Disaggregation performed mainly by molecular chaperones, likely the fastest process, is generally followed by protein refolding or proteasomal degradation 12, 21, 22, 23. In order to cope with these aggregates, cells have developed different strategies 11, 12, including compartmentalization into aggresomes followed by autophagy 13, 14, 15, secretion to the extracellular environment 16 and disaggregation (or resolubilization) 17, 18, 19, 20. Therefore, we propose that a human sHSP is an integral part of the chaperone network for protein disaggregation. HSPB1 itself was also extracted during disaggregation, and its homo-oligomerization ability was not required. Importantly, co-aggregation promoted the efficient disaggregation and refolding of the substrates, led by HSP70. The co-aggregates formed with HSPB1 were smaller and more regularly shaped than those formed in its absence. HSPB1 co-aggregated with unfolded protein substrates, firefly luciferase and mammalian lactate dehydrogenase. Because it is unknown whether a human sHSP has this activity, we investigated the disaggregation role of human HSPB1. The co-aggregated sHSPs then facilitate downstream disaggregation by HSP70. Yeast and bacterial chaperones of the small heat-shock protein (sHSP) family can bind substrates at early stages of misfolding, during the aggregation process. To eliminate aggregates, the HSP70 chaperone machinery extracts and resolubilizes polypeptides for triage to refolding or degradation. In human cells under stress conditions, misfolded polypeptides can form potentially cytotoxic insoluble aggregates.

The chaperone 41 3d comic