An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function

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 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.

miRNA targeting and alternative splicing in the stress response – events hosted by membrane-less compartments

“…Even in evolutionarily distant organisms, for example, plants, yeast, worms, insects and mammals, stress causes the transient formation of SGs, which are linked to the inhibition of translation (Anderson et al, 2015;Buchan and Parker, 2009;Gilks et al, 2004;Guil et al, 2006;Kedersha et al, 2005;Lavut and Raveh, 2012;Mateju et al, 2017;Molliex et al, 2015). SGs contain stalled translation preinitiation complexes, which consist of mRNAs, translation initiation factors, ribosomal subunits and numerous other RNA-binding proteins that regulate mRNA functions (Buchan and Parker, 2009;Kayali et al, 2005).…”

“…SGs contain stalled translation preinitiation complexes, which consist of mRNAs, translation initiation factors, ribosomal subunits and numerous other RNA-binding proteins that regulate mRNA functions (Buchan and Parker, 2009;Kayali et al, 2005). Induced by stress, SGs are very dynamic and continuously exchange RNAs and proteins with the cytoplasm, and their formation can be promoted or impaired by the overexpression and/or depletion of multiple factors (Anderson et al, 2015;Buchan and Parker, 2009;Kroschwald et al, 2015;Mahboubi and Stochaj, 2014;Mateju et al, 2017).…”

“…As a physical chemical phenomenon, the formation of phase-separated compartments is exquisitely sensitive to changes in environmental conditions. This could be, in part, due to changes in cellular salt and/or proton concentration, as a result of stress through a change in temperature, pH, or osmosis, or due to certain intrinsic molecular changes (Hyman et al, 2014;Jain and Parker, 2013;Kroschwald et al, 2015;Mateju et al, 2017;Wu et al, 2011). Intrinsically disordered sequences, such as LCDs, have been linked to protein-protein, protein-DNA and protein-RNA interactions; moreover, multiple post-translational modifications of disordered sequences can modulate their RNA-binding activity, subcellular localization, folding and self-association (Calabretta and Richard, 2015).…”

“…This hypothesis was confirmed experimentally for the LCDcontaining RNA-binding proteins fused in sarcoma (FUS) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), both of which are linked to human diseases. Moreover, misfolded proteins, such as ALS-linked variants of superoxide dismutase 1 (SOD1), can specifically accumulate and aggregate with SGs, which influences their composition and dynamics and triggers an aberrant liquid-tosolid transition (Mateju et al, 2017). Importantly, pathogenic ALScausing mutations in FUS are sufficient to inhibit miRNA biogenesis (Eitan and Hornstein, 2016;Emde et al, 2015).…”

“…1). These compartments are formed through phase-separation of RNAbinding proteins that contain low-complexity sequence domains (LCDs) Hyman et al, 2014;Mateju et al, 2017). These proteins are intrinsically disordered, which makes them impossible to crystalize Uversky, 2016).…”