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U5 小核核糖核蛋白（snRNP）组分PRPF8的组装由热休克蛋白90（HSP90）/R2TP伴侣蛋白控制。

Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones.

作者信息

Malinová Anna, Cvačková Zuzana, Matějů Daniel, Hořejší Zuzana, Abéza Claire, Vandermoere Franck, Bertrand Edouard, Staněk David, Verheggen Céline

机构信息

Institute of Molecular Genetics, Czech Academy of Sciences, 142 20 Prague, Czech Republic.

Faculty of Science, Charles University in Prague, 128 00 Prague, Czech Republic.

出版信息

J Cell Biol. 2017 Jun 5;216(6):1579-1596. doi: 10.1083/jcb.201701165. Epub 2017 May 17.

DOI:10.1083/jcb.201701165
PMID:28515276
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5461031/
Abstract

Splicing is catalyzed by the spliceosome, a complex of five major small nuclear ribonucleoprotein particles (snRNPs). The pre-mRNA splicing factor PRPF8 is a crucial component of the U5 snRNP, and together with EFTUD2 and SNRNP200, it forms a central module of the spliceosome. Using quantitative proteomics, we identified assembly intermediates containing PRPF8, EFTUD2, and SNRNP200 in association with the HSP90/R2TP complex, its ZNHIT2 cofactor, and additional proteins. HSP90 and R2TP bind unassembled U5 proteins in the cytoplasm, stabilize them, and promote the formation of the U5 snRNP. We further found that PRPF8 mutants causing Retinitis pigmentosa assemble less efficiently with the U5 snRNP and bind more strongly to R2TP, with one mutant retained in the cytoplasm in an R2TP-dependent manner. We propose that the HSP90/R2TP chaperone system promotes the assembly of a key module of U5 snRNP while assuring the quality control of PRPF8. The proteomics data further reveal new interactions between R2TP and the tuberous sclerosis complex (TSC), pointing to a potential link between growth signals and the assembly of key cellular machines.

摘要

剪接由剪接体催化，剪接体是一种由五个主要小核核糖核蛋白颗粒（snRNP）组成的复合物。前体mRNA剪接因子PRPF8是U5 snRNP的关键组分，它与EFTUD2和SNRNP200一起形成剪接体的核心模块。我们通过定量蛋白质组学鉴定了包含PRPF8、EFTUD2和SNRNP200的组装中间体，它们与HSP90/R2TP复合物、其ZNHIT2辅助因子及其他蛋白质相关联。HSP90和R2TP在细胞质中结合未组装的U5蛋白，使其稳定，并促进U5 snRNP的形成。我们进一步发现，导致视网膜色素变性的PRPF8突变体与U5 snRNP的组装效率较低，且与R2TP的结合更强，其中一个突变体以R2TP依赖的方式滞留在细胞质中。我们提出，HSP90/R2TP伴侣系统促进U5 snRNP关键模块的组装，同时确保PRPF8的质量控制。蛋白质组学数据进一步揭示了R2TP与结节性硬化复合物（TSC）之间的新相互作用，表明生长信号与关键细胞机器组装之间存在潜在联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/6898489747bb/JCB_201701165_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/0e3fd334da9d/JCB_201701165_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/3c34109f278d/JCB_201701165_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/8f9970d8ac1e/JCB_201701165_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/344df913444d/JCB_201701165_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/b06d7c23df9c/JCB_201701165_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/6807238fc255/JCB_201701165_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/8b0bc54ea394/JCB_201701165_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/b799ad415719/JCB_201701165_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/d6de5d5f7e4c/JCB_201701165_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/6898489747bb/JCB_201701165_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/0e3fd334da9d/JCB_201701165_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/3c34109f278d/JCB_201701165_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/8f9970d8ac1e/JCB_201701165_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/344df913444d/JCB_201701165_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/b06d7c23df9c/JCB_201701165_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/6807238fc255/JCB_201701165_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/8b0bc54ea394/JCB_201701165_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/b799ad415719/JCB_201701165_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/d6de5d5f7e4c/JCB_201701165_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86cb/5461031/6898489747bb/JCB_201701165_Fig10.jpg

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