The R2TP-complex in the molecular pathogenesis of cystic kidney diseases and in ciliary biology

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Recent exciting work has demonstrated that primary cilia play an important role in the pathogenesis of cystic kidney diseases, which include the frequent autosomal-dominant polycystic kidney disease (ADPKD) as well as a number of rare autosomal-recessive syndromic diseases. In the kidney, primary cilia project like antennae from the apical surface of tubular epithelial cells into the lumen of the tubules. Acting as sensory organelles they transmit signals from the environment into the cell. Cilia are built during interphase and have to be reabsorbed before mitotic re-entry. The detailed mechanism of ciliary dynamic and the function of cilia in the kidney are not well understood.When performing a proteomics-based interaction screen with the cystic kidney disease protein nephrocystin-1 as bait we identified the AAA+ proteases and core-components of the R2TP complex Ruvbl1 and Ruvbl2 as novel constituents of the nephrocystin protein complex, which is predominantly localized at the ciliary base. Assuming a role for Ruvbl1/2 in cystic kidney disease we generated a conditional knockout mouse. Interestingly, animals with cre expression specific to the tubular epithelium developed a severe degenerative cystic kidney disease. Moreover, we could identify novel molecular links between nephrocystins and the R2TP-complex. The R2TP-complex is a co-chaperone for HSP90 that promotes both the synthesis of Box C/D small nucleolar ribonucleoproteins (snoRNPs) and the processing of pre-ribosomal RNA, thereby influencing the global protein biosynthesis of cells. This proposal tests the hypothesis that Ruvbl1/2 and the R2TP-complex play vital roles in the pathogenesis of cystic kidneys and in ciliary biology. Specifically, we aim (1) to analyze in detail the importance of Ruvbl1 and Ruvbl2 in tubular epithelium in vivo, (2) to characterize the R2TP-chaperone-complex as a regulator of the nephrocystin-complex as well as the protein composition of primary cilia, and (3) to clarify to what extent cilia and ciliary proteins modulate the activity of the R2TP complex in the regulation of ribosome biogenesis and mTOR activity.