The group led by Liesbeth Veenhoff aims to understand the role of the nuclear pore complex in cellular ageing. The nuclear pore complex is the sole gateway to the interior of the nucleus and its function is essential to all eukaryotic life. We use baker’s yeast, Saccharomyces cerevisiae, as a model system, and microscopic, biochemical and proteomics analysis are the main tools used in the lab. Our ongoing research themes include:
Quality control of the nuclear pore complex
A main research line in the group is to understand the role of the nuclear pore complex (NPC) in ageing. The NPC’s function is intimately connected to the primary hallmarks of ageing of proteins homeostasis and genome stability, and several processes underlying these hallmarks are orchestrated at NPCs. The NPC’s function is compromised in ageing and age-related aggregation pathologies, and we aim to uncover the mechanisms responsible for NPC quality control. Specifically, we aim to uncover the mechanisms that detect damaged NPCs (sensors), the destiny of damaged NPCs (fate), and the mechanisms that prevent damage to NPCs (guardians).
Guardians of protein disorder
Proteins with intrinsically disordered domains (IDP) have the capacity to phase separate and form condensates. The nuclear pore complex is a structure that relies on IDPs for its essential function. IDPs are also prone to aggregation, and amyloid formation of IDPs is often associated with pathology, including neurodegenerative diseases. Two groups of proteins appear critical to ensure proper phase state—chaperones, preventing aggregation of disease related IDPs, and nuclear transport receptors, whose classical function is to shuttle cargo through the NPC. The central question that we will answer is how nuclear transport receptors and chaperones impact the phase transitions of IDPs in guarding the proteome against aggregation, ensuring proper NPC function, and avoiding pathogenesis.
Biophysics of Ageing
We aim to contribute to a better understanding of the cellular ageing process in general. Here, our strategy is to ‘simply’ observe how living cells age, and to quantify new molecular and physicochemical (e.g. pH, crowding) aspects of ageing. pH and crowding are particularly interesting as phase separation sensitively depends on these parameters. For this work we rely on life-long imaging of single yeast cells in microfluidic devises and the use of fluorescent biosensors.