Journal
EMBO JOURNAL
Volume 36, Issue 12, Pages 1669-1687Publisher
WILEY
DOI: 10.15252/embj.201695957
Keywords
protein aggregation; protein misfolding; proteostasis; SOD1; stress granules
Categories
Funding
- Max Planck Society
- Alexander von Humboldt Foundation [GRO/1156614 STP-2]
- German Federal Ministry of Research and Education [BMBF 031A359A MaxSynBio]
- DFG Center for Regenerative Therapies (CRTD) in Dresden
- Agence National de la Recherche
- Medical Research Council
- European Union [643417]
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Stress granules (SG) are membrane-less compartments involved in regulating mRNAs during stress. Aberrant forms of SGs have been implicated in age-related diseases, such as amyotrophic lateral sclerosis (ALS), but the molecular events triggering their formation are still unknown. Here, we find that misfolded proteins, such as ALS-linked variants of SOD1, specifically accumulate and aggregate within SGs in human cells. This decreases the dynamics of SGs, changes SG composition, and triggers an aberrant liquid-to-solid transition of in vitro reconstituted compartments. We show that chaperone recruitment prevents the formation of aberrant SGs and promotes SG disassembly when the stress subsides. Moreover, we identify a backup system for SG clearance, which involves transport of aberrant SGs to the aggresome and their degradation by autophagy. Thus, cells employ a system of SG quality control to prevent accumulation of misfolded proteins and maintain the dynamic state of SGs, which may have relevance for ALS and related diseases.
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