scholarly journals Compositional analysis of ALS-linked stress granule-like structures reveals factors and cellular pathways dysregulated by mutant FUS under stress

2021 ◽  
Author(s):  
Haiyan An ◽  
Gioana Litscher ◽  
Wenbin Wei ◽  
Naruaki Watanabe ◽  
Tadafumi Hashimoto ◽  
...  
Keyword(s):  
Stress Responses ◽  
Cellular Response ◽  
Affinity Purification ◽  
Cellular Stress ◽  
Protein Structures ◽  
Protein Translation ◽  
Cellular Stress Response ◽  
Cytoplasmic Rna ◽  
Cellular Pathways ◽  
Stressed Cells

AbstractFormation of cytoplasmic RNA-protein structures called stress granules (SGs) is a highly conserved cellular response to stress. Abnormal metabolism of SGs may contribute to the pathogenesis of (neuro)degenerative diseases such as amyotrophic lateral sclerosis (ALS). Many SG proteins are affected by mutations causative of these conditions, including fused in sarcoma (FUS). Mutant FUS variants have high affinity to SGs and also spontaneously form de novo cytoplasmic RNA granules. Mutant FUS-containing assemblies (mFAs), often called “pathological SGs”, are proposed to play a role in ALS-FUS pathogenesis. However, global structural differences between mFAs and physiological SGs remain largely unknown, therefore it is unclear whether and how mFAs may affect cellular stress responses. Here we used affinity purification to characterise the protein and RNA composition of normal SGs and mFAs purified from stressed cells. Comparison of the SG and mFA proteomes revealed that proteasome subunits and certain nucleocytoplasmic transport factors are depleted from mFAs, whereas translation elongation, mRNA surveillance and splicing factors as well as mitochondrial proteins are enriched in mFAs, as compared to SGs. Validation experiments for a hit from our analysis, a splicing factor hnRNPA3, confirmed its RNA-dependent sequestration into mFAs in cells and into pathological FUS inclusions in a FUS transgenic mouse model. Furthermore, silencing of the Drosophila hnRNPA3 ortholog dramatically enhanced FUS toxicity in transgenic flies. Comparative transcriptomic analysis of SGs and mFAs revealed that mFAs recruit a significantly less diverse spectrum of RNAs, including reduced recruitment of transcripts encoding proteins involved in protein translation, DNA damage response, and apoptotic signalling. However mFAs abnormally sequester certain mRNAs encoding proteins involved in stress signalling cascades. Overall, our study establishes molecular differences between physiological SGs and mFAs and identifies the spectrum of proteins, RNAs and respective cellular pathways affected by mFAs in stressed cells. In conclusion, we show that mFAs are compositionally distinct from SGs and that they cannot fully substitute for SG functions while gaining novel, potentially toxic functions in cellular stress response. Results of our study support a pathogenic role for stress-induced cytoplasmic FUS assemblies in ALS-FUS.

scholarly journals Effect of Combined Stressors on C. elegans Lifespan

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 667-667
Author(s):  
Bradford Hull ◽  
George Sutphin
Keyword(s):  
Heavy Metal ◽  
Stress Response ◽  
Stress Responses ◽  
Cellular Response ◽  
Multiple Stressors ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
C Elegans ◽  
Arsenic Copper ◽  
The Impact

Abstract Cellular stress is a fundamental component of age-associated disease. Cells experience many forms of stress (oxidative, heavy metal, etc.), and as we age the burden of stress and resulting damage increases while our cells’ ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. By understanding how cells respond to stress we aim to slow age-associated deterioration and develop treatment targets for age-associated disease. The majority of past work has focused on understanding responses to individual stressors. In contrast, how pathology and stress responses differ in the presence of multiple stressors is relatively unknown; we investigate that here. We cultured worms on agar plates with different combinations of arsenic, copper, and DTT (which create oxidative/proteotoxic, heavy metal, and endoplasmic reticulum (ER) stress, respectively) at doses that result in 20% lifespan reduction individually and measured the effect on lifespan. We found that arsenic/copper and arsenic/DTT combinations created additive lifespan reductions while the copper/DTT combination created an antagonistic lifespan reduction when compared to controls (p<0.05). This antagonistic toxicity suggests an interaction either between the mechanisms of toxicity or the cellular response to copper and DTT. We are now evaluating the impact of copper and DTT individually and in combination on unfolded protein and heavy metal response pathways to understand the underlying mechanism of the interaction. Additionally, we are continuing to screen stressors to identify combinations that cause non-additive (synergistic or antagonistic) toxicity to build a comprehensive model of the genetic stress response network in C. elegans.

