Heat shock cognate 71 kDa protein within epichaperome complexes (HSC70-epichaperome)

HSC70 (Heat shock cognate 71 kDa protein, encoded by HSPA8) is a constitutively expressed molecular chaperone that typically functions in protein folding and clathrin-mediated endocytosis. However, under conditions of chronic cellular stress, such as malignancy or neurodegeneration, HSC70 can be rewired into stable, high-molecular-weight protein-protein interaction networks known as epichaperomes (Rodina et al., 2016; Inda et al., 2020). Within these complexes, HSC70 and HSP90 act as nucleating sites for a scaffolding platform that remodels the cellular interactome to favor survival and disease progression (Pillarsetty et al., 2019). Unlike the transient and dynamic nature of canonical chaperones, epichaperomes are long-lived and disease-specific, making them attractive therapeutic targets for precision medicine (Bolaender et al., 2021). Drugs like PU-H71 and Zelavespib (PU-AD) selectively target the epichaperome by binding to the ATP-binding sites of its constituents, leading to the disassembly of the complex (Jhaveri et al., 2020). This dismantling restores normal proteostasis and triggers the degradation of oncogenic or toxic proteins, such as tau in Alzheimer's or various kinases in cancer (Inda et al., 2020). The presence of epichaperomes can be visualized and quantified using theranostic tools like PU-PET imaging, allowing for patient selection based on target abundance (Pillarsetty et al., 2019). While targeting epichaperomes offers high selectivity for diseased cells, potential challenges include the risk of affecting normal chaperone functions and the emergence of resistance through compensatory network remodeling (Bolaender et al., 2021).

Other names

HSPA8Heat shock cognate 70HSC70Epichaperome-associated HSC70Epichaperome constituentChaperome-rewired HSC70

Dismantling of the pathological epichaperome complex to restore normal protein-protein interaction networks and induce degradation of disease-associated proteins.