A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy
Mario Mauthe, Nicole van de Beek, Muriel Mari, Giel Korsten, Parisa Nobari, Kennith Brian Castelino, Eduardo Preusser de Mattos, Ibtisam Ouhida, J. Dijkstra, Sabine Schipper-Krom, Laura Rodríguez de la Ballina, Monja R. Mueller, Anne Simonsen, Mark S. Hipp, Lukas C. Kapitein, Harm H. Kampinga, Fulvio Reggiori
Abstract
Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.