scholarly journals FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1110 ◽  
Author(s):  
Candida Fasano ◽  
Vittoria Disciglio ◽  
Stefania Bertora ◽  
Martina Lepore Signorile ◽  
Cristiano Simone
Keyword(s):  
Stress Response ◽  
Protein Kinase ◽  
Stress Responses ◽  
Target Genes ◽  
Cellular Stress ◽  
Genotoxic Stress ◽  
Cellular Stress Response ◽  
Mitogen Activated Protein Kinase ◽  
Mitochondrial Functions ◽  
Stressed Cells

Cellular stress response is a universal mechanism that ensures the survival or negative selection of cells in challenging conditions. The transcription factor Forkhead box protein O3 (FOXO3a) is a core regulator of cellular homeostasis, stress response, and longevity since it can modulate a variety of stress responses upon nutrient shortage, oxidative stress, hypoxia, heat shock, and DNA damage. FOXO3a activity is regulated by post-translational modifications that drive its shuttling between different cellular compartments, thereby determining its inactivation (cytoplasm) or activation (nucleus and mitochondria). Depending on the stress stimulus and subcellular context, activated FOXO3a can induce specific sets of nuclear genes, including cell cycle inhibitors, pro-apoptotic genes, reactive oxygen species (ROS) scavengers, autophagy effectors, gluconeogenic enzymes, and others. On the other hand, upon glucose restriction, 5′-AMP-activated protein kinase (AMPK) and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -dependent FOXO3a mitochondrial translocation allows the transcription of oxidative phosphorylation (OXPHOS) genes, restoring cellular ATP levels, while in cancer cells, mitochondrial FOXO3a mediates survival upon genotoxic stress induced by chemotherapy. Interestingly, these target genes and their related pathways are diverse and sometimes antagonistic, suggesting that FOXO3a is an adaptable player in the dynamic homeostasis of normal and stressed cells. In this review, we describe the multiple roles of FOXO3a in cellular stress response, with a focus on both its nuclear and mitochondrial functions.

Inhibition of Nonsense Mediated RNA Decay in Hypoxic Cells; Implications for Thalassemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1781-1781
Author(s):  
Lawrence B. Gardner
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Cellular Response ◽  
Globin Gene ◽  
Cellular Stress ◽  
Regulation Of Gene Expression ◽  
Cellular Stress Response ◽  
Rna Decay ◽  
Processing Bodies ◽  
Nonsense Mediated Rna Decay

