Membrane dynamics in physiology and disease

Abstract

The composition and dynamics of cellular membranes determine intra- and extracellular signaling events, and modulate a variety of cellular states including proliferation, survival, migration and more. Eight minireviews covering some aspects of the ESF EuroMEMBRANE programme and conference elucidate phosphoinositide signaling, membrane sorting, topography, lipid dynamics modeling, and mass spectroscopy methods to enlarge the known lipidome. Membranes define the identity of cells: they are crucial for a cell's perception of the environment, they regulate cellular homeostasis, and they function as hubs for extra- and intracellular signals. Countless lipids have been identified, but how they function in various cell organelles is still poorly defined. Dynamic processes such as membrane fusion, fission, aging and elimination are being elucidated, but are not fully understood. We know that localized lipid–protein and lipid–lipid interactions in membranes determine cell function and fate, but much remains to be learned about the exact nature of these processes. Membrane-modifying enzymes, cell-surface receptors and transporters are all important targets in pharmaceutical therapy. To better understand lipid function and dynamics, Gerrit van Meer and Kai Simons initiated the EuroMEMBRANE program (part of EuroCORES, funded by the European Research Foundation). According to Gerrit van Meer, the aim of the program is to learn about ‘membrane lipids, where they are and how they behave’. The final EuroMEMBRANE conference in Basel in 2012 (www.lipidsignaling.org) concluded the program, and covered various aspects of membrane biology. Plenary lectures by Pietro De Camilli on ‘Membrane dynamics and phosphoinositide signaling’ and Robin Irvine on ‘Metabolism and functions of PIPs controlling signaling and membrane identity’ embraced the conference program, and the following mini-reviews illustrate a small subset of the themes presented at the conference. The first mini-review by Raiborg et al. describes the function of the class III phosphoinositide 3–kinase Vps34, and how its lipid product phosphatidylinositol 3–phosphate recruits elements of the endosomal sorting machinery, exploiting lipid-binding domains including PX and FYVE domains. In the second mini-review, Solinger and Spang demonstrate how Caenorhabditis elegans genetics may be exploited to determine the ‘to do list’ of endosomal tethering complexes, and integrate these in endosome maturation processes with V–ATPase, the ESCRT complexes, phosphoinositides, and more. The third mini-review by Koren and Bentires-Alj covers the currently available mouse models that are being used to investigate breast cancer development. In tumorigenesis, palmitoylation of oncogenic proteins such as Ras modulates translocation and activation, but the role of hydrophobic post-translational modification of membrane proteins is less obvious. Blaskovic et al. address this issue in their mini-review ‘What does S-palmitoylation do to membrane proteins?‘. Parmryd and Önfelt discuss the importance of membrane curvature in function, but also describe how membrane topology may affect data acquired by various microscopic techniques. In ‘Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes’, Kopeć et al. show how compounds affect localized lipid environments. In their mini-review, Volinsky and Kinnunen show that lipids age and are turned over, and that these modifications affect membrane properties and cell fate. Finally, Loizides-Mangold provides insight into how novel technologies such as MS-based lipidomics may be utilized to unravel the complexity of the lipidome. Matthias P. Wymann is Professor at the Department of Biomedicine at the University of Basel (Switzerland). He introduced the first PI3K inhibitor, wortmannin, and has since contributed to the understanding of inhibitor–PI3K interactions, molecular functions and the physiological importance of PI3K. He has initiated European consortia (EU: ACID) to promote the development of isoform-specific PI3K inhibitors, and to validate PI3Ks as drug targets in chronic inflammation, allergy and oncology. With the European Science Foundation (ESF)-funded consortium Tracking of Phosphoinositide Pools (TraPPs), he aims to develop advanced tools to track and modulate phosphoinositide signaling. He is co-founder of PIQUR Therapeutics AG, which is engaged in the development of drugs targeting PI3K and mTOR pathways. Kai Simons received his MD degree from the University of Helsinki, Finland. He then performed postdoctoral research at Rockefeller University in New York. In 1975, Simons moved to the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, where he started the Cell Biology Program, which became the focal point for molecular cell biology in Europe. In 2001, Kai Simons moved to Dresden to build up the new Max Planck Institute for Molecular Cell Biology and Genetics, which today is an internationally recognized center of excellence. His recent research has focused on cell membrane organization and function. He has pioneered the concept of lipid rafts as a membrane-organizing principle.