Affinage

HSPA8

Heat shock cognate 71 kDa protein · UniProt P11142

Round 2 corrected
Length
646 aa
Mass
70.9 kDa
Annotated
2026-04-28
130 papers in source corpus 49 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPA8 (Hsc70) is a constitutively expressed, ATP-dependent molecular chaperone that sits at the nexus of protein folding, quality control, and degradation, governing the fate of unfolded, misfolded, and aggregation-prone substrates across multiple proteostasis pathways. Its nucleotide-binding domain (NBD) hydrolyzes ATP to drive substrate-binding domain (SBD) conformational cycling between low-affinity (ATP-bound) and high-affinity (ADP-bound) states, a cycle positively regulated by Hsp40 co-chaperones (DjA1/dj2/dj3) and the nucleotide-exchange factor Hsp110/Apg2, and negatively regulated by CHIP and Hsp105α (PMID:7585962, PMID:10330192, PMID:30521813, PMID:15292236). In collaboration with the E3 ubiquitin ligase CHIP, HSPA8 ubiquitinates aberrant clients such as phospho-tau and immature CFTR for proteasomal degradation, docks at the lysosomal membrane via LAMP2A and phosphatidylserine binding to execute chaperone-mediated autophagy (CMA), oligomerizes to deform endosomal membranes for microautophagy, and functions as an ATP-powered amyloidase that disassembles RHIM-domain functional amyloids to suppress necroptosis (PMID:2799391, PMID:11146634, PMID:34942188, PMID:27405763, PMID:26590345, PMID:37580406). HSPA8 also partners with auxilin/GAK to uncoat clathrin-coated vesicles during endocytosis, acts as an essential co-chaperone for HSP90 client maintenance, and is subject to post-translational tuning by PRMT9-mediated arginine methylation, Mettl21c-mediated lysine trimethylation, and S-nitrosylation, each modulating its stability or activity (PMID:17488288, PMID:18772114, PMID:37715221, PMID:31346037, PMID:30368041).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1989 High

    The first mechanistic question — how are cytosolic proteins selected for lysosomal degradation during serum withdrawal — was answered by showing that a constitutive 73-kDa Hsp70 family member (Hsc70) binds targeting peptides on substrates and promotes their degradation in an ATP-dependent manner, founding the concept of chaperone-mediated autophagy.

    Evidence Cell-free lysosomal proteolysis assay with peptide sequencing and monoclonal antibody identification

    PMID:2799391

    Open questions at the time
    • Lysosomal receptor for Hsc70 docking not yet identified
    • Substrate selectivity rules undefined
    • In vivo relevance not demonstrated
  2. 1995 High

    How the Hsc70 ATPase cycle is regulated was clarified by discovery of Hip, which stabilizes the ADP-bound high-substrate-affinity state after Hsp40-stimulated hydrolysis, establishing the concept of co-chaperone-regulated nucleotide cycling as the central mechanism controlling substrate grip and release.

    Evidence Reconstituted chaperone system with biochemical binding and ATPase measurements

    PMID:7585962

    Open questions at the time
    • Nucleotide exchange factor identity unknown
    • Structural basis of Hip–Hsc70 interaction unresolved
  3. 1999 High

    How the chaperone cycle is negatively regulated was answered by identification of CHIP, which binds the Hsc70 C-terminus, inhibits Hsp40-stimulated ATPase activity, and reduces substrate refolding, revealing a dedicated brake on the Hsc70 folding machine.

    Evidence Yeast two-hybrid, GST pulldown, in vitro ATPase and refolding assays with domain mapping

    PMID:10330192

    Open questions at the time
    • Whether CHIP couples chaperone inhibition to substrate degradation unknown
    • E3 ligase function of CHIP not yet demonstrated
  4. 2001 High

    The question of whether Hsc70 can switch from folding to degradation was resolved by showing CHIP's U-box ubiquitinates Hsc70-bound immature CFTR for proteasomal degradation, converting Hsc70 into a triage factor for ER quality control; subsequent work demonstrated the same CHIP–Hsc70 axis ubiquitinates phosphorylated tau selectively.

    Evidence Ubiquitination assays, co-IP, dominant-negative CHIP in cells (CFTR); reconstituted in vitro ubiquitination with defined phospho-tau substrates

    PMID:11146634 PMID:14612456

    Open questions at the time
    • Full repertoire of CHIP–Hsc70 degradation substrates unknown
    • Structural basis of phospho-tau selectivity unresolved
  5. 2000 High

    Which Hsp40 partners drive Hsc70 function in the cytosol was answered by showing dj2 and dj3 (not dj1) are the primary DnaJ co-chaperones for Hsc70, required for both mitochondrial protein import and luciferase refolding.

    Evidence Depletion/reconstitution of reticulocyte lysate with in vitro import and refolding assays

    PMID:10816573

    Open questions at the time
    • Client specificity of dj2 versus dj3 unclear
    • Whether other J-domain proteins contribute in specific tissues not tested
  6. 2007 High

    How clathrin-coated vesicles are disassembled was mechanistically resolved: Hsc70, recruited by the J-domain proteins auxilin and GAK, catalyzes ATP-dependent clathrin uncoating and additionally chaperones released clathrin and adaptors to prevent aggregation.

    Evidence Gene knockout across organisms combined with in vitro uncoating assays; later confirmed by in vivo domain-deletion rescue showing GAK's J-domain is necessary and sufficient

    PMID:17488288 PMID:26345367

    Open questions at the time
    • Stoichiometry of Hsc70 on the clathrin lattice in vivo uncertain
    • Mechanism distinguishing uncoating from recoating not fully defined
  7. 2008 High

    Structural and functional basis of Hsp110 as an Hsc70 nucleotide-exchange factor was established by the crystal structure of the Hsp110–Hsc70 complex, showing symmetric NBD bridging drives ADP release; subsequent biochemical work revealed Apg2 exerts biphasic (stimulatory then inhibitory) regulation of Hsc70 through its acidic subdomain.

    Evidence X-ray crystallography, EM, nucleotide exchange assays; quantitative ATPase/refolding assays with deletion mutants

    PMID:18550409 PMID:30521813

    Open questions at the time
    • In vivo stoichiometric ratios of Hsp110:Hsc70 not defined
    • Whether biphasic regulation is physiologically relevant unclear
  8. 2008 High

    Whether Hsc70 and Hsp70 are functionally redundant was tested by dual silencing, which — unlike single knockdown — triggered proteasome-dependent degradation of HSP90 client proteins and tumor-specific apoptosis, establishing that Hsc70 shares essential HSP90 co-chaperone activity with Hsp70 but the two isoforms are functionally redundant for this role.

