Pathways of proteolysis affecting renal cell growth.

Abstract

Although the suppression of protein breakdown plays a major role in the growth of the adult kidney in conditions that cause renal hypertrophy, the pathways responsible for controlling proteolysis and the substrates being destroyed have only recently been investigated. This review focuses on the role of the ubiquitin-proteasome pathway in regulating specific substrates during kidney growth, and the role of the lysosomal pathways in the suppression of general protein breakdown and of the substrates of chaperone-mediated autophagy. New insights into the regulation of specific ubiquitin ligases demonstrate how the cell controls the destruction of particular substrates important for growth, including hypoxia-inducible factors and the cell cycle inhibitor, p27. In cell culture, growth factors suppress the lysosomal pathway of chaperone-mediated autophagy leading to the accumulation of specific cytoplasmic proteins containing KFERQ motifs. In a variety of systems, including cultured renal tubular cells, phosphoinositol 3 kinase activity and its downstream mediators control lysosomal proteolysis. Specific ubiquitin ligases and the pathways that control their substrate recognition may be key signalling intermediaries for cell growth, but global alterations in lysosomal pathways account for the decrease in general proteolysis. Functional KFERQ motifs mark proteins that are important in renal growth, including enzymes responsible for the characteristic shift to glycolytic metabolism during growth, transcription factors, and signalling molecules. As altering phosphoinositol 3 kinase changes patterns of vesicular trafficking, it is possible that the regulation of intracellular trafficking may underlie the changes seen in lysosomal proteolysis with growth.