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Mayer Andreas, Full Professor


 

Biography

Andreas Mayer studied biology and chemistry at the University of Munich. In 1995 he obtained a PhD from the same university for studies on protein translocation into mitochondria in the laboratory of Walter Neupert. After postdoctoral studies on organelle inheritance and fusion with William Wickner at Dartmouth Medical School, Andreas Mayer joined the Friedrich-Miescher-Laboratorium of the Max-Planck-Society as a group leader in 1997. In 2003 the group moved to the Department of Biochemistry of the University of Lausanne, continuing its work on the mechanism of membrane fusion and on microautophagic membrane dynamics.

Research Interests

DYNAMICS OF LYSOSOMAL COMPARTMENTS: MEMBRANE FUSION, MEMBRANE FISSION AND OSMOADAPTATION

We study vesicular transport in eukaryotic cells, focusing on the question of how intracellular membranes fuse and fragment and how these processes are coordinated to regulate copy number and size of lysosomal compartments. Furthermore, we study the synthesis and degradation of polyphosphate in the lysosome-like vacuole. Polyphosphates are intimately linked to osmoregulation in many cells, e.g. also in parasites, where they are necessary for the functioning of contractile vacuoles and parasite survival.

1. MEMBRANE FUSION

Membrane fusion is required for vesicular traffic 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 abundance of sugar transporters, or the cytotoxic activity of T-lymphocytes. Also uptake and persistence of intracellular parasites are closely related to vesicular traffic.

Membrane fusion reactions on compartments of the secretory and endocytic pathway share conserved factors. Fusion requires SNAREs which occur in compartment-specific cognate combinations of vesicular (v-) and target (t-) SNAREs. V- and t-SNAREs can form trans-complexes between the two fusion partners which may hold the membranes in close apposition (Fig. 1). We explore how this state of membrane docking evolves into lipid flux and fusion pore opening and how the fusion machine is connected to signal transduction cascades regulating membrane traffic in response to external stimuli. Both issues are studied in a cell-free system reconstituting fusion with purified organelles.

 

 

Fig. 1: Model of SNARE-mediated fusion. V-SNARE in green, t-SNARE in pink. On the left side a similar structure that is adopted by influenza virus fusion proteins during their fusion with endosomal membranes. Adapted from Cell 92 (6), cover picture.

To this end we have established assays that allow us to separately measure the transition of lipids from the outer and inner membrane leaflets and to measure the opening of fusion pores that lead to mixing of vesicle contents (Reese et al., 2005). We try to combine these biochemical and spectroscopic approaches with electrophysiology in order to explore the dynamics of the fusion pore in detail and correlate its behaviour with genetic manipulations of the fusion proteins.

Our model system: Homotypic vacuole fusion

Vacuoles have properties similar to lysosomes, because they are responsible for hydrolytic degradation in yeast cells, but also to acidocalcisomes, because the are essential for osmoregulation and ion homeostasis. Yeast vacuoles fragment and fuse in the course of the cell cycle and in response to changes in osmotic pressure or nutrient availability. Vacuoles are a great model system to study membrane dynamics since they allow to combine the facile manipulation of a genetically accessible organism with the analytical power of a cell-free system. This enables us to develop experiments that could not be performed in higher eukaryotic cells with comparable ease and resolution.

Many factors and events defined by our work on vacuole fusion also have roles in other fusion reactions: Ca2+ release from the organellar lumen and for calmodulin have also been implicated in fusion at the Golgi, at mammalian endosomes and at lysosomes. Protein phosphatase I controls also fusion at the Golgi and the VTC proteins also influence ER-Golgi trafficking. Finally, work by several other groups confirmed that the V0 sector of the V-type H+-ATPase, which is necessary to induce lipid flux in vacuole fusion, also stimulates exocytosis of neurotransmitters, insulin, and multivesicular bodies, and that it is required for phagosome-lysosome fusion. Studying vacuole fusion hence elucidates general aspects of membrane traffic which are also relevant to vesicular transport in higher eukaryotic cells.

