Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Gao, Chao; Gu, Jinge; Zhang, Hong; Jiang, Kai; Tang, Lijie; Liu, Ren; Zhang, Li; Zhang, Pengfei; Liu, Cong; Dai, Bin; Song, Jie

doi:10.1016/j.celrep.2022.111086

Cited by 22 publications

(24 citation statements)

References 63 publications

(71 reference statements)

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“…Here, we found that NaCl and CsCl could elicit FUS cytoplasmic redistribution in a certain concentration range (0.15–0.5 M for NaCl, 0.3–1 M for CsCl), of which 0.3 M was the strongest. It was demonstrated that the salt-stimulated cytoplasmic shuttling of FUS was dependent on the concentration of salt . Currently, FUS cytoplasmic accumulation is observed in some ALS and FTD patients, and investigating stress conditions that can induce FUS nuclear export may help to understand its homeostasis mechanism.…”

Section: Resultsmentioning

confidence: 99%

“…It was demonstrated that the salt-stimulated cytoplasmic shuttling of FUS was dependent on the concentration of salt. 14 Currently, FUS cytoplasmic accumulation is observed in some ALS and FTD patients, and investigating stress conditions that can induce FUS nuclear export may help to understand its homeostasis mechanism.…”

Section: Different Concentrations Of Salt Induce Phase Separation Of ...mentioning

confidence: 99%

“…In addition, the stimulation of these cationic salts on FUS phase separation in living cells is not only due to the hydrophilicity of ions, but also other influencing factors, such as the effect of NH 4 Cl on cell pH; excessive Ca 2+ may cause mitochondrial dysfunctions, aberrant production of reactive oxygen species; 45 and even cell contraction caused by osmotic pressure to enlarge protein concentration. 14 In this paper, these ions were evaluated comprehensively in living cells and the possible rules were summarized.…”

Section: Cation Salt Effects On the Phase Behavior Of Fusmentioning

confidence: 99%

See 2 more Smart Citations

Live-Cell Imaging to Resolve Salt-Induced Liquid–Liquid Phase Separation of FUS Protein by Dye Self-Labeling

Zhang,

Xu,

Yan

et al. 2023

Chemical & Biomedical Imaging

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The aggregation of fusion in sarcoma (FUS) in the cytoplasm and nucleus is a pathological feature of Amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD). Genetic mutations, abnormal protein synthesis, environmental stress, and aging have all been implicated as causative factors in this process. Salt ions are essential to many physiological processes in the body, and the imbalance of them is an important environmental stress factor in cells. However, their effect on liquid−liquid phase separation (LLPS) of FUS proteins in living cells is not well understood. Here, we map the various salt-induced LLPS of FUS in living cells by genetically coding and self-labeling FUS with organic dyes. The brightness and photostability of the dyes enable long-term imaging to track the mechanism of the assembly and disappearance of FUS phase separation. The FUS protein showed a better phase separation tendency under 0.3 M salt stimulation, and there was a large amount of FUS shuttling from the nucleus to the cytoplasm. At this concentration, various salt solutions displayed different effects on the phase separation of FUS protein, following the Hofmeister effects. We further observed that the assembly of FUS droplets underwent a process of rapid formation of small droplets, plateaus, and mutual fusion. Strikingly, The CsCl-stimulated FUS droplets were not completely reversible after washing, and some solid-like granules remained in the nucleus. Taken together, these results help broaden our understanding of the LLPS of FUS proteins in cellular stress responses.

