研究セミナー Chaperone-mediated fragmentation of protein aggregates is essential for their autophagic turnover

Protein quality control is crucial to maintain cellular and organismal homeostasis and ultimately guarantee survival. If this tightly regulated system of interconnected　pathways is disturbed, misfolded proteins and protein aggregates accumulate. When not turned over, protein aggregates can be cytotoxic and in specific instances lead to neurodegenerative disorders, cardiomyopathies and diabetes type II. Elimination of protein aggregates has in part been attributed to a selective form of autophagy known as aggrephagy. The current view is that aggrephagy is initiated by the binding of selective autophagy receptors (SARs) to ubiquitylated aggregates, which leads to the subsequent recruitment of the autophagy-related (ATG) machinery and local formation of autophagosomes. However, the precise regulation, upstream events and requirements of aggrephagy remain to be understood. Using two established systems to study aggrephagy, we show that the recruitment to aggregates of the SARs and ATG machinery is not sufficient to direct them into lysosomal degradation. Rather, we found that aggregate fragmentation is a crucial upstream event of aggrephagy, which is a prerequisite for autophagosome formation and aggregate delivering into lysosomes. Fragmentation requires the HSP70-HSP110 module, which together with specific co-chaperones composes various cellular disaggregation machineries that extract single polypeptides from protein aggregates. In aggrephagy, however, the co-chaperone DNAJB6 together with the HSP70-HSP110 module is required for aggregate fragmentation rather than disaggregation. Collectively, our data reveals the existence of a cellular fragmentation machinery composed of HSP70, HSP110 and DNAJB6, which is crucial for autophagic removal of protein aggregates.