Our recent study identifies a previously unrecognized requirement for protein aggregate fragmentation as a prerequisite for autophagic clearance of amorphous aggregates, a process that has been termed aggrephagy. We show that aggregate fragmentation depends on two distinct but cooperative components: the DNAJB6 (DnaJ heat shock protein family (Hsp40) member B6)-HSPA/HSP70 (heat shock protein family A (Hsp70))-HSPH1/HSP110 chaperone module and the 19S regulatory particles (RPs) of the proteasome. These factors act together to not only to fragment protein aggregates but also to compact them, enabling clustering of selective autophagy receptors (SARs) and subsequent local phagophore formation. Our results show that this fragmentase activity plays a role in the aggrephagic clearance of different aggregate species, including disease-related HTT (huntingtin) aggregates.CLPB-caseinolytic peptidase B protein homolog; DNAJB6-DnaJ heat shock protein family (Hsp40) member B6; dualPIM-dual-particles induced by multimerization; ER-endoplasmic reticulum; HSPA/HSP70-heat shock protein family A (Hsp70); HTT-polyQ119-huntingtin with an expanded polyglutamine stretch of 119 units; RP-regulatory particle; SAR-selective autophagy receptor. Abbreviations:
