Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin.

Autor: Mediani L; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Guillén-Boixet J; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Vinet J; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Genomic and post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy., Franzmann TM; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Bigi I; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Mateju D; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Carrà AD; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Morelli FF; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Tiago T; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Poser I; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany., Alberti S; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.; Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Biotechnology Center (BIOTEC), Dresden, Germany., Carra S; Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2019 Aug 01; Vol. 38 (15), pp. e101341. Date of Electronic Publication: 2019 Jul 04.
DOI: 10.15252/embj.2018101341
Abstrakt: Nuclear protein aggregation has been linked to genome instability and disease. The main source of aggregation-prone proteins in cells is defective ribosomal products (DRiPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DRiPs rapidly diffuse into the nucleus and accumulate in nucleoli and PML bodies, two membraneless organelles formed by liquid-liquid phase separation. We show that nucleoli and PML bodies act as dynamic overflow compartments that recruit protein quality control factors and store DRiPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress-inducible overflow compartments for DRiPs. If DRiPs are not properly cleared by chaperones and proteasomes due to proteostasis impairment, nucleoli undergo amyloidogenesis and PML bodies solidify. Solid PML bodies immobilize 20S proteasomes and limit the recycling of free ubiquitin. Ubiquitin depletion, in turn, compromises the formation of DNA repair compartments at fragile chromosomal sites, ultimately threatening cell survival.
(© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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