Endoplasmic Reticulum-Plasma Membrane Contact Sites Integrate Sterol and Phospholipid Regulation
This week we profile a recent publication in PLoS Biology from Dr. Christopher Beh
and Evan Quon (pictured) at Simon Fraser University.
Can you provide a brief overview of your lab’s current research focus?
The cell is subdivided into many membrane compartments, each with their own function and metabolic activities, all vital to cell growth. The endoplasmic reticulum (ER) is the compartment in the cell where most lipids and membrane proteins are made. The plasma membrane (PM), which envelopes the entire cell, is where most ER-synthesized lipids and membrane proteins end up. There are several unsolved questions: how do ER-made components know how to find their way to the PM? How much does the ER need to make and of what kind? Growth, activity, and movement of each organelle within the cell itself require a high degree of communication and regulation between membrane compartments. The answer to these questions increasingly points to ” membrane contact sites,” where two compartment membranes are stapled together to create a conduit for inter-membrane communication and exchange. In fact, the inner surface of cell membranes is covered with associated ER that is stapled in place, and in yeast cells almost half of the inside surface of the cell membrane is covered with ER. Using molecular genetics, the Beh Lab exploits budding yeast, Saccharomyces cerevisiae, to determine how the ER and the PM are stapled together to communicate the needs of each membrane. What we find in yeast directly impacts the understanding of neurodegenerative disorders like ALS, because several proteins involved in membrane contact sites are defective in these diseases.
What is the significance of the findings in this publication?
Although many of the “tether” proteins that staple the ER and the PM together had been identified in yeast, in this publication we identified that last unidentified tether and deleted its genes along with all the other tether genes. Membrane contact sites occur between many organelles in the cell, however, the most abundant membrane association occurs between the PM and the endoplasmic reticulum (ER). So it was a surprise that cells lacking all tether genes (there are seven in total) can still grow, albeit very slowly. In collaboration with the Menon Lab at Cornell University Weill Medical College, we found that in cells without ER-PM tethers, lipid metabolism was dysregulated and the correct composition of phospholipids in the PM could not be maintained. By adding specific phospholipid precursors, we could restore normal growth to these mutant cells, but membrane contact sites were not re-established. These results indicated that membrane contacts sites were acting to coordinate lipid metabolism between the ER and PM. However, because they could be bypassed, membrane contact sites were not essential conduits or channels for lipid exchange between membrane compartments. In fact, it was thought that sterols, like cholesterol, exchange and are transported between the ER and PM at membrane contact sites. However, we also showed that sterols do not require PM-ER membrane contact for transfer. In addition to specific “signaling lipids” (phosphatidylinositol-4-phosphate), we found that ER-PM membrane contacts serve as a sensory link to coordinate the regulation of lipid metabolism to ensure that the correct amount of phospholipids are synthesized in the ER to match the needs of the PM. Based on these results, we propose that ER-PM contacts do not play a primary role in lipid exchange but rather acts as a regulatory nexus to integrate lipid synthesis pathways.
What are the next steps for this research?
Apart from the tether proteins themselves, there must be additional factors that “sense” when lipid synthesis in the ER must be adjusted for the needs of the PM. In addition, how these membrane contact sites are generated is also an open question. We intend to find the genes and proteins that regulate both sensing and the creation of membrane contact sites. Given that this process appears to be pertinent to neurodegenerative disease, we hope that these findings will lead to direct treatments for these disorders.
This research was funded by:
The Beh Lab is funded by Discovery and Accelerator Supplement Grants from the Natural Sciences and Engineering Research Council (NSERC) of Canada.