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2. CONTROL OF ORGANELLE NUMBER AND SIZE BY MEMBRANE FUSION AND FISSION

Vesicular traffic consists of cycles of membrane fission (vesicle formation) and membrane fusion (vesicle consumption). Similarly, many organelles exist in an equilibrium of fragmentation into smaller units (e.g. during mitosis) and fusion into larger structures. Prominent examples are the Golgi, the nuclear envelope, mitochondria, vacuoles and lysosomes. How are size, copy number and shape of an organelle determined and how are the elementary processes of membrane fission and fusion coordinated in order to control these parameters? We study this evident but poorly explored problem. Our favourite organelle, yeast vacuoles (lysosomes) are an excellent model system for this question: Vacuoles change copy number and size in the cell cycle and upon shifts of media; due to their large diameter (up to 5 µm) these changes can be assayed by fluorescence microscopy and are amenable to genetic screening. Moreover, an in vitro system for vacuole fusion exists and we succeeded in reconstituting also cell-free vacuole fission with purified organelles.

We combine several approaches to build an experimental toolkit for vacuole fission and to characterize this reaction in detail: (1) Identification of fission proteins by mutant screening. To this end we exploit the fact that active vacuole fragmentation can be induced by salt treatments of the cells (Fig. 3). (2) Reconstituting fission in vitro (Fig. 4) and developing methods to quantitate it. (3) Time-resolved confocal fluorescence microscopy of fission proteins in vivo and in vitro. (4) Biochemical characterization of fission protein associations and their changes during fission. With these approaches we hope to identify the vacuolar fission apparatus and elucidate its functioning.

 

 

Fig. 2: Salt-induced vacuole fragmentation in wildtype cells.A group of yeast cells before (left) and <5 min after (right) salt addition. Vacuoles are stained with the red fluorophore FM4-64.

 

In a second line of experiments we explore how the fission apparatus physically and functionally interacts with the – already well-defined – vacuolar membrane fusion machinery. We characterize the impact of cell cycle regulators and signaling pathways on these interactions. These studies may elucidate how membrane fission and fusion components are coordinated to control size and copy number of an organelle (Peters et al., 2004; Baars et al., 2007).


Fig. 3: Fragmentation of isolated vacuoles in vitro. In the presence of an energy source (ATP) vacuoles fragment into clusters of small vesicles.

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3. THE ROLE OF POLYPHOSPHATES IN EUKARYOTES: OSMOREGULATION, PHOSPHATE STORAGE AND THE VIRULENCE OF PARASITES

Inorganic polyphosphate (polyP) is a polymer of dozens to hundreds of orthophosphate (Pi) units linked by energy-rich phosphoanhydride bonds. PolyP occurs in all life forms. In prokaryotes it is a store of phosphate and energy and augments stress resistance. Large quantities of polyP that are synthesized by eukaryotic plankton form marine sediments and influence the global phosphorous cycle. PolyP is important in plant nutrition by mycorrhizal symbioses, participates in calcification of bones in mammals, and is crucial for osmoregulation via contractile vacuoles and acidocalcisomes in parasites such as Leishmania, Plasmodia and Trypanosomes. The identity of a eukaryotic polyP-synthesizing enzyme has long been elusive.



 

Fig. 4: Two representations of the catalytic domain of the yeast polyP polymerase bound to polyP (yellow/red) showing secondary structure (left) and electrostatic potential (right)


Our structural and biochemical analyses have identified this enzyme as a domain of a large vacuolar membrane protein complex. Several crystal structures revealed that this eukaryotic polyP polymerase is completely distinct from bacterial enzymes and shows novel mechanisms of nucleotide binding and turnover (Hothorn et al., Science, in press). We hypothesize that the complex carrying the polyP polymerase activity may not only synthesize polyP at the cytosolic face of the vacuolar membrane but at the same time form a channel that translocates the nascent chain across the membrane into the vacuoles. We now develop assays to measure polyphosphate synthesis in real time and to purify the complex and reconstitute it in liposomes in order to show its function as a polyphosphate translocase. In addition, we try to determine the structure of the whole complex, including its transmembrane parts and the polyphosphate chain. If successful, this might reveal a completely novel type of coupled enzyme/translocase.

