Clearing the protein clutter in human cells: the role of protein disaggregases

Cells rely on multiple protein quality control (PQC) pathways, including molecular chaperone-assisted folding and degradation systems, to maintain proteome integrity and functionality. These pathways work together to reduce the risk of toxic protein aggregation under normal growth conditions and to promote aggregate clearance, restoring protein homeostasis after cellular stress. This integrated action helps protect cells from dysfunction and premature death. In prokaryotes and lower eukaryotes, protein aggregate solubilisation (or disaggregation) is mediated by the joint action of Hsp70 systems and Hsp100 AAA +ATPases. Metazoa lack these Hsp100 AAA +ATPases in their cytosol and nucleus. Yet, they can recover proteins from a (stress-induced) aggregated state. In this review, we highlight the major types of protein aggregates that form in cells and discuss recent advancements in our understanding of various protein disaggregase systems that target these aggregates, with a particular focus on Hsp70-based disaggregases in human cells.