Inactive Proteasomes Routed to Autophagic Turnover Are Confined within the Soluble Fraction of the Cell

Previous studies demonstrated that dysfunctional yeast proteasomes accumulate in the insoluble protein deposit (IPOD), described as the final deposition site for amyloidogenic insoluble proteins and that this compartment also mediates proteasome ubiquitination, a prerequisite for their targeted autophagy (proteaphagy). Here, we examined the solubility state of proteasomes subjected to autophagy as a result of their inactivation, or under nutrient starvation. In both cases, only soluble proteasomes could serve as a substrate to autophagy, suggesting a modified model whereby substrates for proteaphagy are dysfunctional proteasomes in their near-native soluble state, and not as previously believed, those sequestered at the IPOD. Furthermore, the insoluble fraction accumulating in the IPOD represents an alternative pathway, enabling the removal of inactive proteasomes that escaped proteaphagy when the system became saturated. Altogether, we suggest that the relocalization of proteasomes to soluble aggregates represents a general stage of proteasome recycling through autophagy.

Automated summary

Previous studies have shown that dysfunctional yeast proteasomes accumulate in the insoluble protein deposit (IPOD) and are prone to proteasome ubiquitination. However, our study reveals that only soluble proteasomes are targeted for autophagy, challenging the previous belief that sequestered proteasomes in IPOD are the substrates for proteaphagy. Moreover, the IPOD serves as an alternative pathway for the removal of inactive proteasomes that are not cleared by proteaphagy. This suggests that the relocalization of proteasomes to soluble aggregates is a crucial step in proteasome recycling through autophagy.