    Evidence Single and dual siRNA knockdown with Western blot for HSP90 clients, apoptosis, and cell-cycle assays comparing tumor and normal cells

    PMID:18772114

    Open questions at the time
    • Isoform-specific client preferences not resolved
    • Mechanism of tumor selectivity of apoptosis unclear
  9. 2011 High

    How Hsc70 handles intrinsically aggregation-prone substrates was elucidated: Hsc70 sequesters soluble α-synuclein in an assembly-incompetent complex in the ADP/apo state, and separately Hsc70's nucleotide cycle duration determines whether CFTR is refolded or ubiquitinated for degradation.

    Evidence Quantitative in vitro aggregation and affinity assays with nucleotide/co-chaperone controls (α-syn); cell-free translation/degradation with CBag manipulation of ADP–ATP exchange (CFTR)

    PMID:21697503 PMID:21832061

    Open questions at the time
    • Whether in vivo α-synuclein aggregation is limited by Hsc70 capacity not established
    • Structural basis of Hsc70 on fibril ends unknown
  10. 2014 High

    Residue-level resolution of how Hsc70 recognizes aggregation-prone clients was achieved: NMR mapped the binding of the huntingtin exon 1 N-terminal flank and tau MTBR peptides to the canonical SBD cleft, with aggregation-promoting conditions enhancing affinity and Hsc70 efficiently capping fibril ends to block elongation.

    Evidence NMR spectroscopy with NOE-based distance measurements, fluorescence competition, and in vitro aggregation assays for both huntingtin and tau

    PMID:25505179 PMID:29298892 PMID:29764935

    Open questions at the time
    • No high-resolution structure of Hsc70 bound to a full-length disease substrate
    • Whether lid-domain dynamics differ between tau and huntingtin engagement unclear
  11. 2015 High

    How Hsc70 docks at the lysosomal membrane for CMA and deforms endosomal membranes for microautophagy was resolved: Hsc70 directly interacts with LAMP2A's cytoplasmic tail (photo-crosslinking) regulated by LAMP2A's lumenal domain architecture, and separately Hsc70 binds phosphatidylserine via C-terminal LID-domain lysines to oligomerize and drive endosomal membrane deformation for eMI.

    Evidence In-cell photo-crosslinking and domain truncation (LAMP2A); NMR mapping, SPR, and mutagenesis of PS-binding interface; Drosophila genetic epistasis plus liposome deformation screen (eMI)

    PMID:26590345 PMID:27405763 PMID:34942188

    Open questions at the time
    • Structure of the Hsc70–LAMP2A complex at atomic resolution missing
    • Oligomeric state required for membrane deformation not precisely defined
  12. 2015 High

    CHIP-mediated ubiquitination of Hsc70 itself was comprehensively mapped, revealing 16 of 45 lysines are ubiquitinated with isoform-specific sites (K159 unique to Hsc70) and chain types, explaining differential CHIP-dependent turnover of Hsc70 versus Hsp70.

    Evidence In vitro ubiquitination with MS-based site identification, K-to-R ubiquitin mutants, E2 enzyme panel

    PMID:26010904

    Open questions at the time
    • Physiological consequence of self-ubiquitination in vivo not fully demonstrated
    • Which ubiquitin chain types dominate in cells unknown
  13. 2018 High

    Post-translational regulation of Hsc70 was broadened: S-nitrosylation at the NBD impairs CMA and causes senescence-like phenotypes in neuronal cells; FUNDC1 interaction routes unfolded cytosolic proteins to mitochondria for LONP1-mediated degradation; and BAG3/Hsc70 maintains sarcomeric integrity under mechanical stress by chaperoning CapZβ1.

    Evidence Redox proteomics and CMA assay (SNO); co-IP, Apex labeling, and CLEM (FUNDC1); shRNA KD, stretch assay, and bag3−/− mouse (BAG3/CapZ)

    PMID:20884878 PMID:30368041 PMID:30591555

    Open questions at the time
    • Whether SNO-Hsc70 is reversible and regulated by denitrosylases unknown
    • Full client repertoire of the mitochondrial import route via FUNDC1 undefined
  14. 2019 High

    Mettl21c-mediated trimethylation of Hsc70 at K561 was shown to stabilize Hsc70 protein in type I muscle fibers and enhance CMA-dependent degradation of Mef2A/D transcription factors, establishing lysine methylation as a tissue-specific Hsc70 regulatory code.

    Evidence Mettl21c KO/KI mouse, in vitro methylation, CMA assay, Western blot quantification

    PMID:31346037

    Open questions at the time
    • Whether other methyltransferases modify Hsc70 at distinct sites not explored
    • Structural impact of K561 trimethylation on SBD conformation unknown
  15. 2020 High

    Proteome-scale client mapping using UBAIT proximity tagging revealed that Hsc70 and Hsp70 have largely nonoverlapping client repertoires despite high sequence identity, and that disease-associated misfolded proteins (SOD1 mutant) globally remodel the Hsc70 client network toward disordered polypeptides.

    Evidence UBAIT fusion proximity tagging with quantitative MS under basal and SOD1-mutant stress conditions

    PMID:32687490

    Open questions at the time
    • Which SBD residues encode isoform-specific client preferences unknown
    • Whether client remodeling is adaptive or pathological not determined
  16. 2023 High

    A fundamentally new enzymatic activity of Hsc70 was established: HSPA8 acts as an 'amyloidase' that binds RHIM-domain amyloid fibers (RIP1, RIP3, ZBP1, TRIF) through an N(X1)φ(X3) motif in the SBD and uses NBD-driven ATP hydrolysis to disassemble them into non-functional monomers, co-chaperone-independently, thereby suppressing necroptosis signaling.

    Evidence Reconstituted in vitro amyloid formation/disassembly with domain mutants, motif identification, cell-based necroptosis assay, and mouse necroptosis model

    PMID:37580406

    Open questions at the time
    • Whether amyloidase activity extends to non-RHIM amyloids (e.g. Aβ, α-syn fibrils) unknown
    • Structural mechanism of fiber threading/extraction not visualized
    • Kinetics of disassembly versus refolding pathways not compared
  17. 2023 Medium

    PRMT9-mediated arginine methylation of Hsc70 at R76/R100 was identified as a stabilizing modification that suppresses ferroptosis via a CD44 axis in HBV-associated hepatocellular carcinoma, adding arginine methylation to the PTM code that tunes Hsc70 stability and activity.

    Evidence Site-directed mutagenesis, in vitro methylation, transcriptome profiling, tumor xenograft model

    PMID:37715221

    Open questions at the time
    • Whether PRMT9-mediated methylation occurs outside HBV-HCC contexts unknown
    • Direct structural effect of R76/R100 methylation on NBD function not tested
    • Single-lab finding awaits independent replication
  18. 2024 High

    Hsc70 was shown to promote PD-L1 degradation through the endosome–lysosome pathway by competitively displacing the stabilizer CMTM6, enhancing anti-tumor immunity in vivo — extending Hsc70's immune-regulatory role beyond innate inflammasome control.

