Cellular aging impedes stress-activation of a crucial JDP-Hsp70 protein disaggregase

The breakdown of protein homeostasis manifests itself in inappropriate protein aggregation, which can lead to cell death resulting in disease and aging. To resolve aggregates, organisms rely on protein disaggregases. How these disaggregases are regulated in mammals is poorly understood. We report the identification of a protein quality control (PQC) pathway dedicated to boosting protein disaggregation activity in human cells recovering from heat stress. This pathway, termed the stress-induced protein disaggregase activation pathway (siDAP), selectively induces a ternary DNAJA1+DNAJB1-Hsp70 protein disaggregase. Hsp70 disaggregase functions sequentially with AAA ATPase VCP to resolve different populations of aggregates in temporally distinct aggregate clearance phases in repairing cells. siDAP targets aggregates containing immobile tightly packed misfolded proteins that are different from stress-induced phase-separating biomolecular condensates. Strikingly, the assembly of this disaggregase is compromised in cells undergoing replicative aging. However, these cells still retain a fully functional heat shock response, making siDAP one of the first PQC pathways to collapse in aging cells. ### Competing Interest Statement The authors have declared no competing interest.