displaces lobe I, reducing nucleotide affinity, rather than triggering a conformational change in lobe II as the other NEFs do. Crystal structure of HspBP1 alone and in complex with Hsp70 ATPase domain; in vitro nucleotide exchange assays; yeast genetic analysis (Fes1p deletion) Molecular cell High 15694338
2004 HspBP1 inhibits the ubiquitin ligase activity of CHIP when complexed with Hsc70, thereby interfering with CHIP-induced proteasomal degradation of immature CFTR and stimulating CFTR maturation. Co-immunoprecipitation; in vitro ubiquitin ligase assays; CFTR maturation assays; overexpression and knockdown in cells Molecular biology of the cell High 15215316
2002 HspBP1 is a nucleotide exchange factor that promotes nucleotide dissociation from mammalian Hsc70 (and yeast Ssa1p/BiP), and unlike its yeast ortholog Fes1p, inhibits chaperone-mediated protein refolding in vitro. In vitro nucleotide dissociation assays; in vitro luciferase refolding assays FEBS letters High 12417338
2018 HspBP1 employs a flexible N-terminal release domain (RD) with substrate-mimicking properties that contacts the substrate-binding domain of Hsp70, competes with peptide substrate for binding, and is essential for efficient release of persistent substrates from Hsp70; the armadillo domain triggers nucleotide exchange while the RD safeguards substrate release. In vitro binding and competition assays with recombinant proteins; mutagenesis of the release domain; yeast and mammalian cell functional assays Nature structural & molecular biology High 29323280
2003 HspBP1 has two structural domains: an unstructured N-terminal domain I (aa 1-83) and an alpha-helical domain II (aa 84-359); domain II alone is sufficient to bind Hsp70 and alter the conformation of its ATPase domain, and domain I augments these functions. Circular dichroism; limited proteolysis; truncation mutagenesis; in vitro luciferase refolding assay; reticulocyte lysate binding assay The Journal of biological chemistry Medium 12651857
2003 Hsp40 and TPR1 cooperatively reverse HspBP1-mediated inhibition of Hsp70-dependent protein folding; the Hsp70-HspBP1 complex is dissociated only in the presence of both Hsp40 and TPR1 together, revealing a cooperative regulatory mechanism. In vitro luciferase refolding assays; Kd measurements; competition assays; tetracycline-inducible HeLa cell system Molecules and cells Medium 14503850
2014 HSPBP1 inhibits ubiquitylation and proteasomal degradation of inducible HSP70 proteins (HSPA1L and HSPA2) at a posttranslational level; loss of HSPBP1 in mice causes male sterility due to impaired meiosis and massive spermatocyte apoptosis linked to loss of HSPA2-dependent synaptonemal complex disassembly. HSPBP1 knockout mouse generation; Western blot analysis of HSP70 protein levels; ubiquitylation assays; histological analysis of testes Molecular biology of the cell High 24899640
2017 Neurons express abundant HspBP1, which inhibits CHIP activity and thereby reduces CHIP-mediated K48-linked polyubiquitination and degradation of misfolded proteins including mutant huntingtin; CRISPR-Cas9 silencing of HspBP1 in neurons ameliorated mHtt aggregation and neuropathology in HD knockin mice. Western blot; co-immunoprecipitation; CHIP ubiquitination assays; CRISPR-Cas9 knockdown in neurons; HD knockin mouse model analysis Proceedings of the National Academy of Sciences of the United States of America High 28847953
2014 HspBP1 reduces Hsp70 binding to the ligand-binding domain of glucocorticoid receptor (GR) and inhibits GR, mineralocorticoid receptor (MR), and androgen receptor (AR) transcriptional activity, in contrast to BAG-1M which shows a dose-dependent biphasic effect; HspBP1 and BAG-1M differentially regulate the composition of steroid receptor-chaperone folding complexes. Co-immunoprecipitation; GST pull-down assays; reporter gene assays; overexpression in cells PloS one Medium 24454860
