Abstract
ABSTRACTProtein aggregation is intimately associated with cellular stress and is accelerated during aging, disease, and cellular dysfunction. Yeast cells rely on the ATP-consuming chaperone Hsp104 to disaggregate proteins together with Hsp70. Hsp110s are ancient and abundant chaperones that form complexes with Hsp70. Here we provide in vivo data showing that the Saccharomyces cerevisiae Hsp110s Sse1 and Sse2 are essential for Hsp104-dependent protein disaggregation. Following heat shock, complexes of Hsp110 and Hsp70 are recruited to protein aggregates and function together with Hsp104 in the disaggregation process. In the absence of Hsp110, targeting of Hsp70 and Hsp104 to the aggregates is impaired, and the residual Hsp104 that still reaches the aggregates fails to disaggregate. Thus, coordinated activities of both Hsp104 and Hsp110 are required to reactivate aggregated proteins. These findings have important implications for the understanding of how eukaryotic cells manage misfolded and amyloid proteins.
Highlights
Protein aggregation is intimately associated with cellular stress and is accelerated during aging, disease, and cellular dysfunction
We set out to investigate the importance of the yeast Hsp110s Sse1 and Sse2 in the Hsp104-dependent reactivation of aggregated proteins
We tested the influence of Sse1 and Sse2 on the reactivation of aggregated firefly luciferase in the context of complete cytosolic lysates, a setup that likely better mirrors the complexity of the cytosolic chaperone system
Summary
Protein aggregation is intimately associated with cellular stress and is accelerated during aging, disease, and cellular dysfunction. An intricate network of ATP-consuming chaperones with disaggregation and refolding activities disentangles and reactivates aggregated proteins [6]. Hsp40s, Hsp70s, and Hsp110s form dynamic complexes that disentangle and reactivate aggregated proteins in vitro [8,9,10,11,12]. In this process, the substrate and Hsp synergistically stimulate Hsp. Studies have arrived at different conclusions as to whether Hsp110 depends on its ATPase activity to accelerate protein disaggregation in vitro [8, 10, 11].
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