Pathogenic proteotoxicity of cryptic splicing is alleviated by ubiquitination and ER-phagy

• 成果类型: Article
• 署名作者: Prieto-Garcia, Cristian; Matkovic, Vigor; Mosler, Thorsten; Li, Congxin; Liang, Jie; Oo, James A.; Haidle, Felix; Macinkovic, Igor; Cabrera-Orefice, Alfredo; Berkane, Rayene; Giuliani, Giulio; Xu, Fenfen; Jacomin, Anne-Claire; Tomaskovic, Ines; Basoglu, Marion; Hoffmann, Marina E.; Rathore, Rajeshwari; Cetin, Ronay; Boutguetait, Doha; Bozkurt, Sueleyman; Canas, Maria Clara Hernandez; Keller, Mario; Busam, Jonas; Shah, Varun Jayeshkumar; Wittig, Ilka; Kaulich, Manuel; Beli, Petra; Galej, Wojciech P.; Ebersberger, Ingo; Wang, Likun; Muench, Christian; Stolz, Alexandra; Brandes, Ralf P.; Tse, William Ka Fai; Eimer, Stefan; Stainier, Didier Y. R.; Legewie, Stefan; Zarnack, Kathi; Mueller-McNicoll, Michaela; Dikic, Ivan
• 署名单位: Goethe University Frankfurt; Goethe University Frankfurt; Institute of Molecular Biology (IMB); University of Stuttgart; University of Stuttgart; Max Planck Society; German Centre for Cardiovascular Research; Goethe University Frankfurt; German Centre for Cardiovascular Research; Goethe University Frankfurt; Goethe University Frankfurt; Goethe University Frankfurt; Goethe University Frankfurt; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; Institute of Biophysics, CAS; Goethe University Frankfurt; Goethe University Frankfurt; Johannes Gutenberg University of Mainz; European Molecular Biology Laboratory (EMBL); Goethe University Frankfurt; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Kyushu University; Max Planck Society
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10361
• DOI: 10.1126/science.adi5295
• 发表日期: 2024-11-15
• 页码: 768-776
• 关键词: unfolded protein response; computational platform; cancer; dissociation; enrichment; inhibition; expression; regulator; stress; FAMILY

摘要

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.