2011 HspBP1 binds both Hsp70 and Tag7 (PGRP-S innate immunity protein); this interaction eliminates the cytotoxic activity of the Tag7-Hsp70 complex, decreases the ATP concentration required to dissociate Tag7 from Hsp70's peptide-binding site, and inhibits cytotoxic activity secreted by CD8+ lymphocytes. Co-immunoprecipitation; cytotoxicity assays; biochemical binding assays with purified proteins The Journal of biological chemistry Medium 21247889
2007 HspBP1 antagonizes the prosurvival function of Hsp70 in a manner dependent on its ability to bind Hsp70; ectopic HspBP1 expression promotes lysosomal membrane permeabilization, cathepsin release to cytosol, and caspase-3 activation in response to anticancer drugs. RNA interference; ectopic overexpression; lysosomal integrity assays; cathepsin release assays; caspase-3 activation assays The Journal of biological chemistry Medium 17855353
2020 HspBP1 is a component of stress granules (SGs) that regulates their formation: it colocalizes with G3BP1, HuR and TIA-1/TIAR in SGs, associates with these SG proteins by co-immunoprecipitation, binds polyA-RNA directly in vitro, and its knockdown impairs stress-induced SG assembly while overexpression promotes SG formation even in the absence of stress. Immunofluorescence microscopy; co-immunoprecipitation; mass spectrometry; in vitro RNA binding; siRNA knockdown and overexpression Cells Medium 32235396
2021 HSPBP1 promotes RIG-I-mediated antiviral signaling by inhibiting K48-linked ubiquitination of RIG-I, thereby stabilizing RIG-I protein levels and promoting IRF3 activation and IFN-β production in response to Sendai virus infection. Overexpression and knockdown/knockout; ubiquitination assays; co-immunoprecipitation; IRF3 phosphorylation assays; IFN-β reporter/ELISA Molecular immunology Medium 33713958
2022 HspBP1 interacts with BRCA1 and promotes BRCA1-mediated homologous recombination DNA repair; independently of BRCA1 status, HspBP1 also interferes with the association of Hsp70 and Apaf-1 (apoptotic protease-activating factor-1), facilitating cell survival after ionizing radiation. Co-immunoprecipitation; homologous recombination reporter assays; knockdown and overexpression; xenograft tumor models Cell death & disease Medium 35387978
2009 Extracellular HspBP1 (e-HspBP1) co-immunoprecipitates with extracellular Hsp72 in conditioned medium; purified recombinant HspBP1 augments e-Hsp72-mediated phosphorylation of EGFR and downstream ERK1/2 in a concentration-dependent manner, and this activity requires the HspBP1 N-terminal domain. Co-immunoprecipitation from conditioned medium; EGFR and ERK phosphorylation assays; deletion mutant analysis; secretion assays Biology of the cell Low 18986301
2026 HSPBP1 Cys201 was identified as an upstream cellular target contributing to necroptosis regulation; covalent modification of HSPBP1 at Cys201 by parthenolide (confirmed by mass spectrometry co-incubation) confers anti-necroptotic activity, and HSPBP1 knockdown reduces sensitivity to necroptosis. Mass spectrometry covalent modification mapping; HSPBP1 knockdown; co-incubation of purified HSPBP1 with parthenolide; necroptosis assays Cell death & disease Low 42014672

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange. Molecular cell 164 15694338
2004 The cochaperone HspBP1 inhibits the CHIP ubiquitin ligase and stimulates the maturation of the cystic fibrosis transmembrane conductance regulator. Molecular biology of the cell 138 15215316
2002 HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor. FEBS letters 81 12417338
2013 Hsp70 nucleotide exchange factor Fes1 is essential for ubiquitin-dependent degradation of misfolded cytosolic proteins. Proceedings of the National Academy of Sciences of the United States of America 68 23530227
2015 GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: nucleotide exchange factors for Hsp70 molecular chaperones. Sub-cellular biochemistry 48 25487014
2018 Nucleotide exchange factors Fes1 and HspBP1 mimic substrate to release misfolded proteins from Hsp70. Nature structural & molecular biology 44 29323280
2017 Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins. Proceedings of the National Academy of Sciences of the United States of America 42 28847953
