Problems arising during translation of mRNAs lead to ribosome stalling and collisions that trigger a series of quality control events. However, the global cellular response to ribosome collisions has ...not been explored. Here, we uncover a function for ribosome collisions in signal transduction. Using translation elongation inhibitors and general cellular stress conditions, including amino acid starvation and UV irradiation, we show that ribosome collisions activate the stress-activated protein kinase (SAPK) and GCN2-mediated stress response pathways. We show that the MAPKKK ZAK functions as the sentinel for ribosome collisions and is required for immediate early activation of both SAPK (p38/JNK) and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that although ZAK generally associates with elongating ribosomes on polysomal mRNAs, it specifically auto-phosphorylates on the minimal unit of colliding ribosomes, the disome. Together, these results provide molecular insights into how perturbation of translational homeostasis regulates cell fate.
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•Ribosome collisions trigger the ribotoxic stress response•Ribosome collisions activate the GCN2-mediated integrated stress response•The MAPKKK ZAK⍺ functions as a sentinel for colliding ribosomes
Cellular stress, such as amino acid starvation and UV irradiation, causes widespread ribosome collisions. Colliding ribosomes serve as a platform that recruits ZAK⍺ and triggers two inter-related but distinct signaling pathways—the ribotoxic stress response and the integrated stress response—to regulate cell fate decisions.
Autophagy is an intracellular recycling process that degrades harmful molecules and enables survival during starvation, with implications for diseases including dementia, cancer and atherosclerosis. ...Previous studies demonstrate how a limited number of transcription factors (TFs) can increase autophagy. However, this knowledge has not resulted in translation into therapy, thus, to gain understanding of more suitable targets, we utilized a systems biology approach. We induced autophagy by amino acid starvation and mTOR inhibition in HeLa, HEK 293 and SH-SY5Y cells and measured temporal gene expression using RNA-seq. We observed 456 differentially expressed genes due to starvation and 285 genes due to mTOR inhibition (P
< 0.05 in every cell line). Pathway analyses implicated Alzheimer's and Parkinson's diseases (P
≤ 0.024 in SH-SY5Y and HeLa) and amyotrophic lateral sclerosis (ALS, P
< 0.05 in mTOR inhibition experiments). Differential expression of the Senataxin (SETX) target gene set was predicted to activate multiple neurodegenerative pathways (P
≤ 0.04). In the SH-SY5Y cells of neuronal origin, the E2F transcription family was predicted to activate Alzheimer's disease pathway (P
≤ 0.0065). These exploratory analyses suggest that SETX and E2F may mediate transcriptional regulation of autophagy and further investigations into their possible role in neuro-degeneration are warranted.
Although the circadian liver clock is entrained by the feeding cycle, factors such as food volume and starvation interval are poorly understood. Per2::Luc knock-in mice were given two meals per day ...with different food volume sizes and/or with different intervals of starvation between two mealtimes with the total food volume per day fixed at 3.6 g (80 food pellets, ∼75% of free feeding) per mouse. The bioluminescence rhythm in the liver produced a unimodal peak but not bimodal peak under the regimen of two meals per day over 14-15 days. Peak Per2 expression occurred concurrently with the mealtime of the larger food volume, when the first and second meal were given as different food volume ratios under a 12 h feeding interval. When an equal volume of food was given under different starvation interval (8 h:16 h), the peak of the Per2 rhythm was close to peak by mealtime after long starvation (16 h). When food volumes for each mealtime were changed under 8 h:16 h, the peak rhythm was influenced by combined factors of food volume and starvation interval. Food intake after the 16-h starvation caused a significant increase in liver Per2, Dec1, and Bmal1 gene expression compared with food intake after the 8-h starvation with 8 h:16 h feeding intervals. In conclusion, the present results clearly demonstrate that food-induced entrainment of the liver clock is dependent on both food volume and the starvation interval between two meals. Therefore, normal feeding habits may help to maintain normal clock function in the liver organ.