The biology of polyphosphates is virtually unexplored territory in eukaryotes. Since most critical residues are in the catalytic center of the yeast polyphosphate polymerase are conserved we can use our structural and mechanistic information from the yeast enzyme to explore the consequences of shutting down polyphosphate synthesis in other organisms. This concerns e.g. their role in unicellular eukaryotes, among them parasites causing malaria, sleep sickness and leishmaniasis. These organisms concentrate polyphosphates in vacuoles and acidocalcisomes. Here, polyP is assumed to participate in osmoregulation, e.g. by driving the pumping cycles of their contractile vacuoles via rapid polyP hydrolysis and re-synthesis. These issues not only touch fundamental questions of eukaryotic cell biology but offer also interesting biomedical perspectives.

 

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2016 |  2015 |  2014 |  2013 |  2012 |  2011 |  2010 |  2009 |  2008 |  2007 |  2005 |  2004 |  2003 |  2002 |  2001 |  2000 |  1999 |  1998 |  1997 |  1996 |  1995 |  1993 |  1991 |  Thèses (doctorat) | 
 

2016
Gerasimait&#279; R., Mayer A., 2016. Enzymes of yeast polyphosphate metabolism: structure, enzymology and biological roles. Biochemical Society Transactions 44(1) pp. 234-239. [DOI] [Pubmed]
2015
Desfougères Y., D'Agostino M., Mayer A., 2015. A modular tethering complex for endosomal recycling. Nature Cell Biology 17(5) pp. 540-541. [DOI] [Web of Science] [Pubmed]
Pieren M., Desfougères Y., Michaillat L., Schmidt A., Mayer A., 2015. Vacuolar SNARE Protein Transmembrane Domains Serve as Nonspecific Membrane Anchors with Unequal Roles in Lipid Mixing. Journal of Biological Chemistry 290(20) pp. 12821-12832. [DOI] [Web of Science] [Pubmed]
2014
Gerasimait&#279; R., Sharma S., Desfougères Y., Schmidt A., Mayer A., 2014. Coupled synthesis and translocation restrains polyphosphate to acidocalcisome-like vacuoles and prevents its toxicity. Journal of Cell Science 127(23) pp. 5093-5104. [DOI] [Web of Science] [Pubmed]
Vavassori S., Mayer A., 2014. A new life for an old pump: V-ATPase and neurotransmitter release. Journal of Cell Biology 205(1) pp. 7-9. [DOI] [Web of Science] [Pubmed]
2013
Alpadi K., Kulkarni A., Namjoshi S., Srinivasan S., Sippel K.H., Ayscough K., Zieger M., Schmidt A., Mayer A., Evangelista M. et al., 2013. Dynamin-SNARE interactions control trans-SNARE formation in intracellular membrane fusion. Nature Communications 4 p. 1704. [DOI] [Web of Science] [Pubmed]
Gopaldass N., Rompf M., Mayer A., 2013. On the Rab again-the PATh to mTORC1 activation. EMBO Reports 14(5) pp. 398-399. [DOI] [Web of Science] [Pubmed]
2012
Klionsky D.J., Abdalla F.C., Abeliovich H., Abraham R.T., Acevedo-Arozena A., Adeli K., Agholme L., Agnello M., Agostinis P., Aguirre-Ghiso J.A. et al., 2012. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8(4) pp. 445-544. [DOI] [Web of Science] [Pubmed]
Alpadi K., Kulkarni A., Comte V., Reinhardt M., Schmidt A., Namjoshi S., Mayer A., Peters C., 2012. Sequential analysis of trans-SNARE formation in intracellular membrane fusion. PLoS Biology 10(1) pp. e1001243. [DOI] [Web of Science] [Pubmed]
