ArticleThe Journal of biological chemistry2015
Isoform-selective Genetic Inhibition of Constitutive Cytosolic Hsp70 Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- Hsp70 is phosphorylated in a conserved response to DNA damage and contributes to cell cycle control.eLife · 2026Article
- A conserved Hsp70 phosphorylation regulates cell cycle progression after DNA damage.bioRxiv : the preprint server for biology · 2025Article
- Integrative network analysis reveals novel moderators of Aβ-Tau interaction in Alzheimer's disease.Alzheimer's research & therapy · 2025Article
- Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP.Nature communications · 2024Article
- Article
- Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma.Cell chemical biology · 2022Article
- Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies.International journal of molecular sciences · 2021Review
- Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology.The Journal of clinical investigation · 2021Article
- HSP70 regulates Eg5 distribution within the mitotic spindle and modulates the cytotoxicity of Eg5 inhibitors.Cell death & disease · 2020Article
- Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones.The Journal of biological chemistry · 2020Article
- A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation.The Journal of biological chemistry · 2019Article
- BIN1 favors the spreading of Tau via extracellular vesicles.Scientific reports · 2019Article
- Spermidine/spermine-NAlzheimer's research & therapy · 2019Article
- HSP70 is required for the proper assembly of pericentriolar material and function of mitotic centrosomes.Cell division · 2019Article
- Tau Protein Squired by Molecular Chaperones During Alzheimer's Disease.Journal of molecular neuroscience : MN · 2018Review
- Exploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70).Journal of medicinal chemistry · 2018Article
- Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.Nature structural & molecular biology · 2018Article
- Structure-activity relationships of cryptopleurine analogs with E-ring modifications as anti-hepatitis C virus agents.Bioorganic & medicinal chemistry · 2018Article
- Therapeutic Strategies for Restoring Tau Homeostasis.Cold Spring Harbor perspectives in medicine · 2018Review
- A Mechanistic Overview of Triptolide and Celastrol, Natural Products fromFrontiers in pharmacology · 2018Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
The constitutively expressed heat shock protein 70 kDa (Hsc70) is a major chaperone protein responsible for maintaining proteostasis, yet how its structure translates into functional decisions regarding client fate is still unclear. We previously showed that Hsc70 preserved aberrant Tau, but it remained unknown if selective inhibition of the activity of this Hsp70 isoform could facilitate Tau clearance. Using single point mutations in the nucleotide binding domain, we assessed the effect of several mutations on the functions of human Hsc70. Biochemical characterization revealed that one mutation abolished both Hsc70 ATPase and refolding activities. This variant resembled the ADP-bound conformer at all times yet remained able to interact with cofactors, nucleotides, and substrates appropriately, resembling a dominant negative Hsc70 (DN-Hsc70). We then assessed the effects of this DN-Hsc70 on its client Tau. DN-Hsc70 potently facilitated Tau clearance via the proteasome in cells and brain tissue, in contrast to wild type Hsc70 that stabilized Tau. Thus, DN-Hsc70 mimics the action of small molecule pan Hsp70 inhibitors with regard to Tau metabolism. This shift in Hsc70 function by a single point mutation was the result of a change in the chaperome associated with Hsc70 such that DN-Hsc70 associated more with Hsp90 and DnaJ proteins, whereas wild type Hsc70 was more associated with other Hsp70 isoforms. Thus, isoform-selective targeting of Hsc70 could be a viable therapeutic strategy for tauopathies and possibly lead to new insights in chaperone complex biology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.