Novel protein trafficking and signaling pathways in kidney physiology and pathophysiology

Abstract

The nephron's fluid and electrolyte transport properties are determined largely by the inventories of ion transport proteins occupying the apical and basolateral plasma membrane domains of renal tubule epithelial cells. The asymmetric apportioning of ion channels, transporters and pumps among these domains determines the nature of the fluxes maintained by renal epithelia. Generation and maintenance of differentiated plasmalemmal domains requires a cell to possess machinery capable of discriminating among newly synthesized membrane proteins. Information embedded in these proteins' structures serves as sorting signals that specify their appropriate destinations.To follow the fates of newly synthesized membrane proteins in polarized epithelial cells, we have adapted a technique that permits direct observation of temporally defined cohorts of proteins via the combination of fluorescence microscopy with pulse‐chase labeling protocols. Using this technique, we can follow cohorts of protein as they are synthesized and trafficked. We have found that different proteins that are destined for the same destination appear to travel to the cell surface in separate vesicular carriers. We have also found that the base of the primary cilium appears to be a “hot spot” for the delivery of newly synthesized proteins.Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects ~1 in 1,000 people and is the most common potentially lethal genetic condition, leading to end stage renal disease in ~50% of patients. ADPKD is caused by mutations in the genes encoding polycystin‐1 (PC1) and polycystin‐2 (PC2). PC1 is an enormous membrane protein that spans the bilayer 11 times, with a large extracellular N terminal domain and a short C terminal domain that faces the cytoplasm. PC2 is a member of the TRP family of non‐selective calcium‐permeable cation channels. The PC1 and PC2 proteins participate in a number of signaling pathways and exhibit complex patterns of subcellular localization. PC1 and PC2 interact with each other and with numerous other proteins that may modulate their trafficking properties or their involvement in signal transduction. Both PC1 and PC2 localize to the primary cilium where they appear to participate in mechanosensory or chemosensory processes. We have found that polycystin trafficking and function are regulated by oxygen‐sensing pathways. We have also found that the C‐terminal tail of Polycystin‐1 is released by a proteolytic cleavage, allowing it to travel to the nucleus, where it is involved in the regulation of several transcriptional pathways that modulate proliferation, apoptosis and cell fate determination. Finally, we find that PC1 functions as a receptor in a novel signal transduction pathway that regulates cell growth.Support or Funding InformationNIDDK and DoDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.