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

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 ( DR iPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DR iPs 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 DR iPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress‐inducible overflow compartments for DR iPs. If DR iPs 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.

Growth Hormone(s), Testosterone, Insulin-Like Growth Factors, and Cortisol: Roles and Integration for Cellular Development and Growth With Exercise

“…These repair mechanisms may be enhanced with exercise training. This model suggests an intriguing line for future research in the quest to understand roles of aggregated GH in stress biology (129)(130)(131). The potential for lower values of BGH in the blood might be observed if all of the processing systems for mis-folded non-functional GH aggregates are fully engaged, potentially a training adaptation.…”

Protein phase separation and its role in tumorigenesis

“…Lastly, condensates may work as compartments for protein quality control. Under stress conditions, some misfolded proteins accumulate in the granular component (GC) phase of the nucleolus, which prevents irreversible aggregation of misfolded proteins, facilitating refolding during recovery from stress ( Frottin et al, 2019 ; Mediani et al, 2019 ). Phase separation has also been shown to be critical for the formation of proteasome-containing foci and the assembly of the autophagosome ( Fujioka et al, 2020 ; Yasuda et al, 2020 ).…”

“…PML bodies are stress-sensitive nuclear condensates ( Banani et al, 2016 ; Zhu and Brangwynne, 2015 ). They are involved in transcriptional regulation, protein modification, apoptosis, cellular senescence, cell cycle progression, angiogenesis, and protein quality control ( Hsu and Kao, 2018 ; Mediani et al, 2019 ). The formation of the PML body is driven by PML:PML interactions ( Huang et al, 2014 ) and SUMOylation of PML, which promotes the recruitment of proteins containing SUMO-interacting motifs (SIMs) to PML bodies ( Banani et al, 2016 ).…”

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

“…The involvement of chaperones in regulating the dynamics of membraneless compartments is further supported by their function in the nucleolus. The phase-separated nucleolus serves as a PQC compartment which sequesters misfolded protein species (Mediani et al, 2019 ). Prolonged exposure to stress or a failure to dissolve the liquid-like phase causes proteins in the nucleolus to transition into an amyloid state (Azkanaz et al, 2019 ; Frottin et al, 2019 ; Mediani et al, 2019 ).…”

“…The phase-separated nucleolus serves as a PQC compartment which sequesters misfolded protein species (Mediani et al, 2019 ). Prolonged exposure to stress or a failure to dissolve the liquid-like phase causes proteins in the nucleolus to transition into an amyloid state (Azkanaz et al, 2019 ; Frottin et al, 2019 ; Mediani et al, 2019 ). Their resolubilization during the recovery period depends on the refolding activity of Hsp70 family members that re-localize to the nucleolus (Audas et al, 2016 ; Azkanaz et al, 2019 ; Frottin et al, 2019 ; Mediani et al, 2019 ).…”