Vps4 and the MVB sorting pathway.

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DESCRIPTION (provided by applicant): The degradation of membrane proteins via the multivesicular body (MVB) pathway plays an essential role in regulating cell-surface proteins. As a consequence, numerous cellular functions, such as nutrient uptake, cell- cell communication and immune response are dependent on MVBs. The formation of MVBs is executed by a group of highly conserved protein complexes called ESCRTs (Endosomal Sorting Complex Required for Transport). ESCRTs perform a unique membrane budding event, which results in vesicle formation in the lumen of the MVB. Retroviruses, such as HIV, co-opt the ESCRT machinery during viral infection to complete formation of viral particles via a similar membrane budding event at the plasma membrane. Furthermore, cytokinesis requires the ESCRT-dependent fusion of the plasma membrane in order to form two separate cells. Our recent studies indicate that ESCRT function and protein translation are tightly connected. On one hand, the MVB pathway degrades proteins and recycles amino acids for further use in protein translation. On the other hand, we observed that translation efficiency regulates ESCRT function by increasing or decreasing the cellular levels of the ESCRT regulatory protein Ist1. High amino acid levels in the cell increase translation and thus the cellular concentration of Ist1, which in turn decreases ESCRT activity and protein degradation via the MVB pathway. In contrast, starvation induces protein degradation via the MVB pathway by lowering Ist1 levels and by increasing endocytosis of numerous plasma membrane proteins. In addition, we observed that amino acid starvation resulted in the relocalization of some ESCRT components and translation-initiation factors to a filamentous structure, which we termed STICS (STarvation Induced Cytoplasmic Structure). We propose that STICS formation might facilitate the switch from general translation to the specialized protein translation occurring during starvation. Together, our preliminary experiments uncovered a complex regulatory system that coordinates the necessary changes in the activity of translation, endocytosis and protein turnover in the MVB pathway to ensure survival under starvation conditions. The goal of the proposed research is to characterize this regulatory system and to determine how malfunction of this system affects cellular growth and adaptation.