    Evidence Reciprocal co-IP (Hsc70–PD-L1, competitive CMTM6 displacement), flow cytometry, in vivo tumor model with Hsc70 overexpression and pharmacologic induction

    PMID:38762492

    Open questions at the time
    • Whether other immune checkpoint proteins are similarly regulated by Hsc70 unknown
    • Relative contribution of CMA versus eMI in PD-L1 degradation not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the atomic-resolution structure of Hsc70 engaged with full-length disease substrates (tau, α-synuclein), the structural basis of isoform-specific client selection relative to Hsp70, whether the amyloidase activity extends to pathological amyloids beyond RHIM, and how the combinatorial PTM code (methylation, S-nitrosylation, ubiquitination) is integrated to set Hsc70 activity in different tissues and stress states.
  • No high-resolution structure of Hsc70 bound to full-length disease substrate
  • Mechanism discriminating amyloidase versus refolding mode unknown
  • Combinatorial PTM regulation in vivo not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 8 GO:0140657 ATP-dependent activity 8 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 1
Localization
GO:0005764 lysosome 5 GO:0005829 cytosol 5 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9609507 Protein localization 2 R-HSA-5357801 Programmed Cell Death 1
Partners
BAG1BAG3DNAJA1GAKHSPH1HSPH2LAMP2ASTUB1
Complex memberships
BAG3–Hsc70 chaperone complexCHIP–Hsc70 ubiquitin ligase complexHsc70–auxilin/GAK clathrin-uncoating complexHsp110–Hsc70 NEF complex