Abstract Several common β globin gene mutations found in thalassemia are thought to promote rapid degradation of the aberrant mRNA through a specific mechanism termed nonsense mediated RNA decay (NMD). NMD, elicited through mutations leading to premature termination codons, is thought to be responsible not only for the degradation of the β globin PTC 39 mutation, responsible for >90% of thalassemia in Sardinia, but also for the degradation of 30% of all known human mutations and up to 10% of the genome. However, because NMD has been thought of as a constitutive and not a regulated pathway, the potential role of NMD in the dynamic regulation of gene expression has not been well explored. We have determined that NMD is inhibited in hypoxic cells. This hypoxic inhibition of NMD significantly prolongs the half-life of multiple mRNAs degraded by NMD, including the β globin PTC 39 mutation. We have also identified several additional mRNAs whose stabilities are significantly (>2 fold) 1. Increased when Rent1, an RNA helicase necessary for NMD is silenced 2. Decreased when Rent1 is over-expressed and 3. Increased in hypoxic cells when NMD is inhibited. These include the mRNAs that are integral for the cellular response to multiple stresses found in thalassemia, including hypoxic stress. Indeed, we observed that the cellular stress response is augmented when NMD is inhibited. The central component for many cellular stress responses is the phosphorylation of a translation factor, eIF2α. We and others have demonstrated that eIF2α is phosphorylated in hypoxic cells via the kinase PERK. Phosphorylation of eIF2α leads to the suppression of protein synthesis and the translational and transcriptional up-regulation of stress response genes. We hypothesized that phosphorylation of eIF2α was also responsible for the hypoxic inhibition of NMD. Indeed, when we used cells generated from mice in which wild-type eIF2α has been replaced by an eIF2α that cannot be phosphorylated, we found that hypoxic inhibition of NMD did not occur, demonstrating that is eIF2α phosphorylation is necessary for hypoxic inhibition of NMD. Degradation of NMD targets occurs in cytoplasmic processing bodies, which contain many of the enzymes necessary for mRNA catabolism. We noted that a distinct type of mRNA containing body, termed stress bodies, which do not have the capacity for RNA decay, are induced in hypoxic cells. This formation is dependent on PERK phosphorylation of eIF2α. While there are several potential mechanism by which hypoxic phosphorylation of eIF2α could inhibit NMD, our preliminary data suggests a model in which NMD targets are sequestered in cytoplasmic stress granules in hypoxic cells, thus excluding them from cytoplasmic processing bodies. Thus our studies reveal a novel form of gene regulation in hypoxic cells, regulation of NMD via phosphorylation of eIF2α. This finding has potential significance in many disease states, but particularly in thalassemia, where many of the stresses which phosphorylate eIF2α occur, and where the stress response and regulation of mutated β globin mRNAs may be particularly important.

scholarly journals Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 99
Author(s):  
Shweta Devi ◽  
Vijay Kumar ◽  
Sandeep Kumar Singh ◽  
Ashish Kant Dubey ◽  
Jong-Joo Kim
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Neurodegenerative Disorders ◽  
Cell Damage ◽  
Cellular Stress ◽  
Clinical Manifestations ◽  
Cellular Stress Response ◽  
Dramatic Rise ◽  
Cellular Stress Responses

Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

scholarly journals CRISPR-Mediated Endogenous Activation of Fibroin Heavy Chain Gene Triggers Cellular Stress Responses in Bombyx mori Embryonic Cells

Insects ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 552
Author(s):  
Wenbo Hu ◽  
Xiaogang Wang ◽  
Sanyuan Ma ◽  
Zhangchuan Peng ◽  
Yang Cao ◽  
...  
Keyword(s):  
Bombyx Mori ◽  
Heavy Chain ◽  
Stress Responses ◽  
Cellular Stress ◽  
Silk Gland ◽  
Cellular Stress Response ◽  
Molar Ratio ◽  
Chain Gene ◽  
Gland Cells ◽  
Cellular Stress Responses

The silkworm Bombyx mori is an economically important insect, as it is the main producer of silk. Fibroin heavy chain (FibH) gene, encoding the core component of silk protein, is specifically and highly expressed in silk gland cells but not in the other cells. Although the silkworm FibH gene has been well studied in transcriptional regulation, its biological functions in the development of silk gland cells remain elusive. In this study, we constructed a CRISPRa system to activate the endogenous transcription of FibH in Bombyx mori embryonic (BmE) cells, and the mRNA expression of FibH was successfully activated. In addition, we found that FibH expression was increased to a maximum at 60 h after transient transfection of sgRNA/dCas9-VPR at a molar ratio of 9:1. The qRT-PCR analysis showed that the expression levels of cellular stress response-related genes were significantly up-regulated along with activated FibH gene. Moreover, the lyso-tracker red and monodansylcadaverine (MDC) staining assays revealed an apparent appearance of autophagy in FibH-activated BmE cells. Therefore, we conclude that the activation of FibH gene leads to up-regulation of cellular stress responses-related genes in BmE cells, which is essential for understanding silk gland development and the fibroin secretion process in B. mori.

