Elucidating the Morphology of the Endoplasmic Reticulum: Puzzles and Perspectives

[Image: see text] Artificial or synthetic organelles are a key challenge for bottom-up synthetic biology. So far, synthetic organelles have typically been based on spherical membrane compartments, used to spatially confine selected chemical reactions. In vivo, these compartments are often far from being spherical and can exhibit rather complex architectures. A particularly fascinating example is provided by the endoplasmic reticulum (ER), which extends throughout the whole cell by forming a continuous network of membrane nanotubes connected by three-way junctions. The nanotubes have a typical diameter of between 50 and 100 nm. In spite of much experimental progress, several fundamental aspects of the ER morphology remain elusive. A long-standing puzzle is the straight appearance of the tubules in the light microscope, which form irregular polygons with contact angles close to 120°. Another puzzling aspect is the nanoscopic shapes of the tubules and junctions, for which very different images have been obtained by electron microcopy and structured illumination microscopy. Furthermore, both the formation and maintenance of the reticular networks require GTP and GTP-hydrolyzing membrane proteins. In fact, the networks are destroyed by the fragmentation of nanotubes when the supply of GTP is interrupted. Here, it is argued that all of these puzzling observations are intimately related to each other and to the dimerization of two membrane proteins anchored to the same membrane. So far, the functional significance of this dimerization process remained elusive and, thus, seemed to waste a lot of GTP. However, this process can generate an effective membrane tension that stabilizes the irregular polygonal geometry of the reticular networks and prevents the fragmentation of their tubules, thereby maintaining the integrity of the ER. By incorporating the GTP-hydrolyzing membrane proteins into giant unilamellar vesicles, the effective membrane tension will become accessible to systematic experimental studies.