Getting stress out of stressed‐out stress granules

Siwach, Pratibha; Kaganovich, Daniel

doi:10.15252/embj.201797176

Cited by 7 publications

(7 citation statements)

References 12 publications

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“…It has been proposed that the aggregation of TDP‐43 proteins alters the cell's response to stress by two pathways; disrupting mRNA sorting in the cells, required for proper processing and decay, due to massive fibrillary aggregates, and by causing stress granules persistence even after stress resolution. Recently, it was demonstrated that the first steps of ALS pathology are a result of protein misfolding and aggregation that influence the structural properties of stress granules . Specifically, this study has shown that over time misfolded proteins, such as ALS‐linked variants of SOD1, taint the composition of normal stress granules, which in turn leads to the assembly of stress granules with altered and abnormal physical properties.…”

Section: Mrnas Stress Granules and Diseasementioning

confidence: 84%

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mRNPs meet stress granules

Sheinberger

Shav‐Tal

2017

FEBS Letters

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Edited by Wilhelm JustStress granules are cytoplasmic structures that form in response to a variety of cellular stresses. They contain mRNAs and many proteins including numerous types of RNA-binding proteins, and have been studied in connection to major cellular events such as protein synthesis as well as disease. Despite the well-known fact that stress granules encapsulate mRNPs (mRNA-protein complexes), much of the research has naturally focused on the protein components of stress granules. The specific details of mRNP entry into and exit from stress granules and the functional reasons for these dynamics are not fully understood. Here, we review studies that have concentrated on the aspects of mRNP accumulation in stress granules and produced quantitative data concerning mRNP/stress granule interactions.

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Section: Mrnas Stress Granules and Diseasementioning

confidence: 84%

“…Stress granules are not cytoplasmic precipitates, and in fact have the physical properties of liquid droplets, which form by a liquid–liquid phase separation process . It has therefore been recently suggested that the physiological roles of stress granules are connected to their material and biophysical properties .…”

Section: The Formation Of Stress Granulesmentioning

confidence: 99%

mRNPs meet stress granules

Sheinberger

Shav‐Tal

2017

FEBS Letters

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“…Next, we asked whether the inclusions formed by Sod1 were localized in stress granules (SG), and costained cells with an antibody against G3BP, an established marker of SGs [ 23 , 24 ]. We found that none of the inclusions formed by the hSod1 mutants tested in this study colocalized with G3BP (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is still unclear whether Sod1 inclusions are toxic, and additional studies using different model systems will be instrumental to address this. Recent studies have connected protein inclusions with SGs [ 24 ]. Using spinal cord motor neurons [ 40 ] or HeLa cells as models [ 23 ], it was shown that inclusions formed by G93A and A4V Sod1 mutants colocalize with G3BP, an established marker of SGs.…”

Section: Discussionmentioning

confidence: 99%

Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models

et al. 2017

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Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide. Our results showed that only 30% of cells transfected with A4VSod1 showed no inclusions while for the other Sod1 mutants tested (L38V, G93A and G93C), this percentage was at least 70%. In addition, we found that 10% of cells transfected with A4VSod1 displayed more than five inclusions per cell and that A4V and G93A Sod1 formed inclusions more rapidly than L38V and G93C Sod1. Expression of WTSod1 significantly decreased the intracellular oxidation levels in comparison with expression of fALS Sod1 mutants, suggesting the mutations induce a functional impairment. All fALS mutations impaired nuclear localization of Sod1, which is important for maintaining genomic stability. Consistently, expression of WTSod1, but not of fALS Sod1 mutants, reduced DNA damage, as measured by the comet assay. Altogether, our study sheds light into the effects of fALS Sod1 mutations on inclusion formation, dynamics, and localization as well as on antioxidant response, opening novel avenues for investigating the role of fALS Sod1 mutations in pathogenesis.

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“…Even more intriguing, CHX-resistant granules were present already at the rescue. This data suggests that the FUS/TIA-R-positive SGs have switched from a liquid-to-solid phase, evolving toward stable SG-derived inclusions ( Siwach and Kaganovich, 2017 ).…”

Section: Discussionmentioning

confidence: 94%

A Deletion of the Nuclear Localization Signal Domain in the Fus Protein Induces Stable Post-stress Cytoplasmic Inclusions in SH-SY5Y Cells

2021

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Mutations in Fused-in-Sarcoma (FUS) gene involving the nuclear localization signal (NLS) domain lead to juvenile-onset Amyotrophic Lateral Sclerosis (ALS). The mutant protein mislocalizes to the cytoplasm, incorporating it into Stress Granules (SG). Whether SGs are the first step to the formation of stable FUS-containing aggregates is still unclear. In this work, we used acute and chronic stress paradigms to study the SG dynamics in a human SH-SY5Y neuroblastoma cell line carrying a deletion of the NLS domain of the FUS protein (homozygous: ΔNLS–/–; heterozygous: ΔNLS+/–). Wild-type (WT) cells served as controls. We evaluated the subcellular localization of the mutant protein through immunoblot and immunofluorescence, in basal conditions and after acute stress and chronic stress with sodium arsenite (NaAsO2). Cells were monitored for up to 24 h after rescue. FUS was expressed in both nucleus and cytoplasm in the ΔNLS+/– cells, whereas it was primarily cytoplasmic in the ΔNLS–/–. Acute NaAsO2 exposure induced SGs: at rescue,>90% of ΔNLS cells showed abundant FUS-containing if compared to less than 5% of the WT cells. The proportion of FUS-positive SGs remained 15–20% at 24 h in mutant cells. Cycloheximide did not abolish the long-lasting SGs in mutant cells. Chronic exposure to NaAsO2 did not induce significant SGs formation. A wealth of research has demonstrated that ALS-associated FUS mutations at the C-terminus facilitate the incorporation of the mutant protein into SGs. We have shown here that mutant FUS-containing SGs tend to fail to dissolve after stress, facilitating a liquid-to-solid phase transition. The FUS-containing inclusions seen in the dying motor neurons might therefore directly derive from SGs. This might represent an attractive target for future innovative therapies.

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Getting stress out of stressed‐out stress granules

Cited by 7 publications

References 12 publications

mRNPs meet stress granules

mRNPs meet stress granules

Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models

A Deletion of the Nuclear Localization Signal Domain in the Fus Protein Induces Stable Post-stress Cytoplasmic Inclusions in SH-SY5Y Cells

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