<b>Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation</b>

Hill, Shannon E.; Belin, David; Lemus, Andrea; Webster, John H.; Ospina, Santiago Rodriguez; Darling, April L.; Martin, Mackenzie D.; Patel, Shreya; Bridenstine, Liznair; Swonger, Ronald; Paul, Steven M.; Blackburn, Roy J.; Calcul, Laurent; Dickey, Chad A.; Leahy, James W.; Blair, Laura J.

doi:10.1021/acschembio.2c00919

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…93,94 Small-molecule inhibitors of Hsp70, which would presumably reduce disaggregase activity, can prevent pathological tau accumulation. [95][96][97][98][99] Moreover, the Hsp70-disaggregase system can promote protein aggregation and toxicity in C. elegans. 100 Knockdown of C. elegans Hsp110 reduced luciferase disaggregation but also reduced αSyn and polyQ aggregation and toxicity.…”

Section: Discussionmentioning

confidence: 99%

Defining a small-molecule stimulator of the human Hsp70-disaggregase system with selectivity for DnaJB proteins

Chuang,

Cupo,

Bevan

et al. 2024

Preprint

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Hsp70, Hsp40, and Hsp110 form a human protein-disaggregase system that solubilizes and reactivates proteins trapped in aggregated states. However, this system fails to maintain proteostasis in fatal neurodegenerative diseases. Here, we potentiate the human Hsp70-disaggregase system pharmacologically. By scouring a collection of dihydropyrimidines, we disambiguate a small molecule that specifically stimulates the Hsp70-disaggregase system against disordered aggregates and α-synuclein fibrils. The newly identified lead compound stimulates the disaggregase activity of multiple active human Hsp70, Hsp40, Hsp110 chaperone sets, with selectivity for combinations that include DnaJB1 or DnaJB4 as the Hsp40. We find that the relative stoichiometry of Hsp70, Hsp40, and Hsp110 dictates disaggregase activity. Remarkably, our lead compound shifts the composition of active chaperone stoichiometries by preferentially activating combinations with lower DnaJB1 concentrations. Our findings unveil a small molecule that stimulates the Hsp70-disaggregase system, even at suboptimal chaperone stoichiometries, which could be developed for the treatment of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Defining a small-molecule stimulator of the human Hsp70-disaggregase system with selectivity for DnaJB proteins

Chuang,

Cupo,

Bevan

et al. 2024

Preprint

View full text Add to dashboard Cite

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The protein phosphatase-2A subunit PR130 is linked to cytotoxic protein aggregate formation in mesenchymal pancreatic ductal adenocarcinoma cells

Nguyen,

Leydecker,

Mustafa

et al. 2023

Preprint

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Protein phosphatase-2A (PP2A) is a major source of cellular serine/threonine phosphatase activity. PP2A B-type subunits regulate the intracellular localization and the catalytic activity of PP2A-A/PP2A-C complexes towards individual proteins. There is limited knowledge on how PP2A B-type subunits regulate biologically important functions and if these subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with poor prognosis. Mesenchymal PDAC subtypes are more aggressive and metastasis-prone than epithelial subtypes. We show that mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 and its mRNA Ppp2r3a than epithelial PDAC cells (n=38). Among 17 PP2A B-type subunits, this differential regulation is unique for Ppp2r3a and PR130. The higher levels of PR130 in mesenchymal PDAC cells are linked to their vulnerability to the PP2A inhibitor phendione. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in such cells. These processes occur independently of the major tumor suppressor p53, which is frequently mutated in PDAC cells. Proteomic analyses reveal that phendione upregulates the chaperone heat shock protein HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis. We additionally disclose that phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes mesenchymal PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data illustrate pharmacologically amenable, selective dependencies of mesenchymal PDAC cells on PP2A-PR130 and HSP70. PP2A inhibition triggers a harmful accumulation of protein aggregates in neurons. This undesired mechanism might be exploited to kill mesenchymal tumor cells.

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The protein phosphatase-2A subunit PR130 is involved in the formation of cytotoxic protein aggregates in pancreatic ductal adenocarcinoma cells

Nguyen,

Mustafa,

Leydecker

et al. 2024

Cell Commun Signal

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As a major source of cellular serine and threonine phosphatase activity, protein phosphatase-2A (PP2A) modulates signaling pathways in health and disease. PP2A complexes consist of catalytic, scaffolding, and B-type subunits. Seventeen PP2A B-type subunits direct PP2A complexes to selected substrates. It is ill-defined how PP2A B-type subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis. We analyzed the responses of murine and human mesenchymal and epithelial PDAC cells to the specific PP2A inhibitor phendione. We assessed protein levels by immunoblot and proteomics and cell fate by flow cytometry, confocal microscopy, and genetic manipulation. We show that murine mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 than epithelial PDAC cells. This overexpression of PR130 is associated with a dependency of such metastasis-prone cells on the catalytic activity of PP2A. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in murine mesenchymal and human PDAC cells. These processes occur independently of the frequently mutated tumor suppressor p53. Proteomic analyses reveal that phendione upregulates the chaperone HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis and phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes murine and human PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data suggest that the PP2A-PR130 complex dephosphorylates and thereby prevents the aggregation of proteins in tumor cells. Graphical Abstract

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Benzothiazole Substitution Analogs of Rhodacyanine Hsp70 Inhibitors Modulate Tau Accumulation

Cited by 3 publications

References 54 publications

Defining a small-molecule stimulator of the human Hsp70-disaggregase system with selectivity for DnaJB proteins

Defining a small-molecule stimulator of the human Hsp70-disaggregase system with selectivity for DnaJB proteins

The protein phosphatase-2A subunit PR130 is linked to cytotoxic protein aggregate formation in mesenchymal pancreatic ductal adenocarcinoma cells

The protein phosphatase-2A subunit PR130 is involved in the formation of cytotoxic protein aggregates in pancreatic ductal adenocarcinoma cells

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