Sorting membrane proteins into intralumenal vesicles that form within late endosomes is a fundamental process that regulates many biological pathways that rely on maintaining appropriate levels of a given set of cell surface membrane proteins. This is the pathway that guides the delivery and degradation of proteins in lysosomes. This pathway is driven by ubiquitin, which works as a sorting signal when attached to membrane protein cargo. This process controls the degradation of almost all cell surface membrane proteins and understanding this degradative process is significant since it impacts a wide array of normal and pathogenic processes that rely on proper activity of particular membrane proteins such as transporters and signaling receptors at the cell surface. The long-term goal of the competitive renewal proposal is to understand how this ubiquitin-dependent sorting pathway is controlled, and will lead to insights into how disease states such as cancer might be achieved when this process goes awry. To accomplish this we have devised aims to 1) discover how the major family of Nedd4- related ubiquitin ligases are programed to target different cell surface membrane proteins;2) discover how ubiquitinated membrane proteins are recognized by the endosomal sorting machinery and how that cargo plays an active role in organizing the sorting apparatus itself;and 3) discover new proteins that participate in the process of intralumenal vesicle formation using a series of genetic screens.
The proposed research is relevant to public health because it focuses on how multiple cellular functions are regulated through the degradation of cell surface proteins that mediate growth, differentiation, signal- transduction, neuronal signaling, and nutrient uptake. Thus, the proposed research is relevant to mission of the NIH to increase understanding of fundamental life processes that in turn will lay the foundation for advances in disease diagnosis, treatment and prevention.
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