Dataset Information

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 (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.

SUBMITTER: Mediani L

PROVIDER: S-EPMC6669919 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Mediani Laura L Guillén-Boixet Jordina J Vinet Jonathan J Franzmann Titus M TM Bigi Ilaria I Mateju Daniel D Carrà Arianna D AD Morelli Federica F FF Tiago Tatiana T Poser Ina I Alberti Simon S Carra Serena S

The EMBO journal 20190704 15

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 pr ...[more]

PMID: 31271238

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Project description:A subset of class I major histocompatibility complex (MHC)-bound peptides is produced from immature proteins that are rapidly degraded after synthesis. These defective ribosomal products (DRiPs) have been implicated in early alert of the immune system about impending infections. Interferons are important cytokines, produced in response to viral infection, that modulate cellular metabolism and gene expression patterns, increase the presentation of MHC molecules, and induce rapid degradation of proteins and cell-surface presentation of their derived MHC peptides, thereby contributing to the battle against pathogen infections. This study evaluated the role of interferons in the induction of rapid degradation of DRiPs to modulate the repertoire of DRiP-derived MHC peptides. Cultured human breast cancer cells were treated with interferons, and the rates of synthesis and degradation of cellular protein and their degradation products were determined by LC-MS/MS analysis, following the rates of incorporation of heavy stable isotope-labeled amino acids (dynamic stable isotope labeling by amino acids in cell culture, dynamic SILAC) at several time points after the interferon application. Large numbers of MHC peptides that incorporated the heavy amino acids faster than their source proteins indicated that DRiP peptides were abundant in the MHC peptidome; interferon treatment increased by about twofold their relative proportions in the peptidome. Such typical DRiP-derived MHC peptides were from the surplus subunits of the proteasome and ribosome, which are degraded because of the transition to immunoproteasomes and a new composition of ribosomes incorporating protein subunits that are induced by the interferon. We conclude that degradation of surplus subunits induced by the interferon is a major source for DRiP-MHC peptides, a phenomenon relevant to coping with viral infections, where a rapid presentation of MHC peptides derived from excess viral proteins may help alert the immune system about the impending infection.

Dataset Information

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

Publications

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

Similar Datasets

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