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

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 an...

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Detalles Bibliográficos
Autores principales: Mediani, Laura, Guillén‐Boixet, Jordina, Vinet, Jonathan, Franzmann, Titus M, Bigi, Ilaria, Mateju, Daniel, Carrà, Arianna D, Morelli, Federica F, Tiago, Tatiana, Poser, Ina, Alberti, Simon, Carra, Serena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669919/
https://www.ncbi.nlm.nih.gov/pubmed/31271238
http://dx.doi.org/10.15252/embj.2018101341
Descripción
Sumario: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.