GOLGI/ENDOSOME PH IN RENAL EPITHELIAL PROTEIN TRAFFIC

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Many transport functions in the kidney result in movement of ions up an electrochemical gradient and thus require a highly polarized distribution of channels and transporters. This distribution is maintained by selective sorting of proteins, which occurs in acidic intracellular compartments. When acidification of these compartments is disrupted, protein sorting along both the biosynthetic and endocytic pathways is altered. This results in mistargeting of many cell surface proteins, and could have profound effects on epithelial cell function. Defects in acidification has been suggested to play a role in the pathology of diseases as diverse as cystic fibrosis, cancer, and influenza infection. Our goal is to understand the consequences of pH perturbation on traffic through acidified sorting compartments, particularly the trans Golgi network and endosomes. Our approach involves the expression of influenza M2, a protein which modulates intracellular pH of acidic compartments, in polarized Madin-Darby canine kidney cells. Using this molecule, we will dissect the role of acidification in individual steps in protein transport and to determine the mechanism by which pH perturbation disrupts traffic through these compartments.