PHOSPHATIDYLSERINE DYNAMICS
Phosphatidylserine (PS) is an anionic phospholipid that is essential for the proper functioning of eukaryotic cells. Its distribution within the cell is highly asymmetric: its concentration increases approximately fivefold between the endoplasmic reticulum (ER), where it is synthesized, and the plasma membrane (PM), where this abundant lipid provides the negative surface charge required for key cellular processes such as signal transduction and membrane fusion. PS is also predominantly confined to the inner leaflet of the PM. When exposed on the outer leaflet, it serves as a signal that can trigger apoptosis and synaptic pruning.
In the yeast Saccharomyces cerevisiae, the selective transport of PS from the ER to the PM by the lipid transfer protein Osh6 is required for its enrichment at the plasma membrane. Osh6 functions at ER–PM membrane contact sites, where it interacts with the ER-anchored protein Ist2. Ist2 tethers the ER to the PM through its long intrinsically disordered C-terminal domain (see figure below).
ROLE OF IST2 IN THIS DYNAMICS
In this study, conducted in collaboration with the CRBM (CNRS/Université de Montpellier), the IPMC (CNRS/Université Côte d'Azur), and the IBCP (CNRS/Université de Lyon), the authors demonstrate that Ist2 is a membrane transporter that catalyzes the rapid transbilayer movement of lipids across the ER membrane. They further show that this lipid scrambling activity supports the Osh6-mediated transfer of PS between the ER and the PM. Using i) the reconstitution of Ist2 into proteoliposomes and the generation of artificial membrane contact sites in vitro, ii) a fluorescence-based lipid transport assay, iii) in silico structural analyses, and iv) an investigation of the cellular consequences of disrupting Ist2-mediated lipid transport, the researchers demonstrate that the ER transmembrane domain of Ist2 possesses lipid scramblase activity, including for PS. Furthermore, overexpression of Ist2 or deletion of its lipid transport domain alters several ER-associated processes, including COPII vesicle-mediated trafficking and lipid droplet homeostasis. These effects specifically depend on amino acid residues predicted to play a critical role in the lipid scrambling activity of Ist2.
Taken together, these findings demonstrate that Ist2 possesses lipid scramblase activity and establish that Ist2-mediated lipid scrambling in the endoplasmic reticulum (ER) regulates multiple cellular functions, highlighting the importance of lipid dynamics for ER function.
Adapted from I2BC news
Contact : Guillaume Lenoir guillaume.lenoir@i2bc.paris-saclay.fr
- The endoplasmic reticulum (ER) is an organelle found in eukaryotic cells. Continuous with the nuclear envelope, it is the site of synthesis for secreted and membrane proteins, as well as for most cellular lipids.
- Scramblases mediate the passive, bidirectional movement of phospholipids between the two leaflets of biological membranes, thereby promoting lipid symmetry across the membrane bilayer. In the ER, where phospholipid synthesis is restricted to a single membrane leaflet, scramblase activity is essential to ensure balanced membrane expansion.
- COPII vesicles are small intracellular transport vesicles that mediate the trafficking of proteins and lipids from the ER to the Golgi apparatus. They constitute an essential step in the secretory pathway of eukaryotic cells.