Michaillat L., Baars T.L., Mayer A., 2012. Cell-free reconstitution of vacuole membrane fragmentation reveals regulation of vacuole size and number by TORC1. Molecular Biology of the Cell 23(5) pp. 881-895. [DOI] [Web of Science] [Pubmed]
Zieger M., Mayer A., 2012. Yeast vacuoles fragment in an asymmetrical two-phase process with distinct protein requirements. Molecular Biology of the Cell 23(17) pp. 3438-3449. [DOI] [Web of Science] [Pubmed]
2011
Strasser B., Iwaszkiewicz J., Michielin O., Mayer A., 2011. The V-ATPase proteolipid cylinder promotes the lipid-mixing stage of SNARE-dependent fusion of yeast vacuoles. EMBO Journal 30(20) pp. 4126-4141. [DOI] [Web of Science] [Pubmed]
2010
Dawaliby R., Mayer A., 2010. Microautophagy of the nucleus coincides with a vacuolar diffusion barrier at nuclear-vacuolar junctions. Molecular Biology of the Cell 21(23) pp. 4173-4183. [DOI] [Web of Science] [Pubmed]
Pieren M., Schmidt A., Mayer A., 2010. The SM protein Vps33 and the t-SNARE H(abc) domain promote fusion pore opening. Nature Structural and Molecular Biology 17(6) pp. 710-717. [DOI] [Web of Science] [Pubmed]
2009
Hothorn M., Neumann H., Lenherr E.D., Wehner M., Rybin V., Hassa P.O., Uttenweiler A., Reinhardt M., Schmidt A., Seiler J. et al., 2009. Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase. Science 324(5926) pp. 513-516. [DOI] [Web of Science] [Pubmed]
2008
Apel A., Herr I., Schwarz H., Rodemann H.P., Mayer A., 2008. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Research 68(5) pp. 1485-1494. [DOI] [Web of Science] [Pubmed]
Mayer A., 2008. Cell-free reconstitution of microautophagy in yeast. Methods in Enzymology 451 pp. 151-162. [DOI] [Web of Science] [Pubmed]
Uttenweiler A., Mayer A., 2008. Microautophagy in the yeast Saccharomyces cerevisiae. Methods in Molecular Biology 445 pp. 245-259. [DOI] [Pubmed]
2007
Baars T.L., Petri S., Peters C., Mayer A., 2007. Role of the V-ATPase in regulation of the vacuolar fission-fusion equilibrium. Molecular Biology of the Cell 18(10) pp. 3873-3882. [DOI] [Web of Science] [Pubmed]
Uttenweiler A., Schwarz H., Neumann H., Mayer A., 2007. The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Molecular Biology of the Cell 18(1) pp. 166-175. [DOI] [Web of Science] [Pubmed]
2005
Reese C., Heise F., Mayer A., 2005. Trans-SNARE pairing can precede a hemifusion intermediate in intracellular membrane fusion. Nature 436(7049) pp. 410-414. [DOI] [Web of Science] [Pubmed]
Reese C., Mayer A., 2005. Transition from hemifusion to pore opening is rate limiting for vacuole membrane fusion. Journal of Cell Biology 171(6) pp. 981-990. [DOI] [Web of Science] [Pubmed]
Uttenweiler A., Schwarz H., Mayer A., 2005. Microautophagic vacuole invagination requires calmodulin in a Ca2+-independent function. Journal of Biological Chemistry 280(39) pp. 33289-33297. [DOI] [Web of Science] [Pubmed]
2004
Kunz J.B., Schwarz H., Mayer A., 2004. Determination of four sequential stages during microautophagy in vitro. Journal of Biological Chemistry 279(11) pp. 9987-9996. [DOI] [Web of Science] [Pubmed]
