Biology subjects

Korsten, G.

Publications and source records attributed to Korsten, G..

3 recordsLinked to original sources

bioRxiv2026

Rapid removal of nuclear aggregates via proteasome- and VCP-dependent disaggregation

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.

cell biology↗

bioRxiv2022

Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair

Huntingtons disease (HD) is caused by a poly-glutamine expansion of the huntingtin protein, resulting in the formation of poly-glutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here we show that nuclear polyglutamine aggregates deform the nuclear envelope (NE) and induce NE ruptures that are often repaired incompletely. These ruptures coincide with deformations of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntingtons disease and other polyglutamine diseases. One-sentence summaryAggregates associated with Huntingtons Disease induce ruptures of the nuclear envelop that compromise its barrier function

cell biology↗

bioRxiv2021

Direct observation of aggregate-triggered selective autophagy

Degradation of aggregates by selective autophagy is important as damaged proteins may impose a threat to cellular homeostasis. Although the core components of the autophagy machinery are well-characterized, the spatiotemporal regulation of many selective autophagy processes, including aggrephagy, remains largely unexplored. Furthermore, because most live-cell imaging studies have so far focused on starvation-induced autophagy, little is known about the dynamics of aggrephagy. Here, we describe the development and application of the mKeima-PIM assay, which enables live-cell observation of autophagic turnover and degradation of inducible protein aggregates in conjunction with key autophagy players. This allowed us to quantify the relative timing and duration of different steps of aggrephagy and revealed the short-lived nature of the autophagosome. The assay furthermore showed the spatial distribution of omegasome formation, highlighting that autophagy initiation is directly instructed by the cargo. Moreover, we found that nascent autophagosomes mostly remain immobile until acidification occurs. Thus, our assay provides new insights into the spatiotemporal regulation and dynamics of aggrephagy.

cell biology↗