One third of proteins encoded by eukaryotic genomes undergo their biogenesis in an essential membranous organelle called the endoplasmic reticulum (ER)—the cell’s protein factory. Many of these proteins are integral membrane proteins, which must fold in the ER and be inserted into the ER membrane. Following their successful membrane import, these proteins are trafficked through a network of membranous organelles called the secretory pathway.
When membrane proteins are trafficked to their final destination (e.g. the plasma membrane) they fulfill multiple important physiological roles essential for eukaryotic life, including cell signaling.
Surprisingly, the complex biogenesis of many signaling proteins, including those associated with human diseases, remains poorly understood. This, combined with the fact that approximately 60% of current drugs target membrane proteins, illustrates the importance to understand how membrane proteins are successfully made, integrated into the membrane and trafficked within the secretory pathway.
The Membrane Traffic lab is interested in several aspects of membrane protein homeostasis (‘Proteostasis’) including how membrane proteins are made, degraded or trafficked within the secretory pathway.
We use a combination of cellular biochemistry and mouse physiology in our experimental approaches, focusing particularly on models of inflammation and/or metabolic homeostasis.
Our work currently focuses on three areas being developed:
- How membrane trafficking regulates signalling controlled by the metalloprotease ADAM17/TACE.
- Role of quality control in the secretory pathway in vivo in mice, during development and disease.
- Genetic screens to identify novel trafficking factors.
Among the critical players in defining membrane identity and function are Rab GTPases. More than 60 Rabs have been identified in mammalian cells and each one exhibits a specific subcellular localisation. Upon activation by binding GTP, Rabs recruit effector proteins such as molecular motors, enzymes (e.g. PI-3 kinase) and membrane fusion factors, thus conferring specific functions to their target organelles. We are interested in membrane traffic and in particular in the role of Rab GTPases and their interacting partners in the control of vesicle trafficking and organelle motility.
These processes are relevant to many diseases, genetic and acquired. Our approach is to combine fundamental and pathogenesis studies as we believe that each aspect reinforces the other. Therefore, we work on cellular pathogenetic processes that involve dysfunction of intracellular membrane traffic pathways as follows:
1) Host/pathogen interactions in malaria
2) Membrane traffic, retinal pigment epithelium and retinal degenera-tion
3) Novel Therapies
4) Rabs and membrane traffic
5) Molecular Basis of Membrane Identity: Lipid Modifications of Rab GTPases and Membrane Targeting
For more information on each project please click here (PDF)