Laboratories

Research

Main Scientific Achievements

• We identified a factor of translation machinery that is important to withstand oxidative stress conditions in the yeast Saccharomyces cerevisiae.
• We uncovered non-canonical functions of the co-chaperone prefoldin in mitochondrial biogenesis and proteasome assembly.
• We identified ribosomal proteins that can act as sensors of cellular stress and are involved in the adaptation of cytosolic protein synthesis to restore protein homeostasis.
• We identified cellular proteins including ribosomal proteins that undergo redox changes early during yeast chronological changes.

Research Description

Protein homeostasis (proteostasis) is critical for maintaining cellular function and organismal health. Proteostasis is achieved through the coordinated balance of protein synthesis, folding, and degradation, governed by a network of surveillance mechanisms (Topf et al. 2016). While these processes are tightly regulated under normal conditions, they often fail during aging, leading to a decline in cellular function and health. Our research focuses on understanding the limitations within the proteostasis network that contribute to its collapse during aging. By deciphering the intricate crosstalk between these systems, we aim to develop interventions that mitigate age-related health deficits and improve organismal lifespan and healthspan.

Our work spans two key areas: adaptations of the protein synthesis machinery and protein folding mechanisms under stress and aging. Protein synthesis (translation) declines with age, yet interventions that reduce translation early in life can extend lifespan in model organisms. We investigate how translation is regulated, with a particular focus on reactive oxygen species (ROS) as signaling molecules. ROS levels increase during aging, and low ROS levels activate thiol-based redox switches, which might impact protein synthesis. Using S. cerevisiae and C. elegans, we study the redox state of translation machinery components under various stress conditions and during aging (Topf et al., 2018; Jonak et al., 2024). Employing genetic and biochemical approaches, as well as CRISPR/Cas9 technology, we examine how modulating translation affects lifespan and health.

In parallel, we study the role of protein folding machinery, including the chaperonin complex and its co-chaperone prefoldin, in maintaining proteostasis (Tahmaz et al., 2022). These conserved chaperones are essential for assisting nascent protein folding and preventing aggregation. Despite their constitutive expression, emerging evidence suggests they play critical roles during cellular stress. For example, prefoldin moderates protein aggregation linked to neurodegenerative diseases and is upregulated in cancer. We aim to uncover non-canonical functions of prefoldin by identifying its substrate landscape and revealing its role in stress and aging.

By exploring these interconnected systems, our research provides new insights into how to maintain proteostasis to enhance cellular resilience and organismal longevity.

Our studies of cellular mechanisms are complemented by studies of selected pharmacological molecules and micronutrients. We are exploring drug repurposing in the C. elegans model organism as a strategy to use drugs that are approved and safe in humans to study their health benefits in aged worms. We aim to elucidate the molecular mechanisms underlying the health benefits, with a particular focus on the maintenance of protein homeostasis.

• Bibliography

1. Topf et al. Nature Communications 9(1):324. 2018
2. Topf et al. Trends Cell Biol., 26(8):577-86. 2016
3. Jonak et al. Life Science Alliance, 10.26508/lsa.202302300
4. Tahmaz et al. Front Cell Dev Biol., 17;9:816214

Methodology

Our studies use the eukaryotic model organisms yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. We combine proteome-wide approaches to address open-ended questions with protein biochemistry and molecular biology. We also exploit the genetic tractability of our model organisms to delete, deplete, or alter the function of genes. We assess their importance in stress assays and over the lifespan of the organism. Our laboratory is fully equipped to culture, observe, and manipulate C. elegans.

Selected Publications

• Identification of a non-canonical function of prefoldin subunit 5 in proteasome assembly. Shahmoradi Ghahe S., Drabikowski K., Stasiak M., Topf U. Journal of Molecular Biology. 2024. 10.1016/j.jmb.2024.168838.
• Prefoldin 2 contributes to mitochondrial morphology and biogenesis. Tahmaz I., Shahmoradi Ghahe S., Stasiak M., Liput K., Jonak K., Topf U. BMC Biology. 2023. 10.1186/s12915-023-01695-y.
• Analysis of ageing-dependent thiol oxidation reveals early oxidation of proteins involved in core proteostasis functions. Jonak K., Suppanz I., Julian B., Chacinska A., Warscheid B., Topf U. Life Science Alliance. 2024. 10.26508/lsa.202302300.
• The evolving role of ribosomes in the regulation of protein synthesis. Goscinska K. and Topf U. Acta Biochimica Polonica. 2020. org/10.18388/abp.2017

Collaborations

• Marek Tchorzewski, Department of Molecular Biology, Uniwersytet Marii Curie-Skłodowskiej, Lublin, Poland.
• Agnieszka Chacinska, Laboratory of Mitochondrial Biology, CeNT/ University of Warsaw, Poland.

Prizes and Awards

• Katarzyna Jonak. EMBO Postdoctoral Fellowship. 2022-2024.
• Ulrike Topf. Habilitation Fellowship of L’Oréal Poland for Women in Science. 2019. L’Oréal Polska, Poland.