Membrane Traffic in Disease and Novel Therapies

Research Interests

One of the most important challenges for the Biomedical Sciences this century is to develop a comprehensive knowledge of the fundamental unit of life, the cell. One main question in Molecular Cell Biology is focused on understanding how cells achieve their highly sophisticated internal compartmentalisation. Each organelle is individualised by membranes, which contain specific proteins and lipids to execute specific functions. How are proteins and lipids sorted and retained to different locations or in other words how are organelles made, maintained (identified) and how do they communicate with each other? Our work in the last 15 years has dealt with this problem and our approach has been to study both normal cells and disease processes. We are currently working in a variety of diseases with different phenotypes whose common feature is dysfunction of intracellular membrane trafficking pathways. We also wish to apply the fundamental knowledge to develop new therapeutic approaches to these diseases.

Group Members

Research Project

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)

Funding

Fundacão para a Ciência e Tecnologia (FCT)
Wellcome Trust
Medical Reseach Council

Publications

(Selected) Updated January (2009).

Wasmeier C, Hume AN, Bolasco G, Seabra, M.C. (2008). Melanosomes at a glance J Cell Sci 121(Pt 24) :3995-9

Figueiredo, A, Wasmeier, C, Tarafder, AK, Ramalho, JS, Baron, RA and Seabra, M.C. (2008). Rab3GEP is the non-redundant guanine nucleotide exchange factor for Rab27a in melanocytes J Biol Chem 283 :23209-16

Hume, AN, Ushakov, DS, Tarafder, AK, Ferenczi, MF and Seabra, MC. (2007). Rab27a and MyoVa are the primary Mlph interactors regulating melanosome transport in melanocytes J Cell Sci 120 :3111-222

Lopes, VS, Wasmeier, C, Seabra, M.C. and Futter, CE. (2007). Melanosome Maturation Defect in Rab38-deficient Retinal Pigment Epithelium Results in Instability of Immature Melanosomes during Transient Melanogenesis Mol Biol Cell 18 :3914-27

Mizuno K, Tolmachova T, Ushakov DS, Romao M, Åbrink M, Ferenczi MA, Raposo G and Seabra, M.C. (2007). Rab27b regulates mast cell granule dynamics and secretion Traffic 8 :883-92

Lopes VS, Ramalho JS, Owen, DM, Karl MO, Strauss O, Futter CE, and Seabra, M.C. (2007). The ternary Rab27a—Myrip—MyosinVIIa complex regulates melanosome motility in the retinal pigment epithelium Traffic 8 :486-499

Tolmachova T, Åbrink M, Futter CE, Authi KS, and Seabra, M.C. (2007). Rab27b regulates number and secretion of platelet dense granules PNAS 104 :5872-7

Jancic C, Savina A, Wasmeier C, Tolmachova T, El-Benna J, Dang PM, Pascolo S, Gougerot-Pocidalo M, Raposo G, Seabra, M.C. and Amigorena S. (2007). Rab27a regulates phagosomal pH and NADPH-oxidase recruitment to dendritic cell phagosomes Nature Cell Biol 9 :367-78

Wasmeier C., Romao M., Plowright L., Bennett D.C., Raposo G. and Seabra, M.C. (2006). Rab38 and Rab32 control post-Golgi trafficking of melanogenic enzymes J Cell Biol 175 :271-81

Tolmachova, T., Anders, R., Abrink, M., Bugeon, L., Dallman, M. J., Futter, C.E., Ramalho, J, S., Tonagel, F., Tanimoto, N., Seeliger, M.W., Huxley, C. Seabra, M. C. (2006). Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of Choroideremia. J Clin Invest 116 :386-394