研究人员报告了在人类细胞系、斑马鱼幼体和小鼠中，缺乏泛素特异性蛋白酶39（USP39）导致剪接体组装受损，并呈现出以隐性5′剪接位点为特征的细胞毒性剪接模式。破坏性的隐性变异逃避了信使RNA（mRNA）监测途径，并被翻译成错误折叠的蛋白质。
这些蛋白质导致蛋白毒性聚集、内质网（ER）应激，并最终引发细胞死亡。剪接引发的蛋白毒性的有害后果可以通过上调泛素-蛋白酶体系统和选择性自噬得到缓解。该研究为剪接体相关疾病的分子致病机制提供了新的见解。
研究人员表示，RNA剪接使细胞能够在变化的环境中实现功能适应。剪接受损与多种疾病相关，包括视网膜色素变性，但其潜在的分子机制和细胞反应仍然未被充分理解。
附：英文原文
Title: Pathogenic proteotoxicity of cryptic splicing is alleviated by ubiquitination and ER-phagy
Author: Cristian Prieto-Garcia, Vigor Matkovic, Thorsten Mosler, Congxin Li, Jie Liang, James A. Oo, Felix Haidle, Igor Mainkovi, Alfredo Cabrera-Orefice, Rayene Berkane, Giulio Giuliani, Fenfen Xu, Anne-Claire Jacomin, Ines Tomaskovic, Marion Basoglu, Marina E. Hoffmann, Rajeshwari Rathore, Ronay Cetin, Doha Boutguetait, Süleyman Bozkurt, María Clara Hernández Caás, Mario Keller, Jonas Busam, Varun Jayeshkumar Shah, Ilka Wittig, Manuel Kaulich, Petra Beli, Wojciech P. Galej, Ingo Ebersberger, Likun Wang, Christian Münch, Alexandra Stolz, Ralf P. Brandes, William Ka Fai Tse, Stefan Eimer, Didier Y. R. Stainier, Stefan Legewie, Kathi Zarnack, Michaela Müller-McNicoll, Ivan Dikic
Issue&Volume: 2024-11-15
Abstract: RNA splicing enables the functional adaptation of cells to changing contexts. Impaired splicing has been associated with diseases, including retinitis pigmentosa, but the underlying molecular mechanisms and cellular responses remain poorly understood. In this work, we report that deficiency of ubiquitin-specific protease 39 (USP39) in human cell lines, zebrafish larvae, and mice led to impaired spliceosome assembly and a cytotoxic splicing profile characterized by the use of cryptic 5′ splice sites. Disruptive cryptic variants evaded messenger RNA (mRNA) surveillance pathways and were translated into misfolded proteins, which caused proteotoxic aggregates, endoplasmic reticulum (ER) stress, and, ultimately, cell death. The detrimental consequence of splicing-induced proteotoxicity could be mitigated by up-regulating the ubiquitin-proteasome system and selective autophagy. Our findings provide insight into the molecular pathogenesis of spliceosome-associated diseases.
DOI: adi5295
Source: https://www.science.org/doi/10.1126/science.adi5295