Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Biology

Background:

• Cellular proteostasis relies on refolding and degradation to manage misfolded proteins.
• Organized sequestration of misfolded proteins by sequestrases is an emerging quality control strategy.
• Understanding sequestration's role is crucial for comprehending the overall proteostasis network.

Purpose of the Study:

• To elucidate the role of protein sequestration in the proteostasis network of Saccharomyces cerevisiae.
• To investigate the underlying mechanisms of protein sequestration.
• To determine the interplay between sequestrases and the Hsp70 refolding system.

Main Methods:

• Investigated the function of Hsp42 and Btn2 sequestrases in Saccharomyces cerevisiae.
• Examined the interaction between sequestrases and the Hsp70 chaperone system.
• Assessed the impact of sequestration on proteostasis collapse and cell viability under stress conditions.

Main Results:

• Hsp42 and Btn2 sequestrases are functionally linked to the Hsp70 refolding machinery.
• Sequestration by Hsp42 and Btn2 prevents proteostasis collapse and loss of viability when Hsp70 capacity is limited.
• Btn2 exhibits both chaperone and sequestrase activity, resembling small heat shock proteins, and facilitates the recruitment of the Hsp70-Hsp104 disaggregase via Sis1 interaction during stress recovery.

Conclusions:

• Sequestration is a vital third strategy for maintaining cellular proteostasis, complementing refolding and degradation.
• Hsp42 and Btn2 protect the Hsp70 system from overload, ensuring cell survival under stress.
• Btn2 plays a key role in directing sequestered proteins back to the refolding pathway during stress recovery.