At the Laboratory of Protein Metabolism, we study proteostasis –  the coordinated control of protein synthesis, folding, and degradation. Proteostasis is one of the fundamental processes that maintain the proper functioning of cells, tissues, and entire organisms. 

Our research focuses on the ubiquitin–proteasome system, one of the principal mechanisms responsible for protein quality control in the cell. We seek to understand how cells and organisms maintain protein homeostasis under conditions of stress, aging, and disease, and how disruption of these mechanisms leads to pathology. Our research uses the model organism Caenorhabditis elegans, human cell lines, and integrated biochemical, genetic, microscopy-based, omics, and bioinformatics approaches. 

OUR RESEARCH

Our research focuses on the mechanisms through which cells preserve proteome integrity under changing and challenging conditions. We view proteostasis not as a collection of separate pathways, but as a dynamic network of processes that together determine protein quality, abundance, and functionality. 

We are particularly interested in the role of the ubiquitin–proteasome system in protein recognition and degradation, as well as in the mechanisms through which degradation signals, known as degrons, direct specific proteins for removal. 

In 2024–2025, our work contributed to defining proteostasis as a coordinated system connecting organelles, cells, and tissues. We demonstrated that cells not only respond to stress but can also prepare for it by reorganizing structures such as the nucleolus and activating extracellular communication mechanisms. 

Our research also addresses the molecular basis of rare diseases caused by defects in protein quality control. We place particular emphasis on ubiquitin-dependent regulation and the substrate receptors of cullin–RING E3 ligases. 

Key Research Areas 

The Nucleolus as a Stress-Response Hub 

We investigate the nucleolus, a specialized structure within the cell nucleus, as a dynamic regulator of proteostasis. We are interested in how proteotoxic stress induces the reversible remodeling of the nucleolus into a compartment that temporarily prioritizes protein quality control over ribosome biogenesis. This reorganization may help cells restore homeostasis after stress and could provide a potential target for new therapeutic strategies. 

Rare Diseases of Proteostasis 

We investigate the molecular basis of rare diseases caused by defects in protein quality control. We are particularly interested in how impaired substrate recognition by ubiquitin-dependent systems affects tissue proteostasis and leads to disease phenotypes. 

Proteostasis in Adaptive States 

We study how proteostasis is maintained during chronic or recurrent stress. One of our models involves cold-induced adaptive states resembling hibernation, in which growth and biosynthesis are temporarily restricted while cells reorganize their proteome-maintenance pathways. 

The Lipid–Proteasome Axis in Stress and Aging 

Using C. elegans and human cell systems, we investigate how lipid metabolism and inter-tissue signaling modulate proteostasis during chronic stress and aging. We aim to understand how metabolic rewiring supports the long-term stability of the proteome. 

Scientific Impact 

Neuroendocrine Control of Proteostasis 

We discovered a neuroendocrine mechanism that links environmental and social signals with the regulation of proteostasis at the whole-organism level. This mechanism controls the formation of exophers –  large extracellular vesicles involved in the removal or transfer of selected cellular components. 

We also demonstrated that the mere proximity of a potential pathogen can modulate exopher production even before infection occurs. This reveals a preventive, environmentally responsive layer of proteostasis regulation. 

Proteostasis in Reproduction and Stress 

We demonstrated that interactions between HSP70 and CHIP proteins are essential for maintaining germline integrity under heat stress. This mechanism prevents excessive degradation of proteins required for reproduction and reveals a protective layer of ubiquitin-dependent regulation. 

Computational Resources for the Scientific Community 

We created DEGRONOPEDIA, an open-access platform for degron identification and prediction. The platform enables the analysis of protein degradation signals and supports research into the mechanisms that determine when, where, and how proteins are selectively degraded. 

Metabolic Modulation of Proteostasis 

We identified unexpected links between detoxification pathways and the activity of the ubiquitin–proteasome system. We demonstrated that small molecules, including the anticancer drug floxuridine, can modulate proteostasis independently of canonical germline-associated signaling. 

Societal and Educational Impact 

Educational Game 

An important element of our laboratory’s activities is DEGRADATOR, an educational game developed by Natalia Szulc and Prof. Wojciech Pokrzywa. The game provides an accessible explanation of how the ubiquitin–proteasome system works, how cells remove selected proteins, and how this knowledge can be applied in therapeutic strategies based on targeted protein degradation using PROTAC compounds. 

The project was launched in 2024 and includes not only the game itself but also a set of educational resources: quizzes, the Great Encyclopedia of Protein Degradation, a comic, and lesson plans developed in collaboration with the BioCEN Center for Innovative Bioscience Education. All materials are available in Polish and English. 

DEGRADATOR has also been incorporated into the LabXchange platform developed by Harvard University, increasing its accessibility to the international educational community. 

In 2024, DEGRADATOR received third place in the category of fully developed games at the 12th International Educational Games Competition organized at Aarhus University in Denmark. 

The LumiRare Initiative 

Inspired by the laboratory’s research into rare diseases, Prof. Wojciech Pokrzywa founded LumiRare in 2024. The company translates scientific knowledge into personalized reports for families affected by rare genetic variants. These reports help families better understand disease mechanisms, identify possible directions for further scientific investigation, and connect with relevant experts and laboratories. 

Research Plans 

In the coming years, we will investigate how proteostasis is reorganized under chronic and adaptive stress. Particular emphasis will be placed on the nucleolus as a spatial regulator of protein quality control and on its interactions with the ubiquitin–proteasome system, including the immunoproteasome. 

We will also investigate how metabolic rewiring, including the suppression of lipid biosynthesis, restores proteasome function under stress. In addition, we intend to determine how proteostasis is maintained in cold-induced adaptive states resembling hibernation. 

In parallel, we will define how dysfunction of cullin–RING ubiquitin ligases reshapes proteostasis in human disease. This research direction is particularly relevant to understanding the molecular mechanisms of rare, neurodegenerative, and cancer-related diseases associated with impaired protein quality control. 

Laboratory Mission 

Our goal is to uncover the molecular mechanisms that enable cells and organisms to maintain proteome stability under conditions of stress, aging, and disease. We aim to understand how protein degradation systems, cellular organelles, and inter-tissue signaling cooperate to protect proteostasis, and how this knowledge can be used to develop new therapeutic strategies.

THE LABORATORY WEBSITE


     pokrzywalab.com