scholarly journals Stressors and Stress Responses in Cystic Fibrosis

2018 ◽  
Vol 5 (1) ◽  
pp. 11-29 ◽  
Author(s):  
Zsuzsa Bebok ◽  
Lianwu Fu
Keyword(s):  
Cystic Fibrosis ◽  
Stress Response ◽  
Stress Responses ◽  
Genetic Disorder ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Bicarbonate Transport ◽  
Persistent Infections ◽  
Human Disorders ◽  
The Unfolded Protein Response

Abstract Cystic fibrosis (CF) is a life-shortening, genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The primary cause of CF is reduced CFTR-mediated chloride and bicarbonate transport, due to mutations in CFTR. However, inflammation and persistent infections influence clinical outcome. Cellular stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), referred to here as cellular stress response pathways (SRPs), contribute to the pathology of human disorders. Multiple studies have indicated activation of SRPs in CF tissues. We review our present understanding of how SRPs are activated in CF and their contribution to pathology. We conclude that reduced CFTR function in CF organs establishes a tissue environment in which internal or external insults activate SRPs. SRPs contribute to CF pathogenesis by reducing CFTR expression, enhancing inflammation with consequent tissue remodeling. Understanding the contribution of SRPs to CF pathogenesis is crucial even in the era of CFTR “modulators” that are designed to potentiate, correct or amplify CFTR function, since there is an urgent need for supportive treatments. Importantly, CF patients with established pathology could benefit from the targeted use of drugs that modulate SRPs to reduce the symptoms.

scholarly journals Environmental Particulate Air Pollution Exposure and the Oxidative Stress Responses: A Brief Review of the Impact on the Organism and Animal Models of Research

2021 ◽  
Author(s):  
Pauline Brendler Goettems Fiorin ◽  
Mirna Stela Ludwig ◽  
Matias Nunes Frizzo ◽  
Thiago Gomes Heck
Keyword(s):  
Oxidative Stress ◽  
Particulate Matter ◽  
Stress Responses ◽  
Cellular Stress ◽  
Size Composition ◽  
Solid Particles ◽  
Cellular Stress Response ◽  
Liquid Droplets ◽  
Shock Proteins ◽  
Ultrafine Particulate Matter

Particulate matter (PM) is a mixture of solid particles and liquid droplets found in the air, and it is one of the most harmful air pollutants. When inhaled, it affects the pulmonary system, cardiovascular systems, and other tissues. The size, composition, and deposition of PM, mainly related to fine and ultrafine particulate matter, are factors that determine the harmful effects of exposure to particles. Among the main effects is the inducer of ROS production, and consequently oxidative tissue damage in target organs and other responses, mediated by inflammatory cytokines and cellular stress response. The main pathway through which particles are potent mediators of oxidative stress is the damage caused to DNA and lipid molecules, whereas the pro-inflammatory response involves an immune response against PM, which in turn, it is related to cell stress responses observed by heat shock proteins (HSPs) expression and release. Thus, the ability of an organism to respond to PM inhalation requires anti-oxidative, anti-inflammatory, and cellular stress defenses that can be impaired in susceptible subjects as people with chronic diseases as diabetes and obesity. In this chapter, we discuss the mechanistic aspects of PM effects on health and present some animal research models in particle inhalation studies.

scholarly journals Cellular Stress Responses in Radiotherapy

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1105 ◽  
Author(s):  
Kim ◽  
Lee ◽  
Seo ◽  
Kim ◽  
Kim ◽  
...  
Keyword(s):  
Stress Responses ◽  
Molecular Mechanisms ◽  
Cellular Stress ◽  
Treatment Strategies ◽  
Cellular Stress Response ◽  
Cytotoxic Effects ◽  
Cancer Cell Death ◽  
Damage Repair ◽  
Cellular Stress Responses ◽  
Radiation Induced

