General research interest
We are studying proteins and mechanisms that facilitate sculpting of cellular membranes into small vesicular structures, a necessity for trafficking, compartmentalisation and balancing of the membrane integrity of cells.
Membrane sculpting is fundmental for many of cellular processes and malfunction is implicated in a broad range of human diseases such as cancer, infection, lipid and muscle disorders and obesity.
Caveolae biogenesis and dynamics
Caveolae are small relatively stable invaginations of the cell surface. They are found in most cells and thought to play important roles in the control of lipid homeostasis, membrane tension and signalling. Caveolae dysfunction is strongly associated with tumourgenesis, cardiovascular disease, lipodystrophy and muscular dystrophy. Very little has been known about the protein components that build up the caveolae coat and regulate the formation and stability of caveolae. We have contributed to the current leap in molecular and mechanistic understanding of caveolae. We have identified and characterised key components regulating both biogenesis and dynamics of caveolae at the cell surface. We have described the mechanistic cycle by which proteins within the EHD-family of large ATPases can stabilise highly curved membranes in an ATP-dependent manner.
We are working on:
-Characterisation of the protein complex that controls scission and stability of caveolae
-Architecture and assembly of the caveolae coat
-Influence of the lipid composition on the dynamics of caveolae
and further effects on lipid storage and fat cell expancion
Biogenesis of replication vesicles by Tick-borne encephalitis virus
Tick-borne encephalitis virus belongs to the family of Flaviviruses, which cause sever disease worldwide. Directly upon viral entry the viral RNA genome is translated into a single polyprotein. The polyprotein is cleaved post-translation to generate three structural proteins (part of the virus coat) and seven nonstructural (NS) proteins (not part of the virus coat). The NS proteins are involved in protein cleavage, virus replication and the formation of virus factories although their exact functions are still unclear. A crucial part of the viral factory is the formation of small distinct invaginations of ~100 nm in diameter at the endoplasmatic reticulum. These so called replication vesicles, are induced by the viral proteins. Such cavities are open to the cytosol and virus RNA can be efficiently replicated here, well hidden away from the cellular response machinery specialized in detecting and degrading viral RNA. However, there is a lack of knowledge how viral proteins sculpt the membrane into replication vesicles.
-We aim to identify the minimal mechanism for the generation of replication vesicles in order to discover novel drug targets for the combat of infection.
Suppression of metastasis through endocytic maintenance of cell surface integrity and cell polarity
The transformed microenvironment around tumours results in hypoxic and acidic conditions where cells are exposed to unnatural levels of metabolites, growth factors and mechanical stress. This environment promotes metastasis of cells by driving the transition from an epithelial to a mesenchymal phenotype. Proteins that adjust cell surface dynamics in response to such cues have been identified as suppressors of tumour progression and metastasis. We postulate that reservoirs of plasma membrane buffer membrane tension and integrity in order to maintain cell polarity despite alterations in the metabolic microenvironment. Here, the term reservoir is used in the novel sense of internalised plasma membrane vesicle pools and cell surface areas sequestered by invagination.
-This project aims to identify general principles for how the cell surface integrity is maintained in transformed metabolic environments and how this influences the invasive behaviour of cells.