Our research is centered on the dynamics of proteostasis, the balance between protein synthesis, folding, trafficking, and degradation, and how its disruption drives disease. We focus on how cells decide the fate of newly made proteins, with particular emphasis on translation control, the ubiquitin-proteasome system (UPS), and molecular chaperone networks as an integrated quality-control system. A major direction of our work is the molecular basis of rare diseases caused by defects in protein quality control, especially those linked to UPS dysfunction, including disorders associated with genes such as FEM1C or PIGV. We also investigate organelle-specific proteostasis, particularly within the nucleolus, to understand how cells reorganize essential compartments during stress, recovery, and disease. To address these questions, we combine biochemical assays, advanced microscopy, molecular genetics, and bioinformatics in mammalian cell models and the nematode Caenorhabditis elegans, leveraging IIMCB’s state-of-the-art core facilities.
OUR RESEARCH
Rare Diseases of Proteostasis
A central, ongoing research programme of the laboratory focuses on elucidating the molecular basis of rare human diseases arising from defects in protein quality control and ubiquitin-dependent regulation. We are systematically investigating disorders linked to dysfunction of ubiquitin ligases, with particular emphasis on cullin-RING E3 ligase substrate receptors. Our work addresses how impaired substrate recognition destabilises tissue-specific proteomes and leads to multisystem phenotypes encompassing neurodevelopmental, muscular, and metabolic pathologies.
Building on these studies, we are expanding our efforts to include rare metabolic disorders that intersect functionally with proteostasis, including PIGV-related disease and related glycosylation- and lipid-linked syndromes. By integrating patient-derived genetic data with quantitative proteomics and in vivo functional modelling in C. elegans, we are defining shared molecular principles that connect ubiquitination, metabolism, and organismal homeostasis, with the long-term goal of enabling improved diagnostics and mechanism-informed therapeutic strategies. We focus on deciphering mechanisms that alter the abundance and types of cellular messenger RNAs and proteins because these kinds of molecules are critical for live-or-die decisions of the cell. We are also investigating the role of protein quality control networks and the ubiquitin system during C. elegans recovery from cold stress. We also conduct drug screens to identify molecules that support the ability of C. elegans to survive cold stress.
Nucleolus as a Stress-Responsive Hub
An ongoing research focus of the laboratory is the role of the nucleolus as an active, stress-responsive regulator of proteostasis. We are investigating how proteotoxic stress induces a reversible reorganisation of the nucleolus into a specialised protein quality control compartment that transiently prioritises proteome protection over ribosome biogenesis.
Our work aims to define how nucleolar remodelling integrates protein folding, ubiquitination, sequestration, and controlled recovery, generating distinct nucleolar states that encode proteostasis capacity and readiness to resume biosynthetic activity. By linking structural plasticity of the nucleolus to adaptive stress responses, this project positions ribosome biogenesis as a dynamically regulated process and identifies the nucleolus as a central coordination hub safeguarding cellular homeostasis during and after stress.
Proteostasis under Chronic Stress
Our laboratory is actively investigating how cells and tissues maintain proteome integrity under prolonged or recurrent proteotoxic stress. When degradation capacity becomes limiting, organisms must adopt adaptive strategies that extend beyond transient heat-shock or unfolded protein responses. A key objective of this project is to define how proteostasis is preserved when growth and biosynthesis must be temporarily deprioritised in favour of survival.
We are characterising stress-adaptive programmes that involve spatial reorganisation of protein quality control, selective stabilisation of damaged proteomes, and delayed recovery processes reminiscent of dormancy or hibernation-like states. Through a combination of genetics, live imaging, and quantitative proteomics, we aim to determine how these strategies sustain tissue function over time and how their failure contributes to ageing and degenerative disease.
Lipids-Proteasome Axis in Stress & Ageing
An active line of investigation in the laboratory examines how lipid metabolism regulates protein degradation during chronic stress and ageing. We are dissecting a conserved lipid-proteasome axis in which modulation of lipid biosynthetic pathways stabilises proteasome function and preserves cellular fitness under sustained proteotoxic conditions, challenging the traditional view of metabolism as a passive energy supplier to protein quality control.
Using C. elegans and human cell systems, we are analysing how lipid composition and inter-tissue lipid signalling reshape proteostasis networks during prolonged stress. This work aims to define how metabolic rewiring supports long-term survival when canonical stress responses become insufficient, and how similar mechanisms may contribute to pathological adaptations such as resistance to proteasome-targeting therapies in cancer.
FUTURE GOALS
Our laboratory aims to define how the ubiquitin–proteasome system, nucleolar remodelling, and metabolic state jointly govern stress adaptation, ageing, and rare-disease phenotypes, including tissue- and stress-specific rules of substrate selection and degron logic. We integrate patient genetics with quantitative proteomics, targeted bioinformatic discovery, and C. elegans functional modelling and screening to facilitate the discovery of targeted therapies.
COMMENT
"Our research efforts are dedicated to unraveling the complex molecular mechanisms of proteostasis and cellular adaptation, setting the stage for groundbreaking discoveries in biological science and new therapeutic strategies.” — Wojciech Pokrzywa, PhD, DSc Habil