Radiotherapy is one of the major cancer treatment strategies. Exposure to penetrating radiation causes cellular stress, directly or indirectly, due to the generation of reactive oxygen species, DNA damage, and subcellular organelle damage and autophagy. These radiation-induced damage responses cooperatively contribute to cancer cell death, but paradoxically, radiotherapy also causes the activation of damage-repair and survival signaling to alleviate radiation-induced cytotoxic effects in a small percentage of cancer cells, and these activations are responsible for tumor radio-resistance. The present study describes the molecular mechanisms responsible for radiation-induced cellular stress response and radioresistance, and the therapeutic approaches used to overcome radioresistance.

scholarly journals YB-1 Is Important for Late-Stage Embryonic Development, Optimal Cellular Stress Responses, and the Prevention of Premature Senescence

2005 ◽  
Vol 25 (11) ◽  
pp. 4625-4637 ◽  
Author(s):  
Zhi Hong Lu ◽  
Jason T. Books ◽  
Timothy J. Ley
Keyword(s):  
Embryonic Development ◽  
Cell Survival ◽  
Stress Responses ◽  
Cellular Stress ◽  
Cellular Growth ◽  
Cellular Stress Response ◽  
Cdk Inhibitors ◽  
Nucleic Acid Binding ◽  
Small Interfering Rnas ◽  
Nucleic Acid Binding Proteins

ABSTRACT Proteins containing “cold shock” domains belong to the most evolutionarily conserved family of nucleic acid-binding proteins known among bacteria, plants, and animals. One of these proteins, YB-1, is widely expressed throughout development and has been implicated as a cell survival factor that regulates the transcription and/or translation of many cellular growth and death-related genes. For these reasons, YB-1 deficiency has been predicted to be incompatible with cell survival. However, the majority of YB-1 −/− embryos develop normally up to embryonic day 13.5 (E13.5). After E13.5, YB-1 −/− embryos exhibit severe growth retardation and progressive mortality, revealing a nonredundant role of YB-1 in late embryonic development. Fibroblasts derived from YB-1 −/− embryos displayed a normal rate of protein synthesis and minimal alterations in the transcriptome and proteome but demonstrated reduced abilities to respond to oxidative, genotoxic, and oncogene-induced stresses. YB-1 −/− cells under oxidative stress expressed high levels of the G1-specific CDK inhibitors p16Ink4a and p21Cip1 and senesced prematurely; this defect was corrected by knocking down CDK inhibitor levels with specific small interfering RNAs. These data suggest that YB-1 normally represses the transcription of CDK inhibitors, making it an important component of the cellular stress response signaling pathway.

scholarly journals The mammalian decidual cell evolved from a cellular stress response

2018 ◽  
Author(s):  
Eric M. Erkenbrack ◽  
Jamie D. Maziarz ◽  
Oliver W. Griffith ◽  
Cong Liang ◽  
Arun R. Chavan ◽  
...  
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Cellular Stress ◽  
Cell Types ◽  
Monodelphis Domestica ◽  
Cellular Stress Response ◽  
General Mechanism ◽  
Decidual Cell ◽  
Cell Type

AbstractAmong animal species, cell types vary greatly in terms of number and kind. The broad range of number of cell types among species suggests that cell type origination is a significant source of evolutionary novelty. The molecular mechanisms giving rise to novel cell types, however, are poorly understood. Here we show that a novel cell type of eutherian mammals, the decidual stromal cell (DSC), evolved by rewiring an ancestral cellular stress response. We isolated the precursor cell type of DSCs, endometrial stromal fibroblasts (ESFs), from the opossum Monodelphis domestica. We show that, in opossum ESF, the majority of decidual core regulatory genes respond to decidualizing signals, but do not regulate decidual effector genes. Rather, in opossum ESF, decidual transcription factors function in apoptotic and oxidative stress response. We propose that the rewiring of cellular stress responses could be a general mechanism for the evolution of novel cell types.

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