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

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, misfold...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.aaw9157