Philipp Lachenmann: DELPHI Rationale


Habilitationspreis 1998

PD Dr. Albert Haas

Theodor-Boveri-Institut für Biowissenschaften, Biozentrum der Julius-Maximilians-Universität Würzburg

How membranes fuse within cells

Every 'higher' cell, i.e. cell with a nucleus, entertains a very busy trafficking business. Transport vesicles bud off one compartment and bring cargo in a targeted fashion to a defined second compartment (for example, from the Golgi apparatus to the plasma membrane). There is no doubt that such a highly complex network employs regulatory mechanisms that tightly control trafficking.

PD Dr. Albert Haas (Biocenter of the University of Würzburg), while in Prof. William Wickner's laboratory (Dartmouth College), investigated the mechanisms and the regulation of intracellular membrane fusion using yeast vacuoles as a model system. This body of work was now recognized by the "Butenandt-Habilitation Award" of the German Society for Biochemistry and Molecular Biology (GBM), an award sponsored by the Ernst Schering Research Foundation.

In brief, Dr. Haas developed an in vitro assay which allows to quantify the extent of membrane fusion between isolated vacuoles (a part of the vacuole inheritance pathway in baker's yeast). Dr. Haas used this assay to manipulate the fusion conditions in the test tube in a defined manner and, hence, to determine which factors are involved in membrane fusion between vacuoles. Using vacuoles isolated from genetically altered yeast and using specific antibodies and pharmacological inhibitors as probes, Dr. Haas determined that the fusion reaction requires, among others factors, a small GTP-binding regulatory protein (Ypt7p), the yeast homologues of the mammalian protein NSF (Sec18p) and the NSF-adaptor SNAP (in yeast, Sec17p), the membrane-bound SNAP receptors Vam3p and Nyv1p, and the soluble protein IB2.

Some of these components or factors very similar to these had already been demonstrated to be implicated in other fusion events such as the neurotransmission in the human brain or the secretion of hormones by exocrine cells. Dr. Haas demonstrated that the order of events in yeast vacuole fusion is probably very similar to that in such different fusion events. Given the ease in using the vacuole fusion assay, this experimental system became a paradigm for the study of intracellular membrane fusion in general. Most notably, the studies lead to the discovery that NSF and SNAP are not acting in the fusion step as such, but prepare membranes for subsequent fusion; this conclusion was in contradication with the existing hypotheses and has, in the meantime, been validated by data obtained by different groups using different fusion reactions. Furthermore, Dr. Haas' studies could strengthen the theory that membrane-anchored "vesicular" and "target membrane" SNARE proteins (in this case, Nyv1p and Vam3p), are required on opposite membranes for the specific contact between membranes that are destined to fuse with each other (hence supplying one layer of specificity in the transport process). Dr. Haas' research further demonstrated that the ras-like GTPase Ypt7p is required on both partner membranes for subsequent fusion. This finding, too, has in the meantime been validated by other groups using other systems.

In summary, these studies have given new impulses to the study of the many aspects of intracellular vesicular trafficking, particularly by replacing the existing models by a new, testable model which, as is clear by now, describes membrane fusion more precisely than previous hypotheses.

Dr. Haas has recently changed his research direction and is now studying how immune phagocytic cells (macrophages) take up, kill and digest invaded microorganisms and how some illness-causing bacteria can interfere with normal phagocyte functions.

Slusarewicz, P., Z. Xu, K. Seefeld, A. Haas und W. Wickner (1997) Proc. Natl. Acad. Sci. USA 94:5582-5587.
Nichols, B.J., C. Ungermann, H.R.B. Pelham, W.T. Wickner und A. Haas (1997) Nature 387:199-202.
Haas, A. und W. Wickner (1996) EMBO J. 15:3296-3305.
Mayer, A., W. Wickner und A. Haas (1996) Cell 85:83-94.
Haas, A. und W. Wickner (1996) Semin. Cell Developm. Biol., 17:3296-3305.
Haas, A. (1995) Methods Cell Sci. 17:283-294.
Haas, A., D. Scheglmann, T. Lazar, D. Gallwitz und W. Wickner (1995) EMBO J. 14:5258-5270.
Haas, A., B. Conradt und W. Wickner (1994) J. Cell Biol. 126:87-98.
Conradt, B., A. Haas und W. Wickner (1994) J. Cell Biol. 126:99-110.



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