Hsp70 and Hsp90 post-translational modifications and translating the chaperone code.

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Medicine

Background:

• Molecular chaperones, including Heat Shock Protein 70 (Hsp70) and Heat Shock Protein 90 (Hsp90), are crucial for maintaining protein homeostasis (proteostasis).
• Their functions in protein folding, stability, and cellular signaling are regulated by co-chaperones and dynamic post-translational modifications (PTMs).

Purpose of the Study:

• To review the diverse post-translational modifications (PTMs) affecting Hsp70 and Hsp90.
• To explore the concept of the "chaperone code" and its implications in health and disease.
• To highlight the therapeutic potential of targeting PTMs in molecular chaperones.

Main Methods:

• Comprehensive literature review of PTMs on Hsp70 and Hsp90.
• Analysis of how PTMs influence chaperone ATPase activity, localization, and client interactions.
• Discussion of the role of PTMs in cellular pathways and disease pathogenesis.

Main Results:

• Hsp70 and Hsp90 are subject to various PTMs including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation.
• These PTMs collectively form a "chaperone code" that fine-tunes chaperone function, impacting client fate, drug sensitivity, and stress responses.
• Combinatorial PTMs and their crosstalk add regulatory complexity, particularly relevant in cancer, neurodegeneration, and inflammation.

Conclusions:

• The PTM landscape of Hsp70 and Hsp90 significantly impacts cellular processes and disease states.
• Targeting the enzymes involved in writing, erasing, or reading the "chaperone code" offers promising therapeutic strategies.
• Unlocking the chaperone code is essential for directing chaperone activity toward therapeutic benefit in various maladies.