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

Autor: Prieto-Garcia C; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Matkovic V; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany., Mosler T; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Biology (IMB), Mainz, Germany., Li C; Department of Systems Biology and Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany., Liang J; Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Oo JA; Institute for Cardiovascular Physiology, Goethe University Frankfurt, Frankfurt, Germany.; German Centre of Cardiovascular Research (DZHK), Partner Site Rhine-Main, Frankfurt, Germany.; Cardiopulmonary Institute (CPI), Goethe University Frankfurt, Frankfurt, Germany., Haidle F; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany., Mačinković I; Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Cabrera-Orefice A; Institute for Cardiovascular Physiology, Goethe University Frankfurt, Frankfurt, Germany.; Center for Functional Proteomics, Goethe University Frankfurt, Frankfurt, Germany., Berkane R; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany., Giuliani G; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Xu F; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, P.R. China.; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China., Jacomin AC; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Tomaskovic I; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Basoglu M; Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt, Germany., Hoffmann ME; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Rathore R; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Cetin R; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Boutguetait D; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Systems Medicine, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Bozkurt S; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Systems Medicine, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Hernández Cañás MC; Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany., Keller M; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany., Busam J; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany., Shah VJ; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Wittig I; Institute for Cardiovascular Physiology, Goethe University Frankfurt, Frankfurt, Germany.; German Centre of Cardiovascular Research (DZHK), Partner Site Rhine-Main, Frankfurt, Germany.; Center for Functional Proteomics, Goethe University Frankfurt, Frankfurt, Germany., Kaulich M; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Beli P; Institute of Molecular Biology (IMB), Mainz, Germany.; Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-University, Mainz, Germany., Galej WP; European Molecular Biology Laboratory (EMBL), Grenoble, France., Ebersberger I; Applied Bioinformatics Group, Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt, Germany.; Senckenberg Biodiversity and Climate Research Centre (S-BIK-F), Frankfurt, Germany.; LOEWE Centre for Translational Biodiversity Genomics (TBG), Frankfurt, Germany., Wang L; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China.; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P.R. China., Münch C; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Center for Functional Proteomics, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Systems Medicine, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany., Stolz A; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany., Brandes RP; Institute for Cardiovascular Physiology, Goethe University Frankfurt, Frankfurt, Germany.; German Centre of Cardiovascular Research (DZHK), Partner Site Rhine-Main, Frankfurt, Germany.; Cardiopulmonary Institute (CPI), Goethe University Frankfurt, Frankfurt, Germany., Tse WKF; Laboratory of Developmental Disorders and Toxicology, Center for Promotion of International Education and Research, Faculty of Agriculture, Kyushu University, Fukuoka, Japan., Eimer S; Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt, Germany., Stainier DYR; Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany., Legewie S; Department of Systems Biology and Stuttgart Research Center Systems Biology (SRCSB), University of Stuttgart, Stuttgart, Germany., Zarnack K; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany., Müller-McNicoll M; Institute of Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany.; Max-Planck Institute for Biophysics, Frankfurt, Germany., Dikic I; Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Max-Planck Institute for Biophysics, Frankfurt, Germany.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Nov 15; Vol. 386 (6723), pp. 768-776. Date of Electronic Publication: 2024 Nov 14.
DOI: 10.1126/science.adi5295
Abstrakt: 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.
Databáze: MEDLINE
Nepřihlášeným uživatelům se plný text nezobrazuje