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 A 73-kDa member of the Hsp70 family (Hsc70/HSPA8) binds peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal, and in the presence of ATP and MgCl2 enhances protein degradation in cell-free lysosomal proteolysis assays, establishing its role in chaperone-mediated autophagy (CMA). In vitro binding assay, cell-free lysosomal proteolysis assay, peptide sequencing, monoclonal antibody cross-reactivity Science High 2799391
1995 The cochaperone Hip (Hsc70-interacting protein) binds the ATPase domains of Hsc70, dependent on prior ADP state established by Hsp40-stimulated ATP hydrolysis; Hip stabilizes the ADP-bound, high-substrate-affinity state of Hsc70, regulating its substrate binding cycle independently of a GrpE-like nucleotide exchange factor. Biochemical binding assays, ATPase activity measurements, reconstituted chaperone system Cell High 7585962
1999 CHIP (carboxyl terminus of Hsc70-interacting protein) directly binds the C-terminal residues 540–650 of Hsc70 via its tetratricopeptide repeat domain, inhibits Hsp40-stimulated ATPase activity of Hsc70/Hsp70, reduces luciferase refolding and substrate binding, and thereby negatively regulates the Hsc70 chaperone cycle. Yeast two-hybrid, GST pulldown, in vitro ATPase assay, luciferase refolding assay, co-immunoprecipitation from human skeletal muscle Molecular and cellular biology High 10330192
2001 CHIP functions with Hsc70 to sense the folded state of CFTR; CHIP's U-box promotes ubiquitination of aberrant/immature CFTR and targets it for proteasomal degradation, converting Hsc70 from a folding chaperone into a degradation factor in ER quality control. Overexpression/dominant-negative CHIP constructs, ubiquitination assays, co-immunoprecipitation, proteasome inhibitor experiments Nature cell biology High 11146634
2003 The CHIP–Hsc70 complex ubiquitinates phosphorylated tau (but not non-phosphorylated tau) using E2 enzyme UbcH5B; phosphorylation of tau by GSK3β or Cdk5 is a recognition requirement for Hsc70 binding and subsequent CHIP-mediated ubiquitination; CHIP overexpression rescues phospho-tau-induced cell death. In vitro ubiquitination assay, co-immunoprecipitation, mass spectrometry, cell viability assay The Journal of biological chemistry High 14612456
2000 Hsc70 associates with DeltaF508-CFTR in cystic fibrosis epithelial cells (co-immunoprecipitation); 4-phenylbutyrate (4PBA) reduces Hsc70 protein and mRNA expression and decreases Hsc70–CFTR complexes, allowing more mutant CFTR to escape degradation, identifying Hsc70 association as a determinant of ΔF508-CFTR trafficking fate. Co-immunoprecipitation, Western blot, Northern blot, dose-response treatment American journal of physiology. Cell physiology Medium 10666020
2000 DnaJ cochaperones dj2 and dj3 (but not dj1) are the primary partner DnaJs of Hsc70 in mammalian cells; simultaneous depletion of dj2 and dj3 from reticulocyte lysate markedly reduces mitochondrial protein import and luciferase refolding, which are restored by re-addition of either; BAG-1 further stimulates ATPase activity and refolding by Hsc70-dj2 and Hsc70-dj3 pairs. Depletion/reconstitution of reticulocyte lysate, in vitro protein import assay, luciferase refolding assay, ATPase assay, immunocytochemistry The Journal of biological chemistry High 10816573
2004 Gentamicin specifically associates with the peptide-binding domain (C-terminal one-third) of HSP73/Hsc70, induces a conformational change as detected by CD spectroscopy, and suppresses Hsc70 chaperone activity (prevention of rhodanese aggregation) in vitro; in vivo, Hsc70 and gentamicin co-localize in enlarged lysosomes of rat kidney after gentamicin-induced injury. Affinity chromatography (GM-affinity column), CD spectroscopy, in vitro anti-aggregation assay, limited proteolysis, immunohistochemistry The Journal of biological chemistry High 14966137
2004 Hsp105α suppresses Hsc70 chaperone activity by directly binding Hsc70 and inhibiting its ATPase activity; interaction requires specific domains of Hsp105α, and inhibition of Hsc70 ATPase is concurrent with appearance of Hsp105α ATPase activity, indicating Hsp105α is a negative regulator of the Hsc70 substrate-binding cycle. Deletion mutant mapping, ATPase activity assay, in vitro chaperone activity assay The Journal of biological chemistry High 15292236
2007 Hsc70 and auxilin/GAK are required for ATP-dependent uncoating of clathrin-coated vesicles in vivo; J-domain proteins stimulate Hsc70 binding to clathrin-coated vesicles; Hsc70 and auxilin also chaperone clathrin and adaptor proteins after dissociation to prevent aggregation and facilitate rebinding to the plasma membrane for new coated-pit formation. Gene knockout in cells and organisms, in vitro uncoating assay, functional endocytosis assays Traffic (Copenhagen, Denmark) High 17488288
2007 BAG-1 associates with the Hsc70–Tau complex in an Hsc70-dependent manner; BAG-1 overexpression inhibits 20S proteasome-mediated degradation of tau without affecting tau ubiquitination, leading to tau accumulation; BAG-1 knockdown decreases total tau and promotes its hyperphosphorylation, demonstrating that BAG-1 regulates Hsc70-directed tau proteostasis. Co-immunoprecipitation, overexpression/siRNA knockdown, 20S proteasome degradation assay, phosphorylation analysis The Journal of biological chemistry Medium 17954934
2007 Hsc70 co-immunoprecipitates with and is overexpressed relative to ASIC2 in high-grade glioma cells; Hsc70 siRNA knockdown reduces the constitutively activated amiloride-sensitive current, decreases cell migration, and increases ASIC2 surface expression, indicating Hsc70 promotes ASIC2 retention in the ER and thereby sustains the glioma-specific channel phenotype. Co-immunoprecipitation, siRNA knockdown, electrophysiology (patch clamp), migration assay, surface expression analysis The Journal of biological chemistry Medium 17878160
2008 The crystal/EM structure of the Hsp110–Hsc70 nucleotide exchange complex reveals that Hsp110 acts as a nucleotide exchange factor (NEF) for Hsc70 through extensive protein–protein interactions and symmetric bridging between the nucleotides in each partner's NBD; an electropositive pore allows nucleotide entry/exit and the open-closed NBD isomerization drives nucleotide exchange. X-ray crystallography, electron microscopy, analytical ultracentrifugation, nucleotide exchange assays Molecular cell High 18550409
2008 Simultaneous silencing of both Hsc70 and HSP72 (but not either alone) induces proteasome-dependent degradation of HSP90 client proteins, G1 cell-cycle arrest, and extensive tumor-specific apoptosis in cancer cells, while sparing non-tumorigenic cells, demonstrating functional redundancy between isoforms for HSP90 co-chaperone activity. siRNA knockdown (single and dual), Western blot for HSP90 clients, cell cycle analysis, apoptosis assay Cancer cell High 18772114
2009 Cytosolic chaperones Hsc70 and Hsp90 complex with mitochondrial carrier precursors in the cytosol and interact with the Tom70 import receptor to promote mitochondrial import; deletion of the PiC presequence reduces Hsc70 binding and Hsc70-dependent import without affecting Hsp90, and the PiC presequence confers Hsc70 binding to heterologous fusion proteins. In vitro import assay, co-immunoprecipitation, GST-fusion binding assay, deletion constructs The Biochemical journal High 19143589
2010 BAG3 promotes association between Hsc70 and the actin capping protein CapZβ1, facilitating CapZβ1 localization to proper sarcomeric sites; BAG3 knockdown in cardiomyocytes causes rapid myofibril disruption under mechanical stretch, CapZ ubiquitin-proteasome-mediated degradation, and loss of contractile activity, establishing a BAG3/Hsc70/CapZβ1 axis in mechanical stress resistance. shRNA knockdown, mechanical stretch assay, co-immunoprecipitation, ubiquitination assay, contractility assay, bag3−/− mouse model Circulation research High 20884878
2010 Multiple Hsc70 molecules and a DjA1 dimer bind independently to an unfolded substrate protein; association rates and binding sites differ between Hsc70 and DjA1; Hsc70 binding induces a conformational change in its substrate-binding domain (increased trypsin resistance), and DjA1 binds bivalently to distinct peptide sequences from Hsc70, arguing against a simple DnaJ-to-Hsp70 substrate transfer model. Surface plasmon resonance, gel filtration, crosslinking, tryptic protection assay, peptide array binding The Journal of biological chemistry High 20363747