Peters C., Baars T.L., Bühler S., Mayer A., 2004. Mutual control of membrane fission and fusion proteins. Cell 119(5) pp. 667-678. [DOI] [Web of Science] [Pubmed]
2003
Bayer M.J., Reese C., Buhler S., Peters C., Mayer A., 2003. Vacuole membrane fusion: V0 functions after trans-SNARE pairing and is coupled to the Ca2+-releasing channel. Journal of Cell Biology 162(2) pp. 211-222. [DOI] [Web of Science] [Pubmed]
2002
Mayer A., 2002. Membrane fusion in eukaryotic cells. Annual Review of Cell and Developmental Biology 18 pp. 289-314. [DOI] [Web of Science] [Pubmed]
Müller O., Bayer M.J., Peters C., Andersen J.S., Mann M., Mayer A., 2002. The Vtc proteins in vacuole fusion: coupling NSF activity to V(0) trans-complex formation. EMBO Journal 21(3) pp. 259-269. [DOI] [Web of Science] [Pubmed]
2001
Mayer A., 2001. What drives membrane fusion in eukaryotes? Trends in Biochemical Sciences 26(12) pp. 717-723. [DOI] [Web of Science] [Pubmed]
Müller O., Johnson D.I., Mayer A., 2001. Cdc42p functions at the docking stage of yeast vacuole membrane fusion. EMBO Journal 20(20) pp. 5657-5665. [DOI] [Web of Science] [Pubmed]
Peters C., Bayer M.J., Bühler S., Andersen J.S., Mann M., Mayer A., 2001. Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature 409(6820) pp. 581-588. [DOI] [Web of Science] [Pubmed]
2000
Mayer A., Scheglmann D., Dove S., Glatz A., Wickner W., Haas A., 2000. Phosphatidylinositol 4,5-bisphosphate regulates two steps of homotypic vacuole fusion. Molecular Biology of the Cell 11(3) pp. 807-817. [Web of Science] [Pubmed]
Müller O., Sattler T., Flötenmeyer M., Schwarz H., Plattner H., Mayer A., 2000. Autophagic tubes: vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. Journal of Cell Biology 151(3) pp. 519-528. [DOI] [Web of Science] [Pubmed]
Sattler T., Mayer A., 2000. Cell-free reconstitution of microautophagic vacuole invagination and vesicle formation. Journal of Cell Biology 151(3) pp. 529-538. [DOI] [Web of Science] [Pubmed]
1999
Mayer A., 1999. Intracellular membrane fusion: SNAREs only? Current Opinion in Cell Biology 11(4) pp. 447-452. [DOI] [Web of Science] [Pubmed]
Peters C., Andrews P.D., Stark M.J., Cesaro-Tadic S., Glatz A., Podtelejnikov A., Mann M., Mayer A., 1999. Control of the terminal step of intracellular membrane fusion by protein phosphatase 1. Science 285(5430) pp. 1084-1087. [DOI] [Web of Science] [Pubmed]
1998
Rapaport D., Mayer A., Neupert W., Lill R., 1998. cis and trans sites of the TOM complex of mitochondria in unfolding and initial translocation of preproteins. Journal of Biological Chemistry 273(15) pp. 8806-8813. [DOI] [Web of Science] [Pubmed]
1997
de Kroon A.I., Dolis D., Mayer A., Lill R., de Kruijff B., 1997. Phospholipid composition of highly purified mitochondrial outer membranes of rat liver and Neurospora crassa. Is cardiolipin present in the mitochondrial outer membrane? Biochimica et Biophysica Acta. Bioemembranes 1325(1) pp. 108-116. [DOI] [Web of Science] [Pubmed]
Xu Z., Mayer A., Muller E., Wickner W., 1997. A heterodimer of thioredoxin and I(B)2 cooperates with Sec18p (NSF) to promote yeast vacuole inheritance. Journal of Cell Biology 136(2) pp. 299-306. [DOI] [Web of Science] [Pubmed]