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Section: Resultsmentioning

confidence: 99%

Section: Different Concentrations Of Salt Induce Phase Separation Of ...mentioning

confidence: 99%

Section: Cation Salt Effects On the Phase Behavior Of Fusmentioning

confidence: 99%

See 1 more Smart Citation

Live-Cell Imaging to Resolve Salt-Induced Liquid–Liquid Phase Separation of FUS Protein by Dye Self-Labeling

Zhang,

Xu,

Yan

et al. 2023

Chemical & Biomedical Imaging

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“…[ 41 ] For example, it has been reported that FUS and TDP‐43 granules can be generated in both the nucleus and cytoplasm under weak hyperosmotic stress. [ 42 ] Furthermore, the formation and dynamics of SGs are devoted to circumventing stress and maintaining homeostasis, which can influence RNA localization, translation, and degradation. It was confirmed that the SG association of long noncoding RNAs was reduced and transported by nuclear import receptors (NIRs), which can equilibrate the localization of SGs.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐Induced FUS–circTBC1D14 Stress Granules Promote Autophagy in TNBC

Liu

et al. 2023

Advanced Science

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Triple‐negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is suggested to be associated with hypoxia. This study is the first to identify a novel circular RNA (circRNA), circTBC1D14, whose expression is significantly upregulated in TNBC. The authors confirm that high circTBC1D14 expression is associated with a poor prognosis in patients with breast cancer. circTBC1D14‐associated mass spectrometry and RNA‐binding protein‐related bioinformatics strategies indicate that FUS can interact with circTBC1D14, which can bind to the downstream flanking sequence of circTBC1D14 to induce cyclization. FUS is an essential biomarker associated with stress granules (SGs), and the authors find that hypoxic conditions can induce FUS–circTBC1D14‐associated SG formation in the cytoplasm after modification by protein PRMT1. Subsequently, circTBC1D14 increases the stability of PRMT1 by inhibiting its K48‐regulated polyubiquitination, leading to the upregulation of PRMT1 expression. In addition, FUS–circTBC1D14 SGs can initiate a cascade of SG‐linked proteins to recognize and control the elimination of SGs by recruiting LAMP1 and enhancing lysosome‐associated autophagy flux, thus contributing to the maintenance of cellular homeostasis and promoting tumor progression in TNBC. Overall, these findings reveal that circTBC1D14 is a potential prognostic indicator that can serve as a therapeutic target for TNBC treatment.

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“…We demonstrate an important role of chloride ions in NaCl in modulating ferroptosis. Hyperosmotic stress is involved in diseases and NaCl is frequently utilized to generate hyperosmotic stress 45–47 . A recent study using high NaCl to introduce hyperosmotic stress on cells showed that ferroptosis is promoted under hypertonicity 48 .…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis is determined by chloride ions

Huang

Dai

Wang

et al. 2023

Preprint

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Ferroptosis has emerged as a deliberate type of programmed cell death that manifests marked importance ubiquitously in health and diseases. However, after a decade of research, the mechanisms of ferroptosis execution remain unclear. Here we identify chloride ions (Cl-) as essential determinants of ferroptosis. Water homeostasis manipulated by extracellular solute concentration disrupts ferroptotic cell death. Hyperosmotic stress attenuates ferroptosis and endues cells with high lipid peroxidation. Analyses of a fluorescent chloride probe show that Cl- fluxes into the cytoplasm during ferroptosis, substantiating a role for Cl- to drive water flow. Depletion of extracellular chloride ions ([Cl-]o) from culture media congruously confers resistance to ferroptosis. The [Cl-]o-depleted ferroptotic cells fall into two populations: cells with low lipid peroxidation; cells with high lipid peroxidation but not cell swelling or cell rupture. Contrarily, solitary [Cl-]o overload is sufficient to elicit ferroptosis without canonical ferroptosis inducers. Further experiments show that ferroptotic cells depolarize and [Cl-]o is positively correlated with this process. Membrane depolarization upregulates the level of lipid peroxidation, suggesting that membrane potential may be a universal mechanism governing ferroptosis. Together, our findings reveal that ferroptosis is determined by chloride ions.

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Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Cited by 22 publications

References 63 publications

Live-Cell Imaging to Resolve Salt-Induced Liquid–Liquid Phase Separation of FUS Protein by Dye Self-Labeling

Live-Cell Imaging to Resolve Salt-Induced Liquid–Liquid Phase Separation of FUS Protein by Dye Self-Labeling

Hypoxia‐Induced FUS–circTBC1D14 Stress Granules Promote Autophagy in TNBC

Ferroptosis is determined by chloride ions

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