CRF-like diuretic hormone receptor (CRF/DHR), also known as DH44R in insects, are G-protein coupled receptors (GPCRs) that play a role in regulating osmotic balance in various insect species. These ...receptors have the potential to be targeted for the development of insecticides. However, our understanding of the role of DHR genes in aphids, including Rhopalosiphum padi, a major wheat pest, is currently limited. In this study, we isolated and characterized two R. padi DHRs (RpDHR1 and RpDHR2). The expression levels of RpDHR1 increased after starvation and were restored after re-feeding. The expression levels of RpDHR1 gene decreased significantly 24 h after injection of dsRNA targeting the gene. Knockdown of RpDHR1 increased aphid mortality under starvation conditions (24, 36, 48 and 60 h). Under starvation and desiccation condition, the aphid mortality decreased after knockdown of RpDHR1. This is the first study to report the role of DHR genes in the starvation and desiccation response of aphids. The results suggest that RpDHR1 is involved in the resistance of R. padi to starvation and dehydration, making it a potential target for insecticide development. Novel insecticides could be created by utilizing DHR agonists to disrupt the physiological processes of insect pests.
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•Two DH44R genes were identified in Rhopalosiphum padi.•Starvation and desiccation the expression of RpDHR1, but do not affect RpDHR2.•R. padi adults significantly increased water content after knockdown of the RpDHR1.•Novel insecticides could be developed by targeting RpDHR.
Aquatic animals, such as the marine mussel, Mytilus coruscus, are regularly subjected to starvation due to conditions of food scarcity brought about by environmental change. Silent mating type ...information regulation 2 homolog 1 (sirt1) is triggered during animal starvation and participates in inflammation and stress responses. However, the function of sirt1 in Mytilus remains unknown; thus, exploring the effects of sirt1 will improve the understanding of the resistance of Mytilus to starvation. In this study, Mytilus coruscus were fasted for 9 days and treated with 20 μM resveratrol. The results indicated that sitr1 mRNA expression levels in the gonads and gills of mussels increased significantly after 3 days of starvation and significantly decreased after 9 days of starvation. 20 μM resveratrol significantly up-regulated sirt1 expression in the gonads and gills of mussels starved for 9 days. The condition factor and gonadal index considerably decreased in mussels under starvation stress. The activities of antioxidants SOD, CAT, GSH, GPX, and AKP were elevated after fasting for 3 days, but were reduced after starvation for 9 days, accompanied by histopathological damage in the gills and gonads. Resveratrol alleviates histological damage caused by starvation stress by enhancing antioxidant activity and reducing MDA production. Additionally, resveratrol decreased the mRNA expression levels of tlr4, myd88, and nfkb and increased the mRNA expression levels of ampk, foxo, and gadd45. Overall, the results suggest that resveratrol-induced sirt1 expression exerts a protective effect on mussels risking starvation by regulating TLR4/NFκB and AMPK/FOXO signaling pathways. This study might give us fresh insight into the effects of sirt1 on the response to starvation stress in mussels.
•Starvation stress induces a temporary increase in the antioxidant capacity in mussels.•Prolonged starvation stress induced oxidative damage in mussels.•Resveratrol alleviates starvation stress induced histological damage via enhancing the antioxidant ability of mussels.•Resveratrol protects starvation stressed mussels by regulating sirt1-mediated TLR4/NFκB and AMPK/FOXO signaling pathways.
Ataxin-2 is a cytoplasmic protein, product of the ATXN2 gene, whose deficiency leads to obesity, while its gain-of-function leads to neural atrophy. Ataxin-2 affects RNA homeostasis, but its effects ...are unclear. Here, immunofluorescence analysis suggested that ataxin-2 associates with 48S pre-initiation components at stress granules in neurons and mouse embryonic fibroblasts, but is not essential for stress granule formation. Coimmunoprecipitation analysis showed associations of ataxin-2 with initiation factors, which were concentrated at monosome fractions of polysome gradients like ataxin-2, unlike its known interactor PABP. Mouse embryonic fibroblasts lacking ataxin-2 showed increased phosphorylation of translation modulators 4E-BP1 and ribosomal protein S6 through the PI3K-mTOR pathways. Indeed, human neuroblastoma cells after trophic deprivation showed a strong induction of ATXN2 transcript via mTOR inhibition. Our results support the notion that ataxin-2 is a nutritional stress-inducible modulator of mRNA translation at the pre-initiation complex.