2011 Hsc70 sequesters soluble α-synuclein in an assembly-incompetent complex in the absence of ATP; ATP addition alone or with co-chaperones Hdj1/Hdj2 reduces Hsc70's affinity for soluble α-Syn and abolishes aggregation inhibition; Hsc70 binds α-Syn fibrils with ~5-fold higher affinity than soluble α-Syn, and fibril-coated Hsc70 shows reduced cellular toxicity. In vitro aggregation assay, affinity measurement (fluorescence), co-chaperone modulation, toxicity assay The Journal of biological chemistry High 21832061
2011 Hsc70 binding cycle controls dual outcomes for CFTR: during co-translational folding Hsc70 has a modest pro-folding role, but posttranslational Hsc70 binding is dominant and essential for CFTR ubiquitination, dislocation from the ER, and proteasomal degradation; accelerating ADP-ATP exchange (CBag) blocks ubiquitination, showing that the duration of Hsc70 binding determines CFTR fate. Cell-free reconstituted translation/degradation system, CBag (BAG-1 C-terminal domain) as ADP-ATP exchange accelerator, ubiquitination assay, proteasome inhibition Molecular biology of the cell High 21697503
2014 Hsc70 physically interacts with Rab1A in a chaperone-dependent manner; Hsc70 knockdown decreases Rab1A protein levels and increases its ubiquitination under stress, showing Hsc70 prevents ubiquitin-proteasome-mediated degradation of stress-denatured Rab1A to support cancer cell autophagy and survival. Affinity purification–mass spectrometry, co-immunoprecipitation, siRNA knockdown, ubiquitination assay, autophagosome formation assay PloS one Medium 24801886
2014 Hsc70 binds the 17-residue N-terminal flank of huntingtin exon 1 (HttEx1) via its substrate-binding cleft (NMR mapping to residue level); this interaction competes with homotypic N-terminal flank interactions that nucleate polyQ aggregation; Hsc70 together with Hsp40 co-chaperones inhibits HttEx1 aggregation in a polyQ-length-independent manner and modifies fibril seeding properties. NMR spectroscopy (surface interface mapping), in vitro aggregation assay, peptide competition The Journal of biological chemistry High 25505179
2015 The J-domain of GAK is required for Hsc70-dependent clathrin uncoating; a 62-kDa fragment comprising only GAK's clathrin-binding and J-domains rescues clathrin trafficking defects in GAK-knockout fibroblasts and lethality from brain-specific GAK/auxilin double knockout, demonstrating the PTEN-like domain is dispensable for Hsc70-mediated clathrin chaperoning. Conditional knockout mice, domain-deletion rescue transgene, clathrin trafficking assay, behavioral analysis Journal of cell science High 26345367
2015 Drosophila Hsc70-4 (ortholog of HSPA8) oligomerizes to deform membranes and promotes endosomal microautophagy (eMI) and turnover of specific synaptic proteins; its cochaperone Sgt can switch Hsc70-4 from eMI mode to chaperone-refolding mode; loss of eMI slows neurotransmission while gain of eMI increases it. In vitro liposome membrane-deformation screen, Drosophila genetics (loss- and gain-of-function), electrophysiology, imaging Neuron High 26590345
2015 HSC70 is identified as a chaperone client handler for cardiac MYBPC3; HSC70 is the most abundant chaperone co-immunoprecipitated with both WT and mutant MYBPC3; HSC70 knockdown slows degradation of both forms while pharmacologic HSC70/Hsp70 activation accelerates it, placing HSC70 as the primary regulator of MYBPC3 protein turnover. Unbiased co-IP/mass spectrometry, siRNA knockdown, pharmacologic activation, pulse-chase degradation assay in primary cardiomyocytes JCI insight High 29875314
2015 HSC70 interacts with the cytoplasmic tail of LAMP2A directly (photo-crosslinking in cells) and the lumenal two-domain architecture of LAMP2A supports this interaction; truncation of the membrane-distal lumenal domain reduces Hsc70 co-immunoprecipitation with LAMP2A, revealing that LAMP2A structure regulates Hsc70 docking at the lysosomal surface for CMA. Site-specific photo-crosslinking in cells, co-immunoprecipitation, domain truncation Experimental cell research High 34942188
2016 Hsc70 physically and functionally interacts with tyrosine hydroxylase (TH); in vitro binding assays show TH binds the substrate-binding and C-terminal domains of Hsc70 directly; purified Hsc70 increases TH enzyme activity in dopaminergic cells and synaptic vesicles; Hsc70 overexpression raises TH activity and dopamine levels while Hsc70 knockdown reduces them and decreases TH association with synaptic vesicles. Co-immunoprecipitation from brain/cells, in vitro domain-binding assay, TH enzyme activity assay, shRNA knockdown, dopamine HPLC measurement The Journal of biological chemistry High 27365397
2016 Hsc70 directly interacts with phosphatidylserine (PS) at the endosomal limiting membrane through a specific interface mapped to the C-terminus of its LID domain involving 4–5 lysine residues (KD ~4.7 µM); this PS interaction is required for cytosolic cargo internalization into endosomes during endosomal microautophagy. Surface plasmon resonance, NMR spectroscopy, site-directed mutagenesis, endosomal binding experiment, eMI assay The Journal of biological chemistry High 27405763
2016 Connexin 43 (Cx43) competes with CDK inhibitor p27 for binding to Hsc70; Cx43 overexpression decreases Hsc70 in the cyclin D1–CDK4–p27 complex, preventing nuclear translocation of the complex and blocking G1/S transition; co-overexpression of Hsc70 restores p27 nuclear accumulation and G1/S progression. Co-immunoprecipitation, overexpression, cell cycle analysis (FACS), nuclear fractionation Scientific reports Medium 26481195
2017 Hsc70 regulates the IRES activity of Enterovirus A71 (EV-A71) and promotes viral replication; Hsc70 knockdown reduces IRES activity and viral RNA/protein levels while overexpression enhances them; Hsc70 binds the viral genomic RNA (not directly the IRES), interacts with 2A protease, and promotes eIF4G cleavage. siRNA knockdown, ectopic overexpression, IRES reporter assay, RNA immunoprecipitation, viral replication assay, inhibitor treatment Antiviral research Medium 29180285
2017 TDP-43 overexpression in ALS motor neurons post-transcriptionally reduces Hsc70-4/HSPA8 expression by sequestering hsc70-4 mRNA and impairing its translation; reduced HSPA8 impairs the CSP/Hsc70 chaperone complex and dynamin function, causing synaptic vesicle endocytosis defects that can be partially rescued by overexpression of Hsc70-4, CSP, or dynamin. Drosophila ALS model, electrophysiology, imaging, genetic interaction (overexpression rescue), mRNA sequestration assay, mouse NMJ analysis, human iPSC neurons Cell reports High 28978466
2018 Hsc70 interacts with Alzheimer's tau peptides at the canonical substrate-binding cleft (NMR); the BETA construct (SBD lacking lid) binds the tau sequence GKVQIINKKG with KD ~500 nM under aggregation-promoting conditions and undergoes dramatic rigidification upon substrate binding, similar to DnaK binding geometry but with isoform-specific affinity differences. NMR spectroscopy (NOE distance measurements), fluorescent competition assay, allostery assay The Journal of biological chemistry High 29764935
2018 HspB1 and Hsc70 inhibit tau fibril formation by distinct mechanisms: Hsc70 is highly efficient at preventing fibril elongation (likely by capping fibril ends) and binds tau significantly tighter under aggregation-promoting conditions, whereas HspB1 weakly delays early aggregation steps; both recognize aggregation-prone motifs in tau's microtubule-binding repeat region. Fluorescence spectroscopy, NMR spectroscopy, in vitro fibril formation assay, kinetic analysis The Journal of biological chemistry High 29298892
2018 FUNDC1 (mitochondrial outer membrane protein) interacts with HSC70 to promote translocation of unfolded cytosolic proteins to mitochondria for degradation by LONP1 or formation of mitochondria-associated protein aggregates (MAPAs) upon proteasome inhibition; excessive accumulation impairs mitochondrial integrity, activates AMPK, and induces cellular senescence. Co-immunoprecipitation, csCLEM, Apex proximity labeling, biochemical fractionation, AMPK signaling analysis The EMBO journal High 30591555
2018 Nitric oxide S-nitrosylates Hsc70/HSPA8 within its nucleotide-binding site in neuronal cells constitutively expressing nNOS; this SNO modification impairs Hsc70 function in CMA (shown by LAMP2a loss and accumulation of CMA substrates), leading to protein homeostasis defects and a senescence-like phenotype. Redox proteomics, SNO-site identification by MS, full proteome analysis, CMA assay, ubiquitination assay, cell cycle analysis Redox biology Medium 30368041
