Age-related deterioration of protein quality control systems and the manifestation of protein misfolding diseases are directly linked to decreased cellular adaptability towards proteotoxic stress. During stress, protein aggregates are formed when the generation of misfolded proteins exceeds the refolding and degradative capacity of a cell.1,2 Protein aggregation is a reversible process, which is primarily mediated by a novel class of Hsp70 chaperone-based protein disaggregases in human cells.3 The mechanism and regulation of this activity in cells remain poorly understood. Recent work has shown that interclass J-domain protein (JDP) complex formation power the human Hsp70 machinery and accelerate the solubilization of aggregated proteins.4 Mechanistically, these transiently formed higher-order complexes of JDPs can not only efficiently select various aggregate types but also recruit multiple Hsp70 molecules to assemble the disaggregases.4,5 We have carried out extensive protein-protein interaction studies that allowed us for the first time to specifically trace the dynamics of the primary stress-induced protein disaggregase in human cells. We have identified a key regulatory role played by the Heat Shock Response (HRS) that “programs” the activation of this molecular machine during cell repair. We observe that this chaperone machine largely targets a population of aggregated proteins that evade rapid post-stress degradation. Taken together, our findings suggest that protein disaggregation in human cells plays a key role in rescuing a subset of heat-induced aggregated proteins perhaps important for facilitating cellular stress recovery.
References
1 Goldberg, A. L. (2003) Nature 426, 895-9
2 Tyedmers, J. et al. (2010) Nat Rev Mol Cell Biol 11, 777-88
3 Nillegoda, N. B. et al. (2018) Trends Biochem Sci 43, 285-300
4 Nillegoda, N. B. et al. (2015) Nature 524, 247-251
5 Wentink, A. S. et al. (2020) Nature (in press)