Mechanism of nutrient dependent plasma membrane remodeling

Growth and survival of all cells depends on their ability to respond to growth factors and nutrient fluctuations in their environment. This includes the remodeling of the cell surface. Some proteins will be added while other proteins will be selectively removed at the same time. The selective removal of membrane proteins is called endocytosis. During endocytosis cell surface proteins will be package into small membrane vesicles that bud into the cell. Once inside the cell, these vesicle together with the membrane proteins will be degraded in lysosomes. We could recently show that nutrient starvation triggers the endocytosis and degradation of many different membrane proteins. Why? Interestingly, the starvation-induced degradation of membrane proteins maintains the function of essential metabolic pathways during starvation and thereby ensures cell survival. Yet so far, the molecular mechanisms of starvation-induced endocytosis are not understood. Therefore it is the goal of this proposal to (i) identify genes that are required for this process and (ii) to determine how the function to (iii) obtain a complete mechanistic understanding of starvation-induced endocytosis. To achieve these goals we will combine yeast genetics with high-throughput imaging and quantitative proteomics. We are confident that the genes and basic regulatory concepts that we will identify in our studies are going to be evolutionary conserved in humans. Thus, our results will have broad biological implications and will help to understand how cells adjust their membrane proteome to specific growth conditions, which may be central to many metabolic diseases and cancer.

How cells control what and how much they eat: The growth of all cells depends on their ability to take up nutrients from their environment. This requires nutrient transporters at their cell surface. Under certain conditions, some nutrient transporters will be to the cell surface, while other nutrient transporters will be selectively removed. The selective removal of membrane proteins from the plasma membrane is called endocytosis. During endocytosis nutrient transporters will be package into small membrane vesicles that bud into the cell. Once inside the cell, these vesicles together with the nutrient transporter proteins will be degraded in lysosomes. We could recently show that nutrient starvation triggers the endocytosis and degradation of many different nutrient transporters. Why? Interestingly, the starvation-induced degradation of nutrient transporters maintains the function of essential metabolic pathways during starvation and thereby ensures cell survival. Now we have deciphered the molecular mechanism that control starvation induced endocytosis. Cells employ different metabolic signaling pathways to activate so-called ubiquitin ligase complexes that mark specific nutrient transporters for endocytosis and subsequent lysosomal degradation. We also provide first hints that help to explain how the activated ubiquitin ligase complexes interact specifically with those nutrient transporters that are no longer need. We are confident that the basic regulatory concepts that we have identified in our studies will have broad biological implications because they inform us how cells adjust nutrient uptake. In other words, we now have testable concepts that explain how cells that grow, can increase nutrient uptake, while cells that no longer need to grow, reduce nutrient uptake sufficient to maintain metabolic homeostasis. These results provide interesting new concepts that can be important for a better understanding of metabolic diseases and for cancer, since cancer cells take up large quantities of nutrient to afford rapid cell growth.