The nucleolus functions as a phase-separated protein quality control compartment

• Published in: Science (American Association for the Advancement of Science) Vol. 365; no. 6451; pp. 342 - 347
• Main Authors: Frottin, F, Schueder, F, Tiwary, S, Gupta, R, Körner, R, Schlichthaerle, T, Cox, J, Jungmann, R, Hartl, F U, Hipp, M S
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 26-07-2019
• Subjects: Agglomeration; Aggregates; Amyotrophic lateral sclerosis; Autophagy; Biosynthesis; Cell culture; Cell Nucleolus - metabolism; Cellular stress response; Chaperones; Control systems; Cytoplasm; Disease control; Disruption; Domains; Endoplasmic reticulum; Fluorescence; Folding; Growth conditions; Heat shock proteins; Heat stress; Heat tolerance; HEK293 Cells; Homeostasis; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Maintenance; Membrane proteins; Mitochondria; Mobility; Neurodegenerative diseases; Neurological diseases; Nuclear Proteins - chemistry; Nucleoli; Nucleolin; Phagocytosis; Phase separation; Phase Transition; Phase transitions; Properties (attributes); Proteasomes; Protein Folding; Proteins; Proteome; Proteomics; Quality control; Recovery; Ribonucleic acid; Ribosomal proteins; RNA; Sequestering; Surface tension; Tissue culture; Tissue Culture Techniques; Toxicity
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aaw9157

The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation. Refolding and extraction of proteins from the nucleolus during recovery from stress was Hsp70-dependent. The capacity of the nucleolus to store misfolded proteins was limited, and prolonged stress led to a transition of the nucleolar matrix from liquid-like to solid, with loss of reversibility and dysfunction in quality control. Thus, we suggest that the nucleolus has chaperone-like properties and can promote nuclear protein maintenance under stress.