2016 Cytosolic splice isoform of Hsp70 nucleotide exchange factor Fes1 is required for the degradation of misfolded proteins in yeast. Molecular biology of the cell 36 26912797
2007 Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells. The Journal of biological chemistry 26 17855353
2003 HspBP1, an Hsp70 cochaperone, has two structural domains and is capable of altering the conformation of the Hsp70 ATPase domain. The Journal of biological chemistry 26 12651857
2014 HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis. Molecular biology of the cell 24 24899640
2003 Increased expression of the Hsp70 cochaperone HspBP1 in tumors. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 15004487
2014 Hsp70 cochaperones HspBP1 and BAG-1M differentially regulate steroid hormone receptor function. PloS one 21 24454860
2011 The heat shock-binding protein (HspBP1) protects cells against the cytotoxic action of the Tag7-Hsp70 complex. The Journal of biological chemistry 19 21247889
2019 Activity of the yeast cytoplasmic Hsp70 nucleotide-exchange factor Fes1 is regulated by reversible methionine oxidation. The Journal of biological chemistry 18 31806703
2008 HspBP1 levels are elevated in breast tumor tissue and inversely related to tumor aggressiveness. Cell stress & chaperones 17 18987994
2003 Cooperative interaction of Hsp40 and TPR1 with Hsp70 reverses Hsp70-HspBp1 complex formation. Molecules and cells 17 14503850
2023 Nucleotide Exchange Factors for Hsp70 Molecular Chaperones: GrpE, Hsp110/Grp170, HspBP1/Sil1, and BAG Domain Proteins. Sub-cellular biochemistry 14 36520302
2020 The Co-Chaperone HspBP1 Is a Novel Component of Stress Granules that Regulates Their Formation. Cells 14 32235396
2009 Extracellular HspBP1 and Hsp72 synergistically activate epidermal growth factor receptor. Biology of the cell 12 18986301
2022 HspBP1 is a dual function regulatory protein that controls both DNA repair and apoptosis in breast cancer cells. Cell death & disease 11 35387978
2012 Effect of exercise on the expression of HSPBP1, PGLYRP1, and HSPA1A genes in human leukocytes. Bulletin of experimental biology and medicine 11 23113305
2005 Development of a sensitive assay for the measurement of antibodies against heat shock protein binding protein 1 (HspBP1): increased levels of anti-HspBP1 IgG are prevalent in HIV infected subjects. Journal of medical virology 11 15977250
2019 Hsp70-nucleotide exchange factor (NEF) Fes1 has non-NEF roles in degradation of gluconeogenic enzymes and cell wall integrity. PLoS genetics 9 31242183
2006 Expression of the cochaperone HspBP1 is not coordinately regulated with Hsp70 expression. Cell biology international 8 16677834
2022 Identification of 5' upstream sequence involved in HSPBP1 gene transcription and its downregulation during HIV-1 infection. Virus research 5 36581045
2021 HSPBP1 facilitates cellular RLR-mediated antiviral response by inhibiting the K48-linked ubiquitination of RIG-I. Molecular immunology 5 33713958
2015 Quantitative analysis of the interplay between hsc70 and its co-chaperone HspBP1. PeerJ 4 26713263
2011 Extracellular HspBP1 inhibits formation of a cytotoxic Tag7-Hsp70 complex in vitro and in human serum. Biochimie 4 22037021
2010 Long-term exercises increase the concentration of HspBP1, a co-chaperone of 70-KDa heat shock protein. Bulletin of experimental biology and medicine 4 21165407
2000 Isolation and characterization of isoforms of HspBP1, inhibitors of Hsp70. Biochimica et biophysica acta 4 10786638
2020 Heat-stress induced expression of stress-inducible nucleotide exchange factor Fes1 in seagrass Zostera japonica. Ecotoxicology (London, England) 3 32162033
2019 HspBP1 and anti-HspBP1 levels in the serum of HIV-infected individuals are associated to the disease progression. Journal of applied microbiology 3 30786116
2024 HspBP1 in Complex with the Peptide of the Innate Immunity Protein Tag7 is Able to Lyse Tumor Cells Carrying TNFR1 Receptor. Doklady. Biochemistry and biophysics 1 38189890
2026 Identification of human MLKL Cys184 and HSPBP1 Cys201 as novel cellular targets for necroptosis. Cell death & disease 0 42014672