Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis

Abstract

Maintenance of cellular proteostasis is achieved by a multi-layered quality control network, which counteracts the accumulation of misfolded proteins by refolding and degradation pathways. The organized sequestration of misfolded proteins, actively promoted by cellular sequestrases, represents a third strategy of quality control. Here we determine the role of sequestration within the proteostasis network in Saccharomyces cerevisiae and the mechanism by which it occurs. The Hsp42 and Btn2 sequestrases are functionally intertwined with the refolding activity of the Hsp70 system. Sequestration of misfolded proteins by Hsp42 and Btn2 prevents proteostasis collapse and viability loss in cells with limited Hsp70 capacity, likely by shielding Hsp70 from misfolded protein overload. Btn2 has chaperone and sequestrase activity and shares features with small heat shock proteins. During stress recovery Btn2 recruits the Hsp70-Hsp104 disaggregase by directly interacting with the Hsp70 co-chaperone Sis1, thereby shunting sequestered proteins to the refolding pathway.

Abstract

The sequestration of misfolded proteins into large assemblies by sequestrases is now considered as the third pillar in protein quality control besides chaperones and proteases. Here the authors characterise the functions of the sequestrases Hsp42 and Btn2 in the proteostasis network of S. cerevisiae and find that they protect cells from too exhaustive depletion of the Hsp70 system.