1996
1995
Mayer A., Driessen A., Neupert W., Lill R., 1995. Purified and protein-loaded mitochondrial outer membrane vesicles for functional analysis of preprotein transport. Methods in Enzymology 260 pp. 252-263. [Web of Science] [Pubmed]
Mayer A., Nargang F.E., Neupert W., Lill R., 1995. MOM22 is a receptor for mitochondrial targeting sequences and cooperates with MOM19. EMBO Journal 14(17) pp. 4204-4211. [Web of Science] [Pubmed]
Mayer A., Neupert W., Lill R., 1995. Translocation of apocytochrome c across the outer membrane of mitochondria. Journal of Biological Chemistry 270(21) pp. 12390-12397. [Web of Science] [Pubmed]
Nargang F.E., Künkele K.P., Mayer A., Ritzel R.G., Neupert W., Lill R., 1995. 'Sheltered disruption' of Neurospora crassa MOM22, an essential component of the mitochondrial protein import complex. EMBO Journal 14(6) pp. 1099-1108. [Web of Science] [Pubmed]
1993
Mayer A., Lill R., Neupert W., 1993. Translocation and insertion of precursor proteins into isolated outer membranes of mitochondria. Journal of Cell Biology 121(6) pp. 1233-1243. [DOI] [Web of Science] [Pubmed]
1991
Phd thesis
Kohl K., 2014. Role and regulation of polyphosphate in leishmania parasites. 105 p., Université de Lausanne, Faculté de biologie et médecine, Mayer A. (dir.).
Rompf M., 2013. Differential phosphoproteomics of fragmenting yeast vacuoles. 201 p., Université de Lausanne, Faculté de biologie et médecine, Mayer, A. (dir.).
Sharma S., 2012. Characterization of polyphosphate synthesis by isolated yeast vacuoles. 88 p., Université de Lausanne, Faculté de biologie et médecine, Mayer, A. (dir.).
Zieger M., 2012. Characterization of high osmolarity-induced vacuole fragmentation in "Saccharomyces c.". 104 p., Université de Lausanne, Faculté de biologie et médecine, Mayer, A. (dir.).
Strasser B., 2010. The role of the vacuolar H+ - ATPase in membrane fusion. 108 p., Université de Lausanne, Faculté de biologie et médecine, Mayer, A. (dir.).
Dawaliby R., 2009. Insights into the molecular machinery of piecemeal microautophagy of the nucleus in "Saccharomyces cerevisiae". 106 p., Université de Lausanne, Faculté de biologie et médecine, Mayer A. (dir.).
Michaillat L., 2009. "In vitro" reconstitution of the fragmentation of vacuoles. 104 p., Université de Lausanne, Faculté de biologie et médecine, Mayer A. (dir.). [embargo unspecified]
 
 
 
 
 
 
 
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Véronique Comte-Miserez Technician Unisciences
Thibault Courtellemont Postdoctoral fellow Unisciences
Massimo D'Agostino Postdoctoral fellow Unisciences
Maria Giovanna De Leo Postdoctoral fellow Unisciences
Ruta Gerasimaite Postdoctoral fellow Unisciences
Navin Gopaldass Postdoctoral fellow Unisciences
Sandra Klompmaker Postdoctoral fellow Unisciences
Lydie Michaillat Mayer Research associate Unisciences
Andrea Schmidt Luther Technician Unisciences
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Andreas Mayer

andreas.mayer@unil.ch

Tel: + 41 21 692 5704

Chemin des Boveresses 155 - CH-1066 Epalinges  - Switzerland  -  Tel. +41 21 692 5700  -  Fax +41 21 692 5705
Swiss University