Cellular proteostasis is essential for cellular proteome integrity, which is exquisitely sensitive to the redox environment. Heat shock proteins (HSPs) are the central chaperones that sense and adapt to these redox fluctuations. Emerging evidence demonstrates dysregulation of cellular HSPs-modulated redox-proteostasis in protein aggregation diseases, including cancers, senescence, neurodegenerative diseases, limb-girdle muscular dystrophy type D1, and β-thalassemia, making HSPs promising therapeutic targets in disease treatment.
Recent Advances:
Redox post-translational modifications (PTMs) serve as master switchboards to dynamically modulate the structure and chaperone function of HSPs. Redox PTMs allow HSPs to participate in protein synthesis and folding, conformational maintenance, and degradation, thereby maintaining cellular proteostasis. Beyond their chaperone functions, HSPs also play critical roles in organelle-specific stress responses, such as mitochondrial unfolded protein response, endoplasmic reticulum (ER) stress, and unfolded protein response.
Critical Issues:
Despite the well-known contributions of HSPs to redox-proteostasis, the double-edged functions of HSPs in protein aggregation diseases remain unclear. The main issues covered in this review include the regulation of HSPs by redox PTMs, the important role of HSPs in proteostasis and organelle-specific stress responses, dual modulation of HSPs in protein aggregation diseases, and pharmacological agents targeting HSPs.
Further Directions:
The functional diversity of HSPs in redox-proteostasis makes them promising therapeutic targets in disease treatment. Further studies should focus on exploiting agents that precisely target cysteine residues modifications on HSPs with good blood–brain barrier (BBB) penetration and low toxicity. Antioxid. Redox Signal. 45, 78–112.
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