2018 Blocking nuclear export of HSPA8 after heat shock (using P140 phosphopeptide that binds HSPA8 near its nuclear import/export signals) prevents cytoplasmic re-localization of HSPA8 during the recovery phase and severely impairs cell survival when a second oxidative stress is applied, demonstrating that the nuclear-cytoplasmic shuttling of HSPA8 is required for cytoprotection against ROS. Stress treatment, P140 peptide tool compound, crosslinking proteomics, fluorescence microscopy, cell viability assay Scientific reports Medium 30429537
2018 Apg2 (human Hsp110) shows biphasic regulation of Hsc70 (HspA8): at low concentration it stimulates Hsc70 ATPase activity, aggregate binding, and refolding; at high concentration it inhibits all three. The acidic subdomain of Apg2 acts as a conformational switch that prevents premature ATP dissociation and controls complex dissociation from Hsc70(ATP). ATPase assay, aggregate binding assay, refolding assay, deletion mutant analysis, affinity measurements Journal of molecular biology High 30521813
2019 LAMP2A directly interacts with Hsc70 at the cytoplasmic surface of lysosomes (photo-crosslinking); its two-domain lumenal architecture regulates this interaction such that the membrane-distal domain is required for full Hsc70 co-immunoprecipitation. Site-specific photo-crosslinking in living cells, co-immunoprecipitation, domain truncation constructs Experimental cell research High 34942188
2019 NLRC4 forms a complex with HSC70 which negatively regulates caspase-1 activation; the autoinflammatory NLRC4-H443P mutant shows enhanced HSC70 interaction via its NBD and LRR domains (not CARD); cold-induced reduction of NLRC4-H443P–HSC70 interaction leads to increased ASC-speck formation and caspase-1 activation, establishing HSC70 as a temperature-sensitive brake on NLRC4 inflammasome activity. Co-immunoprecipitation, siRNA knockdown, ASC-speck formation assay, caspase-1 activation assay, temperature manipulation PNAS High 31597739
2019 Mettl21c trimethylates Hspa8 at Lys-561 in type I myofibers, enhancing Hspa8 protein stability; Mettl21c knockout reduces Hspa8 trimethylation and protein levels in slow muscle, and Mettl21c overexpression increases them; Mettl21c-stabilized Hspa8 promotes CMA-dependent degradation of client transcription factors Mef2A and Mef2D. Mettl21c knockin/knockout mouse model, co-immunoprecipitation/MS, in vitro methylation assay, Western blot, CMA assay The Journal of biological chemistry High 31346037
2020 HSC70 and HSP70 have largely nonoverlapping client specificities despite high sequence similarity; both preferentially associate with newly synthesized polypeptides; expression of a misfolded ALS-linked SOD1 mutant induces global changes in HSC70/HSP70 client association toward disordered polypeptides, revealing network-wide chaperone remodeling. UBAIT proximity-tagging fusion strategy, quantitative mass spectrometry, chaperone client identification under normal and stress conditions PLoS biology High 32687490
2020 Hsc70 binds to phosphoglycerate kinase (PGK) in living human cells in a cooperative manner that directly correlates with protein thermal unfolding (an 'unfolded-state holding' mechanism), in contrast to Hsp70 which binds before full unfolding; this mechanistic difference correlates with Hsc70's constitutive expression and its multiple cellular functions beyond heat shock. In-cell fluorescence binding assay, thermal unfolding correlation, comparison with Hsp70 isoform The journal of physical chemistry. B Medium 32275442
2021 LAMP2A directly interacts with Hsc70 at the cytoplasmic surface, and this interaction requires the intact two-domain lumenal architecture of LAMP2A; truncation of the membrane-distal lumenal domain reduces Hsc70 co-immunoprecipitation, revealing intramolecular structural regulation of the Hsc70–LAMP2A CMA docking interaction. Site-specific photo-crosslinking in living cells, co-immunoprecipitation, domain truncation Experimental cell research High 34942188
2022 Oxidized PRL2 is a substrate selectively recognized by HSC70 under oxidative stress; HSC70 mediates degradation of PRL2 via endosomal microautophagy and CMA, promoting osteoclastogenesis; inhibition of autophagy (hydroxychloroquine) blocks inflammation-induced PRL2 degradation and bone destruction in vivo. In vivo mouse models (PRL2 KO, arthritis), co-immunoprecipitation, CMA/eMI assay, hydroxychloroquine rescue Cell death and differentiation Medium 36182990
2023 HSPA8 acts as an 'amyloidase' that disassembles RHIM-domain functional amyloids to inhibit necroptosis; the SBD domain of HSPA8 binds RHIM-containing proteins (RIP1, ZBP1, TRIF, RIP3) through a hydrophobic hexapeptide N(X1)φ(X3) motif, preventing amyloid fiber formation; the NBD domain supplies ATP hydrolysis energy to break pre-formed RHIM-amyloids into non-functional monomers, independently of co-chaperones. In vitro amyloid formation/disassembly assay, domain mutagenesis, cell-based necroptosis assay, mouse necroptosis model Cell research High 37580406
2023 HSPA8 directly interacts with the KIFSN motif on caveolin-1 (CAV1) and promotes CMA-dependent degradation of CAV1; this interaction is enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation; CAV1 degradation releases β-catenin to the nucleus, activating Wnt/β-catenin signaling and driving BRAF V600E colorectal cancer progression. Co-immunoprecipitation, CMA assay, p38 MAPK inhibition, β-catenin nuclear translocation assay, in vivo CRC mouse model, VER155008 inhibitor Advanced science Medium 37973552
2023 PRMT9 methylates HSPA8 at arginine residues R76 and R100; this arginine methylation stabilizes HSPA8 and suppresses ferroptosis in HBV-associated HCC by upregulating CD44 expression; HBx promotes PRMT9 expression to create an HBx/PRMT9/HSPA8/CD44 anti-ferroptosis axis. Co-immunoprecipitation, site-directed mutagenesis, in vitro methylation, transcriptome profiling, in vivo tumor model Journal of translational medicine Medium 37715221
2023 HSPA8 enhances HBV replication by recruiting hepatitis B core protein (HBc) to the cccDNA minichromosome; HSPA8 also suppresses ferroptosis by upregulating SLC7A11/GPX4 and decreasing ROS and Fe2+ accumulation; HBx coactivates HSF1 to upregulate HSPA8, forming a positive feedback loop for viral replication. ChIP assay (HSPA8 on cccDNA), co-immunoprecipitation, siRNA knockdown, ROS/Fe2+ measurement, in vivo xenograft Cancer research Medium 36745032
2023 HSC70 (TGEV M protein SBD interaction): HSC70 binds the coronavirus TGEV membrane protein via its substrate-binding domain; this interaction localizes HSC70 and M protein to the cell surface early in infection and mediates viral internalization through clathrin-mediated endocytosis; HSC70 ATPase activity is required for efficient CME. Co-immunoprecipitation, co-localization, anti-M antibody blocking of HSC70 interaction, dynasore/CME inhibitor experiments, ATPase inhibitor Journal of virology Medium 36975782
2024 Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway by binding PD-L1 and blocking the CMTM6–PD-L1 interaction that normally promotes PD-L1 recycling; either Hsc70 overexpression or AUY-922-induced Hsc70 upregulation reduces PD-L1 surface levels, inhibits tumor growth, and enhances anti-tumor immunity in vivo. Co-immunoprecipitation (Hsc70–PD-L1; competitive displacement of CMTM6), flow cytometry for PD-L1 levels, in vivo tumor mouse model, Hsc70 overexpression and pharmacologic induction Nature communications High 38762492
2023 HSPA8 uses its NBD and LID domains to bind RHOB (residues 1–42 and 89–118) and BECN1's ECD domain; HSPA8 drives liquid-liquid phase separation (LLPS) via intrinsically disordered regions to form droplets that concentrate RHOB and BECN1, enhancing their interaction and protein stability, and thereby promoting anti-bacterial autophagy. Co-immunoprecipitation, domain mapping, LLPS assay (droplet formation), intracellular bacteria clearance assay, BECN1/RHOB degradation assay Autophagy Medium 37312409
2015 CHIP ubiquitinates Hsc70 itself at multiple lysine residues (16 of 45 detectable), with K159 ubiquitinated in Hsc70 but not Hsp70; multiple Ub chain types are formed with different E2 enzymes; Ube2W preferentially modifies the N-terminal amine of Hsc70; these differences explain why CHIP promotes Hsp70 degradation more efficiently than Hsc70. In vitro ubiquitination assay, mass spectrometry-based proteomics, K-R ubiquitin mutants, E2 enzyme comparison PloS one High 26010904

