Grant: Operating Grant

To preserve cellular homeostasis, proteins with impaired architecture have to be repaired or eliminated from living cells in a timely manner. Since structural errors are frequently incorporated in newly synthesized proteins, as well as imposed by various environmental stresses (e.g. thermal, oxidative and osmotic stress) during the lifespan of polypeptides, sophistical mechanisms have evolved to eliminate impaired proteins from the cell. Surprisingly, the removal mechanism of damaged proteins from the cell surface, termed peripheral quality control, is not known. We designed model systems to investigate the cellular fate of damaged membrane protein from the cell surface. Using biochemical, genetic and proteomic techniques, we showed that ubiquitination plays a central role in the degradation of damaged protein from the cell surface. Remarkably, our pilot studies suggest that similar mechanism appears to be responsible for four other mutant receptors and transporters degradation from the cell surface, associated with various genetic disease. The present application aims at elucidating three specific steps in the degradation pathway of damaged membrane proteins from the cell surface: the internalization, the endosomal sorting and the lysosomal delivery. The proposed experiments will identify components and mechanism of each of these sorting steps. The results will potentially identify novel drug targets that may be utilized to rescue the membrane protein stability defect in certain conformational diseases.