Abstract
Efficient elimination of misfolded proteins by the proteasome system is critical for proteostasis. Inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, a hallmark of neurodegenerative disease. The proteasome system cannot degrade aggregated proteins; however, it stimulates autophagy-dependent aggregate clearance by producing unanchored lysine (K)63-linked ubiquitin chains via the proteasomal deubiquitinating enzyme Poh1. The canonical function of Poh1, which removes ubiquitin chains en bloc from proteasomal substrates prior to their degradation, requires intact 26S proteasomes. Here we present evidence that during aggresome clearance, 20S proteasomes dissociate from protein aggregates, while Poh1 and selective subunits of 19S proteasomes are retained. The dissociation of 20S proteasome components requires the molecular chaperone Hsp90. Hsp90 inhibition suppresses 26S proteasome remodeling, unanchored ubiquitin chain production, and aggresome clearance. Our results suggest that 26S proteasomes undergo active remodeling to generate a Poh1-dependent K63-deubiquitinating enzyme to facilitate protein aggregate clearance.
Highlights
Proteasomes facilitate HDAC6-dependent aggresome clearance by producing unanchored ubiquitin chains via previously reported that subunits of both 19S (Poh1) deubiquitinating enzyme
20S Proteasomes and ATPase Subunits Dissociate from the Aggresome during Its Clearance—We have previously reported that subunits of both 19S (Poh1) and 20S (PSMA2) proteasomes are concentrated at aggresomes induced by a proteasome inhibitor, MG132 [13]
As the overall abundance of proteasome subunits is not affected by MG132 washout, these results indicate that 20S proteasomes dissociate from protein aggregates during aggresome clearance while Poh1, a component of the 19S proteasome, remains concentrated
Summary
Proteasomes facilitate HDAC6-dependent aggresome clearance by producing unanchored ubiquitin chains via Poh deubiquitinating enzyme. The proteasome system cannot degrade aggregated proteins; it stimulates autophagy-dependent aggregate clearance by producing unanchored lysine (K)63-linked ubiquitin chains via the proteasomal deubiquitinating enzyme Poh. In Poh1deficient cells, aggresome clearance can be effectively restored by exogenous free K63-linked, but not K48-linked, ubiquitin chains [13] These findings indicate that Poh produces ubiquitin chains of different linkages in 26S proteasome- and autophagy-mediated degradation. Inhibition of Hsp suppresses K63-linked ubiquitin chain production, HDAC6 activation and subsequent aggresome clearance These findings suggest that Hsp90-dependent proteasome remodeling liberates Poh from the canonical 26S proteasomes to function as a K63-deubiqinaiting enzyme, thereby activating HDAC6- and autophagy-dependent aggresome clearance
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