Stress granule formation inhibits stress-induced apoptosis by selectively sequestering executioner caspases

Fujikawa, Daichi; Nakamura, Takanori; Yoshioka, Daisuke; Li, Zizheng; Moriizumi, Hisashi; Taguchi, Mari; Tokai‐Nishizumi, Noriko; Kozuka‐Hata, Hiroko; Oyama, Masaaki; Takekawa, Mutsuhiro

doi:10.1016/j.cub.2023.04.012

Cited by 26 publications

(12 citation statements)

References 56 publications

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“…Upon persistent activation, however, the induced expression of CHOP in mammals and XRP1 in Drosophila complicates the outcomes, as their transcriptional targets not only promote stress recovery but also can induce cell death ( 18, 39–43 ). Similarly, SGs can serve a transient protective function by limiting translation of a subset of mRNAs and confining caspases, ( 12, 14, 28 ), but their persistent presence can also promote neurodegeneration ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

“…SGs are membrane-less liquid-liquid phase-separated ribonucleoprotein organelles in the cytoplasm ( 12, 13 ). SGs can serve a transient protective function ( 14 ), followed by their dissolution once homeostasis is restored ( 15, 16 ). Under chronic stress, however, persistent SGs accumulate additional markers such as p62 (also known as Sequestosome-1 in mammals or Ref(2)p in Drosophila) and may serve as seeds for the aggregation of proteins related to neurodegenerative diseases ( 13 ).…”

Section: Main Textmentioning

confidence: 99%

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Visual impairment cell non-autonomously dysregulates brain-wide proteostasis

Shekhar,

Wert,

Krämer

2023

Preprint

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Loss of hearing or vision has been identified as a significant risk factor for dementia but underlying molecular mechanisms are unknown. In different Drosophila models of blindness, we observe non-autonomous induction of stress granules in the brain and their reversal upon restoration of vision. Stress granules include cytosolic condensates of p62, ATF4 and XRP1. This cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets during cellular stress. Cytosolic condensates of p62 and ATF4 were also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate conservation of the link between loss of sensory input and dysregulation of stress responses critical for protein quality control in the brain.

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Section: Discussionmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Visual impairment cell non-autonomously dysregulates brain-wide proteostasis

Shekhar,

Wert,

Krämer

2023

Preprint

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“…Various pathogens and cancer cells activate stress kinases leading to the formation of SGs as an attempt to maintain cellular homeostasis. In addition, stress granules sequester components of apoptosis (executioner caspases 3/7) [ 203 ], pyroptosis [ 9 ] and necroptosis [ 40 , 204 ] to favor pro-survival pathways. Sustained exposure to stress triggers one or the other forms of the RCD pathway.…”

Section: Discussionmentioning

confidence: 99%

Cellular Stress: Modulator of Regulated Cell Death

Lamichhane,

Samir

2023

Biology

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Cellular stress response activates a complex program of an adaptive response called integrated stress response (ISR) that can allow a cell to survive in the presence of stressors. ISR reprograms gene expression to increase the transcription and translation of stress response genes while repressing the translation of most proteins to reduce the metabolic burden. In some cases, ISR activation can lead to the assembly of a cytoplasmic membraneless compartment called stress granules (SGs). ISR and SGs can inhibit apoptosis, pyroptosis, and necroptosis, suggesting that they guard against uncontrolled regulated cell death (RCD) to promote organismal homeostasis. However, ISR and SGs also allow cancer cells to survive in stressful environments, including hypoxia and during chemotherapy. Therefore, there is a great need to understand the molecular mechanism of the crosstalk between ISR and RCD. This is an active area of research and is expected to be relevant to a range of human diseases. In this review, we provided an overview of the interplay between different cellular stress responses and RCD pathways and their modulation in health and disease.

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“…eIF4G), non-translating mRNAs and many RNA-binding proteins (RBPs) such as Ras-GTPase-activating protein-binding proteins 1 and 2 (G3BP1/2) and T-cell intracellular antigen 1 (TIA-1). In addition, SGs include many other proteins involved in diverse cellular functions ( 2 , 3 ) . However, despite recent progress, a complete list of SG components is still lacking.…”

Section: Abbreviationsmentioning

confidence: 99%

Formation of the NLRP3 inflammasome inhibits stress granule assembly by multiple mechanisms

Yoshioka,

Nakamura,

Kubota

et al. 2024

The Journal of Biochemistry

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Proper regulation of cellular response to environmental stress is crucial for maintaining biological homeostasis and is achieved by the balance between cell death processes, such as the formation of the pyroptosis-inducing NLRP3 inflammasome, and pro-survival processes, such as stress granule (SG) assembly. However, the functional interplay between these two stress-responsive organelles remains elusive. Here, we identified DHX33, a viral RNA sensor for the NLRP3 inflammasome, as a SG component, and the SG-nucleating protein G3BP as an NLRP3 inflammasome component. We also found that a decrease in intracellular potassium (K+) concentration, a key common step in NLRP3 inflammasome activation, markedly inhibited SG assembly. Therefore, when macrophages are exposed to stress stimuli with the potential to induce both SGs and the NLRP3 inflammasome, such as cytoplasmic poly(I:C) stimulation, they preferentially form the NLRP3 inflammasome but avoid SG assembly by sequestering G3BP into the inflammasome and by inducing a reduction in intracellular K+ levels. Thus, under such conditions, DHX33 is primarily utilized as a viral RNA sensor for the inflammasome. Our data reveal the functional crosstalk between NLRP3 inflammasome-mediated pyroptosis and SG-mediated cell survival pathways, and delineate a molecular mechanism that regulates cell-fate decisions and anti-viral innate immunity under stress.

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Stress granule formation inhibits stress-induced apoptosis by selectively sequestering executioner caspases

Cited by 26 publications

References 56 publications

Visual impairment cell non-autonomously dysregulates brain-wide proteostasis

Visual impairment cell non-autonomously dysregulates brain-wide proteostasis

Cellular Stress: Modulator of Regulated Cell Death

Formation of the NLRP3 inflammasome inhibits stress granule assembly by multiple mechanisms

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