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Systematic and quantitative assessment of the ubiquitin-modified proteome. Molecular cell 1334 21906983
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
1989 A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science (New York, N.Y.) 794 2799391
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
1999 Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Molecular and cellular biology 766 10330192
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Molecular & cellular proteomics : MCP 749 21890473
2011 Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. Journal of translational medicine 719 21235781
2001 The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature cell biology 708 11146634
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2010 Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 639 20850016
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2003 CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. The Journal of biological chemistry 389 14612456
1995 Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle. Cell 363 7585962
2013 HSPA8/HSC70 chaperone protein: structure, function, and chemical targeting. Autophagy 327 24121476
2008 Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer cell 269 18772114
2000 Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR. American journal of physiology. Cell physiology 221 10666020
2012 Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacology & therapeutics 218 22960394
2008 Structure of the Hsp110:Hsc70 nucleotide exchange machine. Molecular cell 177 18550409
2007 Multiple roles of auxilin and hsc70 in clathrin-mediated endocytosis. Traffic (Copenhagen, Denmark) 175 17488288
2007 Interaction between SGT1 and cytosolic/nuclear HSC70 chaperones regulates Arabidopsis immune responses. The Plant cell 158 18065690
2015 Hsc70-4 Deforms Membranes to Promote Synaptic Protein Turnover by Endosomal Microautophagy. Neuron 136 26590345
2010 BAG3 and Hsc70 interact with actin capping protein CapZ to maintain myofibrillar integrity under mechanical stress. Circulation research 121 20884878
2000 Human DnaJ homologs dj2 and dj3, and bag-1 are positive cochaperones of hsc70. The Journal of biological chemistry 113 10816573
2019 HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates. Cells 112 31394830
2011 Hsc70 protein interaction with soluble and fibrillar alpha-synuclein. The Journal of biological chemistry 102 21832061
2018 A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity. The EMBO journal 93 30591555
2023 HBx-Induced HSPA8 Stimulates HBV Replication and Suppresses Ferroptosis to Support Liver Cancer Progression. Cancer research 88 36745032
1995 In vivo and in vitro association of hsc70 with polyomavirus capsid proteins. Journal of virology 86 7494292
2007 BAG-1 associates with Hsc70.Tau complex and regulates the proteasomal degradation of Tau protein. The Journal of biological chemistry 83 17954934
2017 Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS. Cell reports 82 28978466
2008 Effects of HSPA8, an evolutionarily conserved oviductal protein, on boar and bull spermatozoa. Reproduction (Cambridge, England) 82 18996976
1999 Tissue-specific expression of dominant negative mutant Drosophila HSC70 causes developmental defects and lethality. Molecular biology of the cell 82 10397752
2001 Sodium 4-phenylbutyrate downregulates HSC70 expression by facilitating mRNA degradation. American journal of physiology. Lung cellular and molecular physiology 77 11404244
2018 HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation. The Journal of biological chemistry 75 29298892
2005 Treatment with extracellular HSP70/HSC70 protein can reduce polyglutamine toxicity and aggregation. Journal of neurochemistry 70 15992387
2014 Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation. The Journal of biological chemistry 69 25505179
2020 Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells. PLoS biology 65 32687490
1992 Molecular cloning and characterization of a constitutively expressed heat-shock-cognate hsc71 gene from rainbow trout. European journal of biochemistry 62 1371753
2003 Tissue- and stressor-specific differential expression of two hsc70 genes in carp. Biochemical and biophysical research communications 61 12893250
2000 Characteristics of the interaction between Hsc70 and the transferrin receptor in exosomes released during reticulocyte maturation. The Journal of biological chemistry 61 11133993
2016 Structural and Biological Interaction of hsc-70 Protein with Phosphatidylserine in Endosomal Microautophagy. The Journal of biological chemistry 59 27405763
2018 Maslinic acid induces autophagy by down-regulating HSPA8 in pancreatic cancer cells. Phytotherapy research : PTR 58 29516568
2016 Identification of HSPA8 as a candidate biomarker for endometrial carcinoma by using iTRAQ-based proteomic analysis. OncoTargets and therapy 56 27110132
2016 CaM/BAG5/Hsc70 signaling complex dynamically regulates leaf senescence. Scientific reports 52 27539741
2007 Participation of the chaperone Hsc70 in the trafficking and functional expression of ASIC2 in glioma cells. The Journal of biological chemistry 51 17878160
1989 Heat-shock cognate protein (hsc71) and related proteins in mouse spermatogenic cells. Biology of reproduction 50 2665832
2009 Mitochondrial carrier protein biogenesis: role of the chaperones Hsc70 and Hsp90. The Biochemical journal 48 19143589
2018 Expression of HSP90AA1/HSPA8 in hepatocellular carcinoma patients with depression. OncoTargets and therapy 46 29872313
2004 Hsp105alpha suppresses Hsc70 chaperone activity by inhibiting Hsc70 ATPase activity. The Journal of biological chemistry 45 15292236
2005 Primate chaperones Hsc70 (constitutive) and Hsp70 (induced) differ functionally in supporting growth and prion propagation in Saccharomyces cerevisiae. Genetics 44 16299395
2020 Mechanism and Complex Roles of HSC70 in Viral Infections. Frontiers in microbiology 41 32849328
2011 Role of Hsc70 binding cycle in CFTR folding and endoplasmic reticulum-associated degradation. Molecular biology of the cell 41 21697503
2000 Heat-induced alterations in the localization of HSP72 and HSP73 as measured by indirect immunohistochemistry and immunogold electron microscopy. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 39 10681386
2024 Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation. Nature communications 38 38762492
2021 High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia. BMC cancer 38 33926391
2016 Rotenone down-regulates HSPA8/hsc70 chaperone protein in vitro: A new possible toxic mechanism contributing to Parkinson's disease. Neurotoxicology 36 27133439
2018 The disorderly conduct of Hsc70 and its interaction with the Alzheimer's-related Tau protein. The Journal of biological chemistry 35 29764935
2014 Hsc70 contributes to cancer cell survival by preventing Rab1A degradation under stress conditions. PloS one 35 24801886
2023 Arginine methylation of HSPA8 by PRMT9 inhibits ferroptosis to accelerate hepatitis B virus-associated hepatocellular carcinoma progression. Journal of translational medicine 34 37715221
2017 Hsc70 regulates the IRES activity and serves as an antiviral target of enterovirus A71 infection. Antiviral research 34 29180285
