Philipp Lachenmann: DELPHI Rationale


Habilitation Prize 2003

Dr. Andreas Mayer

Friedrich Miescher Laboratory, Tübingen

Membrane fusion

My research group studies the molecular mechanisms of vesicular transport in eukaryotic cells, focussing on intracellular membrane fusion. Membrane fusion is a basic biochemical reaction prerequisite to the compartimentation of eukaryotic cells into discrete organelles with specialized functions. It is required for transport of proteins and lipids between organelles. In exocytosis it controls many vital processes, such as signal transduction among neurons, secretion of hormones or digestive enzymes, the regulation of sugar transporters, or the cytotoxic activity of T-lymphocytes.

In all of these examples controlled membrane fusion is the key event for the delivery and activation of signaling molecules, cytotoxic substances, receptors etc. at the cell surface. Also reconstitution of many cellular organelles such as the Golgi or ER, which disperse into small vesicular fragments in every mitosis, occurs by fusion. Also uptake and persistence of intracellular parasites are closely related to vesicular trafficking. For example, some Mycobacteria can survive inside cells by actively inhibiting fusion of their phagosomes with lysosmes. It is therefore obvious that the ability to influence intracellular vesicular transport and exocytosis can be of therapeutic interest. Knowing the molecules involved in the process and understanding their interplay provides a valuable basis for this.

It has become clear through the work of many groups in different systems that membrane fusion in eukaryotes is a very conserved process. A similar enzymatic apparatus appears to function in diverse organisms - and at different stations of vesicular traffic within a cell. Due to this conservation genetic studies in the yeast Saccharomyces cerevisiae can contribute to the elucidation of the mechanism of membrane fusion. The results could be applied to and integrated with studies in mammalian systems.

My group has been studying the fusion of vacuoles (lysosomes) from yeast. This fusion reaction can be reconstituted in a cell free system with purified organelles and combines the power of in vitro systems with the excellent genetic accessibility of yeast. Kinetic analysis of the reaction allowed to dissect it into four distinct phases: activation, membrane binding, Ca2+ efflux from the lumen and, finally, membrane and contents mixing. We could identify low molecular weight inhibitors specifically interfering with the terminal phase of vacuole fusion, i.e. with the transition from membrane binding to bilayer mixing. We used them to identify potential target proteins on the vacuolar membrane. This yielded several novel proteins which participate in the final steps of vacuole fusion. Currently, we investigate the interplay of these proteins and their relevance to the induction of lipid mixing and/or the opening of the fusion pore.



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