The cellular proteome and its organisation are remarkably complex. An average human cell expresses around 10,000 different proteins with copy number varying from a few molecules to tens of thousands. To maintain homeostasis, cell must carefully balance its proteome by controlling protein quality, localisation and abundance. Maintaining a healthy proteome (proteostasis) requires cells to coordinate the functions of three interconnected arms: protein synthesis and de-novo folding, quality control of existing proteins and macrocomplexes and protein degradation. In our laboratory we are interested in the molecular basis of proteostasis regulation with primary focus on protein clearance pathways and its relevance in human diseases.
Protein degradation is essential for adapting protein levels to cellular and environmental changes. Efficient and timely removal of proteins prevents the accumulation of misfolded, faulty, and toxic species, including mutant or mislocalised proteins. A decline in protein clearance pathways is a major driver of age-related cellular dysfunction, while the accumulation of toxic protein species is linked to numerous neurodegenerative diseases, including Huntington’s, Alzheimer’s, and Parkinson’s.
To investigate cellular proteostasis, we employ advanced molecular and biochemical techniques, including high-throughput CRISPR/Cas9-based screening and mass spectrometry. We also utilize state-of-the-art fluorescence microscopy and cellular models of neurodegenerative diseases, such as human iPSC-derived neuronal cultures and organoids.
Our goal is to expand our understanding of proteostasis networks in both healthy and diseased tissues. We believe our findings will provide valuable insights into disease pathogenesis and serve as a foundation for developing new therapeutic strategies to restore cellular proteostasis.
Protein degradation is essential to adapt protein levels to cellular or environmental changes. Protein degradation occurs through two major cellular pathways: the ubiquitin-proteasome system (UPS) and autophagosomal-lysosomal pathway. In our laboratory, we focus on the ubiquitin-proteasome system and its critical role in clearing aberrant proteins.
Proper protein folding and structural integrity are crucial for cellular function. However, proper folding is often challenged by destabilizing factors such as mutations or environmental stressors. Misfolded polypeptides can engage in aberrant interactions and aggregate, depleting functional proteins from the proteome while also forming potentially cytotoxic species. Timely removal of these faulty proteins is crucial for cellular fitness and survival. Failure to maintain effective proteolysis leads to the accumulation of toxic protein aggregates, contributing to the progressive neurodegeneration observed in diseases such as Huntington’s and Parkinson’s.
In our laboratory, we study the mechanisms underlying impaired protein clearance in these disorders and explore strategies to enhance protein quality control to promote neuronal health.
Maintenance of cellular proteostasis requires temporally and spatially controlled degradation of regulatory and erroneous proteins. Nuclear protein quality control (PQC) system, including the nuclear UPS, plays a pivotal role in genome stability, transcription and RNA splicing control, DNA damage repair and other essential processes. The nucleus is highly enriched in proteasome complexes and contains various ubiquitin enzymes, together with nuclear-specific proteasome activators and regulators. Yeast has been the primary model organism for discovering nuclear degradation pathway components, yet our understanding of their mammalian counterparts remains limited. Precise regulation of the nuclear UPS is particularly crucial in neurons, which are long-live postmitotic cells that lack the ability to eliminate damaged proteins or aggregates from nucleus through cell division.
We are currently exploring how the ubiquitin-proteasome system is modulated in the mammalian nucleus and how does it crosstalk with the cytosolic protein degradation machinery.
Transport between the cytosol and the nucleus, across the nuclear envelope, is precisely regulated. The bidirectional exchange of molecules, such as RNA and proteins, occurs through the nuclear pore complexes (NPCs), channels embedded in the nuclear envelope.
We are interested in the mechanism regulating nucleocytoplasmic shuttling of the ubiquitin-proteasome system components, including the proteasome and major cellular protein unfoldase VCP/p97. VCP (also known as p97) is an abundant protein unfoldase, playing key roles in the ubiquitin-proteasome system and in autophagy-lysosomal pathway, both crucial for cellular proteostasis. Our recent work indicates that precise VCP localisation has a profound impact on the regulation of localised protein degradation and ability of cells to respond to stress. Mutations in VCP that cause multisystem proteinopathy (MSP) and frontotemporal dementia (FTD) disrupt its nuclear localisation and impair cellular DNA damage response (Wrobel et al.; Sci.Adv.2024).
In our laboratory, we investigate how nucleocytoplasmic shuttling of ubiquitin-proteasome system components is regulated and how it changes with ageing and in diseases conditions.
Our research is supported by:
