Regulation of ESCRT mediated cell surface remodeling

Cells use a wide variety of proteins on their surface to sense their environment. Many of them are embedded in the membrane. These membrane proteins have a variety of essential tasks. Some transmit signals from growth factors into the cell and others import nutrients such as amino acids or sugars and thus enable cell growth and cell division. To control cell growth and nutrient uptake, the abundance of membrane proteins at the cell surface is precisely controlled. One aspect in regulating membrane protein abundance is their selective degradation. A key step of membrane protein degradation is executed by the endosomal complexes required for transport (ESCRTs). These protein complexes form a molecular machinery that recognizes membrane proteins and packages them for degradation. Consequently, the ESCRT machinery is involved in diverse cellular processes and its dysfunction contributes to many diseases including cancer and neuro-degeneration. Moreover, the ESCRT machinery is hijacked by HIV to promote its release from infected host cells. Probably all components of the core ESCRT machinery have been identified. Yet, the molecular mechanism underlying the regulation of ESCRT activity and the consequences of its dysfunction, raise important questions. Among the most important are: 1. How is the activity of the ESCRT machinery regulated? 2. How do cell react/adapt to the loss of ESCRT function and the subsequent accumulation of membrane proteins? Due to the universal function of the ESCRT machinery during evolution, yeast functions as best suited model system to address these questions. By addressing these fundamental questions we have made three discoveries: Our work provides detailed insight into the mechanistic principles of the ESCRT machinery. We now understand where the ESCRT machinery assembles, how many molecules are involved and how long the machinery operates to package membrane proteins. We identified the genetic networks that couple cellular metabolism to nutrient transporter endocytosis.We have discovered a novel membrane protein degradation mechanism that functions independent of the ESCRT machinery. This process appears to play an important role in the regulation of lipid metabolism.