Cells and their internal compartments are surrounded by lipid membranes that need to be remodelled (reshaped, cut, fused) in order to maintain cellular integrity and homeostasis. One of the machineries mediating membrane-remodelling are the Endosomal Protein Complexes Required for Transport (ESCRT)-III. In the lab, we investigate the molecular mechanism of the ESCRT-III machinery in order to understand how it cuts and deforms lipid membranes.
Structure of ESCRT-III assemblies
Membrane-bound ESCRT-III proteins (hetero)polymerise into filaments. Depending on the ESCRT-III subunit composition and/or stoichiometry, the respective filaments display different organisations. We want to solve the structures of membrane-bound ESCRT-III polymers to understand how they control membranes’ shape and orientation. Comparing ESCRT-III polymers on intact membranes with those on detergent-stabilised membranes will give important mechanical insight. To this end, we use cryogenic electron microscopy (cryo-EM) and tomography (cryo-ET).
Dynamic changes within ESCRT-III assemblies
During membrane remodelling, different ESCRT-III subunits are recruited to the membrane and polymerise into filamentous (hetero-)polymers. The ESCRT-III subunits incorporated and/or their respective ratio within the filament change during the remodelling event, under the influence of the AAA ATPase Vps4. This results in different polymer organisations that translate into membrane shape or topology changes. We want to learn how subunits reorganise within a polymer to allow for the structural changes within the filament.
Role of lipids in membrane remodelling
Membranes are the target of the ESCRT-III machinery, but they also play a major role in the machinery’s efficiency. We study how the lipid composition of membranes affects the activity of the ESCRT-III and how it can facilitate membrane deformation and fission. In vitro reconstitutions on artificial membranes allow us to study directly the effect of individual lipids, lipid phases and their respective biophysical features in detail.
Pfitzner A-K, Mercier V, Jiang X, Moser von Filseck J
, Baum B, Šarić A and Roux A “An ESCRT-III Polymerization Sequence Drives Membrane Deformation and Fission” Cell 182, 1-16 (2020). https://doi.org/10.1016/j.cell.2020.07.021
Moser von Filseck J
, Barberi L, Talledge N, Johnson I, Frost A, Lenz M and Roux A “Anisotropic ESCRT-III architecture governs helical membrane tube formation” Nat Commun 11, 1516 (2020). https://doi.org/10.1038/s41467-020-15327-4
Mierzwa BE, Chiaruttini N, Redondo-Morata L, Moser von Filseck J
, König J, Larios J, Poser I, Müller-Reichert T, Scheuring S, Roux A and Gerlich DW “Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodeling during cytokinesis” Nat Cell Biol 19, 787-798 (2017). https://doi.org/10.1038/ncb3559
|PhD student with Guillaume Drin in Bruno Antonny’s lab, Institute for Molecular and Cellular Pharmacology, Valbonne, France
|PhD (Biochemistry), University of Nice-Sophia Antipolis, Nice, France
|Postdoc with Aurélien Roux, Biochemistry Department, University of Geneva, Geneva, Switzerland
||Emmy Noether Group Leader at the Heidelberg University Biochemistry Center (BZH)
Pfitzner A, Moser von Filseck J and Roux A “Principles of membrane remodeling by dynamic ESCRT-III polymers” Trends Cell Biol
31(10), 856-868. https://doi.org/10.1016/j.tcb.2021.04.005
Pfitzner A-K, Mercier V, Jiang X, Moser von Filseck J, Baum B, Šarić A and Roux A “An ESCRT-III Polymerization Sequence Drives Membrane Deformation and Fission” Cell 182, 1-16. https://doi.org/10.1016/j.cell.2020.07.021
Moser von Filseck J, Barberi L, Talledge N, Johnson I, Frost A, Lenz M and Roux A “Anisotropic ESCRT-III architecture governs helical membrane tube formation” Nat Commun 11, 1516. https://doi.org/10.1038/s41467-020-15327-4
Wang L, Sadler S, Cao T, Xie X, Moser von Filseck J and Bakker E “Simplified Fabrication for Ion-Selective Optical Emulsion Sensor with Hydrophobic Solvatochromic Dye Transducer: A Cautionary Tale” Anal Chem 91(14), 8973-8978. https://doi.org/10.1021/acs.analchem.9b01145
Mierzwa BE, Chiaruttini N, Redondo-Morata L, Moser von Filseck J, König J, Larios J, Poser I, Müller-Reichert T, Scheuring S, Roux A and Gerlich DW “Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodeling during cytokinesis” Nat Cell Biol 19, 787-798. https://doi.org/10.1038/ncb3559
Moser von Filseck J and Drin G “Running up that hill: how to create cellular lipid gradients by lipid counter-flows” Biochimie 130, 115-121. https://doi.org/10.1016/j.biochi.2016.08.001
Drin G, Moser von Filseck J and Copic A “New molecular mechanisms of inter-organelle lipid transport” Biochem Soc Trans 44(2), 486-492. https://doi.org/10.1042/BST20150265
Moser von Filseck J, Copic A, Delfosse V, Vanni S, Jackson CL, Bourguet W and Drin G “Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate” Science 349(6246), 432-436 (2015). https://doi.org/10.1126/science.aab1346
Moser von Filseck J, Vanni S, Mesmin B, Antonny B and Drin G "A phosphatidylinositol 4-phosphate powered exchange mechanism to create a lipid gradient between membranes." Nat Commun 6, 6671 (2015). https://doi.org/10.1038/ncomms7671
Moser von Filseck J, Mesmin B, Bigay J, Antonny B and Drin G “Building lipid ‘PIPelines’ throughout the cell by ORP/Osh proteins” Biochem Soc Trans 42(5), 1465-1470. https://doi.org/10.1042/BST20140143
Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G and Antonny B “A Four-Step Cycle Driven by PI(4)P Hydrolysis Directs Sterol/PI(4)P Exchange by the ER-Golgi Tether OSBP” Cell 155, 830–843. https://doi.org/10.1016/j.cell.2013.09.056
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