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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Bibliographic Details
Published in:	The EMBO journal Vol. 38; no. 15; pp. e101341 - n/a
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-08-2019 Blackwell Publishing Ltd John Wiley and Sons Inc
Subjects:	Agglomeration Amyloidogenesis Cell Nucleus - genetics Cell Nucleus - metabolism Cell survival Chaperones Compartments Cytoplasm defective ribosomal products Deoxyribonucleic acid Depletion DNA DNA Repair EMBO13 EMBO31 EMBO32 Fitness Genomes Genomic Instability HeLa Cells Humans Immobilization Liquid phases membraneless organelles molecular chaperones Molecular Chaperones - metabolism Nuclei Nucleoli nucleus Organelles Overflow Phase separation Proteasome Endopeptidase Complex - metabolism Proteasomes Protein interaction Proteins proteostasis Quality control Ribosomes Ribosomes - metabolism Stability Ubiquitin Ubiquitin - metabolism nucleus membraneless organelles molecular chaperones proteostasis defective ribosomal products
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Summary:	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. Synopsis Defective ribosomal products (DRiPs) are a key source of aggregation‐prone proteins in cells. Here, nuclear bodies are found as dynamic overflow compartments recruiting quality control factors and storing DRiPs for later clearance. DRiPs diffuse into nuclei and accumulate in nucleoli and PML bodies. DRiPs convert nucleoli and PML bodies into a solid aggregated‐like state revertable by chaperones. Solid PML bodies immobilize ubiquitin, 20S proteasomes and chaperones. Ubiquitin immobilization impairs genome integrity and cell fitness. Graphical Abstract Nucleoli and PML bodies act as dynamic overflow compartments recruiting quality control factors and storing DRiPs for later clearance, failure of which threatens cell survival.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The copyright line for this article was changed on 1 August 2019 after original online publication.
ISSN:	0261-4189 1460-2075
DOI:	10.15252/embj.2018101341