Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin. (4th July 2019) - Mediani, Laura
Abstract: 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. 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.