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.
Highlights
The fidelity in the flow of genetic information from DNA to RNA and, to protein is essential for cellular life
defective ribosomal products (DRiPs) could be detected inside the nucleus, where they accumulated in microscopic large clusters that resembled nucleoli
DRiPs were already detected in nucleoli after 15 min of exposure to OP-puro and their accumulation increased over the time-course of 2 h (Fig 1A and B, and data not shown)
Summary
The fidelity in the flow of genetic information from DNA to RNA and, to protein is essential for cellular life. Many errors can occur during DNA replication, transcription, and translation, which lead to the production of mutated or truncated polypeptides that cannot acquire their native folding state, impairing protein homeostasis (Kapur & Ackerman, 2018). The main sources of misfolded proteins in mammalian cells are newly synthesized polypeptides that have not yet reached their native state and defective ribosomal products (DRiPs), which result from the misincorporation of amino acids, premature translation termination, damaged mRNAs, or DNA mutations (Schubert et al, 2000). Ribosome occupancy has been observed for many 50 untranslated regions (50-UTRs) and could potentially generate substantial amounts of aberrant peptides even under physiological conditions (Ingolia et al, 2014). These peptides are thought to be highly unstable, but their biological effects remain to be explored
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