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

R2TP 复合物在囊性肾病的分子发病机制和纤毛生物学中的作用

• 批准号: 314732659
• 负责人: Professor Dr. Bernhard Schermer
• 金额: --
• 依托单位: Nephrologisches Forschungslabor
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314732659?language=en
• 关键词: R2TP; complex; molecular; pathogenesis; cystic

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.

最近令人兴奋的研究表明，原发性纤毛在囊性肾病（包括常见的常染色体显性多囊肾病（ADPKD）以及一些罕见的常染色体隐性综合征）的发病机制中起着重要作用。在肾脏中，初级纤毛像触角一样从小管上皮细胞的顶端表面伸入小管的管腔。作为感觉细胞器，它们将环境中的信号传递到细胞中。纤毛在间期形成，必须在有丝分裂重新进入前被重新吸收。肾脏纤毛动力学的详细机制和纤毛的功能尚不清楚。当以囊性肾病蛋白肾囊素-1为诱饵进行基于蛋白质组学的相互作用筛选时，我们发现AAA+蛋白酶和R2TP复合物Ruvbl1和Ruvbl2的核心成分是肾囊素蛋白复合物的新成分，主要定位于睫状碱基。假设Ruvbl1/2在囊性肾病中的作用，我们产生了一个条件敲除小鼠。有趣的是，小管上皮特异性表达cre的动物发展为严重的退行性囊性肾病。此外，我们可以确定肾囊素和r2tp复合物之间的新分子联系。r2tp复合物是HSP90的共伴侣，促进Box C/D小核核核糖核蛋白（snoRNPs）的合成和核糖体前RNA的加工，从而影响细胞的整体蛋白质生物合成。这一提议验证了Ruvbl1/2和r2tp复合物在囊性肾的发病机制和睫状体生物学中发挥重要作用的假设。具体而言，我们的目标是(1)详细分析Ruvbl1和Ruvbl2在体内小管上皮中的重要性，(2)表征R2TP-伴侣复合物作为肾囊素复合物和初级纤毛蛋白质组成的调节剂，以及(3)阐明纤毛和纤毛蛋白在调节核糖体生物发生和mTOR活性中在多大程度上调节R2TP复合物的活性。

项目成果

Activation of Hypoxia-Inducible Factor Signaling Modulates the RNA Protein Interactome in Caenorhabditis elegans

• DOI: 10.1016/j.isci.2019.11.039
• 发表时间: 2019-12-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Esmaillie, Reza;Ignarski, Michael;Fabretti, Francesca
• 通讯作者: Fabretti, Francesca

Enzyme Replacement Therapy Clears Gb3 Deposits from a Podocyte Cell Culture Model of Fabry Disease but Fails to Restore Altered Cellular Signaling.

• DOI: 10.33594/000000077
• 发表时间: 2019-01-01
• 期刊: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
• 作者: Braun, Fabian;Blomberg, Linda;Kurschat, Christine E
• 通讯作者: Kurschat, Christine E

A protein-RNA interaction atlas of the ribosome biogenesis factor AATF

核糖体生物合成因子 AATF 的蛋白质-RNA 相互作用图谱

• DOI: 10.1038/s41598-019-47552-3
• 发表时间: 2019
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Kaiser;Ignarski;Van Nostrand;Cukoski;Heinen;Schaechter;Seufert;Frommolt;Keller;Schermer;Benzing;Hopker;Dieterich
• 通讯作者: Dieterich