An Aberrant Phase Transition of Stress Granules Triggered by Misfolded Protein and Prevented by Chaperone Function

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2017 Apr 6

PMID 28377462

Citations 238

Authors

Daniel Mateju

Titus M Franzmann

Avinash Patel

Andrii Kopach

Edgar E Boczek

Shovamayee Maharana

Hyun O Lee

Serena Carra

Anthony A Hyman

Simon Alberti

Affiliations

Soon will be listed here.

Abstract

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 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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