1998 Effects of long-term changes in medullary osmolality on heat shock proteins HSp25, HSP60, HSP72 and HSP73 in the rat kidney. Pflugers Archiv : European journal of physiology 34 9479024
2023 HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 33 37973552
2019 Physicochemical changes in liver and Hsc70 expression in pikeperch Sander lucioperca under heat stress. Ecotoxicology and environmental safety 33 31176247
2015 A central role for HSC70 in regulating antigen trafficking and MHC class II presentation. Molecular immunology 33 25953005
2019 miR-26b-5p helps in EpCAM+cancer stem cells maintenance via HSC71/HSPA8 and augments malignant features in HCC. Liver international : official journal of the International Association for the Study of the Liver 32 31276277
2008 BCR-ABL1-induced expression of HSPA8 promotes cell survival in chronic myeloid leukaemia. British journal of haematology 32 18537972
2018 Nitric oxide contributes to protein homeostasis by S-nitrosylations of the chaperone HSPA8 and the ubiquitin ligase UBE2D. Redox biology 30 30368041
2016 EF1A1/HSC70 Cooperatively Suppress Brain Endothelial Cell Apoptosis via Regulating JNK Activity. CNS neuroscience & therapeutics 30 27324700
2023 HSPA8 acts as an amyloidase to suppress necroptosis by inhibiting and reversing functional amyloid formation. Cell research 29 37580406
2017 Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes. Human molecular genetics 29 29016855
2015 Biochemical and Proteomic Analysis of Ubiquitination of Hsc70 and Hsp70 by the E3 Ligase CHIP. PloS one 29 26010904
2018 HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C. JCI insight 28 29875314
2018 Blocking nuclear export of HSPA8 after heat shock stress severely alters cell survival. Scientific reports 28 30429537
1997 Stress protein (hsp73)-mediated, TAP-independent processing of endogenous, truncated SV40 large T antigen for Db-restricted peptide presentation. European journal of immunology 28 9295040
2023 HSPA8 regulates anti-bacterial autophagy through liquid-liquid phase separation. Autophagy 27 37312409
2022 Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy. Liver international : official journal of the International Association for the Study of the Liver 27 36254713
2019 Overexpression of Hsc70 promotes proliferation, migration, and invasion of human glioma cells. Journal of cellular biochemistry 27 30816582
2018 Neuronal Preconditioning Requires the Mitophagic Activity of C-terminus of HSC70-Interacting Protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 29934347
2016 The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization. The Journal of biological chemistry 27 27365397
2004 73-kDa molecular chaperone HSP73 is a direct target of antibiotic gentamicin. The Journal of biological chemistry 26 14966137
2019 Methyltransferase-like 21c methylates and stabilizes the heat shock protein Hspa8 in type I myofibers in mice. The Journal of biological chemistry 25 31346037
2010 Genetic variations in HSPA8 gene associated with coronary heart disease risk in a Chinese population. PloS one 25 20300519
2004 Expression of HSP70/HSC70 in swine blastocysts: effects of oxidative and thermal stress. Molecular reproduction and development 24 15349842
2019 HSC70 regulates cold-induced caspase-1 hyperactivation by an autoinflammation-causing mutant of cytoplasmic immune receptor NLRC4. Proceedings of the National Academy of Sciences of the United States of America 23 31597739
2018 Regulation of Human Hsc70 ATPase and Chaperone Activities by Apg2: Role of the Acidic Subdomain. Journal of molecular biology 23 30521813
2010 Multiple molecules of Hsc70 and a dimer of DjA1 independently bind to an unfolded protein. The Journal of biological chemistry 23 20363747
2019 HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation. Amyotrophic lateral sclerosis & frontotemporal degeneration 22 31663379
2016 The stress protein heat shock cognate 70 (Hsc70) inhibits the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel. Molecular pain 22 27558883
2015 The clathrin-binding and J-domains of GAK support the uncoating and chaperoning of clathrin by Hsc70 in the brain. Journal of cell science 22 26345367
2023 Macrophage-Specific NLRC5 Protects From Cardiac Remodeling Through Interaction With HSPA8. JACC. Basic to translational science 21 37325412
2019 GKN2 promotes oxidative stress-induced gastric cancer cell apoptosis via the Hsc70 pathway. Journal of experimental & clinical cancer research : CR 21 31382983
2012 Rotavirus receptor proteins Hsc70 and integrin αvβ3 are located in the lipid microdomains of animal intestinal cells. Acta virologica 20 22404611
2007 EWI-2/CD316 is an inducible receptor of HSPA8 on human dendritic cells. Molecular and cellular biology 20 17785435
1993 An immunoassay for heat shock protein 73/72: use of the assay to correlate HSP73/72 levels in mammalian cells with heat response. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 20 8366304
2020 Chaperones Hsc70 and Hsp70 Bind to the Protein PGK Differently inside Living Cells. The journal of physical chemistry. B 19 32275442
2015 Interaction of Cx43 with Hsc70 regulates G1/S transition through CDK inhibitor p27. Scientific reports 19 26481195
2014 The critical roles of HSC70 in physiological and pathological processes. Current pharmaceutical design 19 23944377
2000 Pharmacological hepatic preconditioning: involvement of 70-kDa heat shock proteins (HSP72 and HSP73) in ischaemic tolerance after intravenous administration of doxorubicin. The British journal of surgery 19 10971423
2022 HSC70 mediated autophagic degradation of oxidized PRL2 is responsible for osteoclastogenesis and inflammatory bone destruction. Cell death and differentiation 18 36182990
2012 Matrine modulates HSC70 levels and rescues ΔF508-CFTR. Journal of cellular physiology 18 22170045
2024 The novel lnc-HZ12 suppresses autophagy degradation of BBC3 by preventing its interactions with HSPA8 to induce trophoblast cell apoptosis. Autophagy 17 38836496
2021 Deacetylation of HSC70-4 Promotes Bombyx mori Nucleopolyhedrovirus Proliferation via Proteasome-Mediated Nuclear Import. Frontiers in physiology 17 33679433
2021 The two-domain architecture of LAMP2A regulates its interaction with Hsc70. Experimental cell research 17 34942188
2016 Ubiquitin-like protein MNSFβ noncovalently binds to molecular chaperone HSPA8 and regulates osteoclastogenesis. Molecular and cellular biochemistry 17 27581120
2009 Transgenic expression of Hsc70 in pancreatic islets enhances autoimmune diabetes in response to beta cell damage. Journal of immunology (Baltimore, Md. : 1950) 17 19812207
2023 The TGEV Membrane Protein Interacts with HSC70 To Direct Virus Internalization through Clathrin-Mediated Endocytosis. Journal of virology 16 36975782
2016 A novel heat shock protein alpha 8 (Hspa8) molecular network mediating responses to stress- and ethanol-related behaviors. Neurogenetics 16 26780340
2014 Regulation of FSP27 protein stability by AMPK and HSC70. American journal of physiology. Endocrinology and metabolism 16 25315694
2017 Rabies viruses leader RNA interacts with host Hsc70 and inhibits virus replication. Oncotarget 15 28388579
2015 iTRAQ-Based Quantitative Proteomic Analysis Identified HSC71 as a Novel Serum Biomarker for Renal Cell Carcinoma. BioMed research international 15 26425554
2013 Heat shock cognate 71 (HSC71) regulates cellular antiviral response by impairing formation of VISA aggregates. Protein & cell 15 23636689