Korsten, G.; Smith, G. P.; Nijenhuis, W.; Janssen, A.; Kapitein, L. C.

Cells use multiple protein quality control (PQC) mechanisms to counteract the toxic effects of protein aggregation caused by cellular stress, ageing or disease. While it is known that PQC mechanisms differ between cellular compartments, studying such differences has remained challenging. Previously, we developed an assay to study cytosolic PQC using aggregates formed through chemically-induced dimerization (termed PIMs, particles induced by multimerization). Here, we introduce nuclear PIMs as a tool to study nuclear quality control. Using high-resolution and high-throughput imaging, we show that nuclear aggregate removal depends on the proteasome and the unfoldase VCP, but not on Hsp70. Strikingly, following dissolution many PIM subunits were exported to the cytosol via exportin-1-dependent shuttling, indicating that disaggregation and resolubilization dominated over degradation. Proteasomal disaggregation was confirmed using live-cell turnover experiments. Together, these findings reveal a mechanism in which the proteasome and VCP disaggregate, rather than degrade, nuclear protein aggregates, with the resulting subunits subsequently cleared via cytosolic aggrephagy.