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•Ataxin-2 transcript is induced by starvation via mTOR signals.•Its deficiency increases mTOR/PI3K phosphorylation signals controlling translation.•The protein localizes and immunoprecipitates with translation preinitiation factors.•It sediments with 40S ribosomal subunits, unlike its interactor PABP.•Its absence during cell stress does not prevent stress granule formation.
Nonstructural carbohydrates (NSCs) facilitate the adaptation of trees to drought stress. There have been a large number of studies exploring NSC changes in individual plant species and individual ...organ under drought and showed different trends; however, an understanding of the universal pattern of the plant NSCs responses to drought, particularly to drought duration, is still lacking. Here, we compiled data from 47 experimental studies on 52 tree species and conducted a meta‐analysis to evaluate the responses of soluble sugars, starch, and TNSC (total nonstructural carbohydrates including both soluble sugars and starch) concentrations in different tree organs (leaf, stem, and root) to drought intensity and duration. We found that starch in all organs decreased and soluble sugars in leaf increased with prolonged experiment time, and the changes in soluble sugars in all organs were stronger under severe drought than under slight‐to‐moderate drought. Under slight‐to‐moderate drought, the NSC content of each organ varied with time, while with the extension of the drought duration, the NSCs gradually approached the control value (no drought stress); this trend remained in the late drought, which means that trees activated physiological regulation processes to increase carbon storage and reduce the risks of carbon starvation. In contrast, long‐term severe drought could lead to a net loss of carbohydrates, especially in the root, implying that prolonged severe drought could lead to NSC depletion in the whole plant. As prolonged drought duration has occurred in and is projected for many regions, this paper could shed light into studies on how trees respond and adapt extending drought duration through nonstructural carbon production, transportation, and reallocation.
Under slight‐to‐moderate drought, the NSC content of each organ varied with time, while with the extension of the drought duration, the NSCs gradually approached the control value (no drought stress); this trend remained in the late drought, which means that trees activated physiological regulation processes to increase carbon storage and reduce the risks of carbon starvation. In contrast, long‐term severe drought could lead to a net loss of carbohydrates, especially in the root, implying that prolonged severe drought could lead to NSC depletion in the whole plant.
Nitrogen is an important nutrient in alcoholic fermentation because its starvation affects both fermentation kinetics and the formation of yeast metabolites. In most alcoholic fermentations, yeasts ...have to ferment in nitrogen-starved conditions, which requires modifications of cell functions to maintain a high sugar flux and enable cell survival for long periods in stressful conditions. In this review, we present an overview of our current understanding of the responses of the wine yeast Saccharomyces cerevisiae to variations of nitrogen availability. Adaptation to nitrogen starvation involves changes in the activity of signaling pathways such as target of rapamycin (TOR) and nitrogen catabolite repression (NCR), which are important for the remodeling of gene expression and the establishment of stress responses. Upon starvation, protein degradation pathways involving autophagy and the proteasome play a major role in nitrogen recycling and the adjustment of cellular activity. Recent progress in the understanding of the role of these mechanisms should enable advances in fermentation management and the design of novel targets for the selection or improvement of yeast strains.
Autophagy in animal development Allen, Elizabeth A; Baehrecke, Eric H
Cell death and differentiation,
03/2020, Letnik:
27, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Macroautophagy (autophagy) delivers intracellular constituents to the lysosome to promote catabolism. During development in multiple organisms, autophagy mediates various cellular processes, ...including survival during starvation, programmed cell death, phagocytosis, organelle elimination, and miRNA regulation. Our current understanding of autophagy has been enhanced by developmental biology research during the last quarter of a century. Through experiments that focus on animal development, fundamental mechanisms that control autophagy and that contribute to disease were elucidated. Studies in embryos revealed specific autophagy molecules that mediate the removal of paternally derived mitochondria, and identified autophagy components that clear protein aggregates during development. Importantly, defects in mtDNA inheritance, or removal of paternal mtDNA via mitochondrial autophagy, can contribute to mitochondrial-associated disease. In addition, impairment of the clearance of protein aggregates by autophagy underlies neurodegenerative diseases. Experiments in multiple organisms also reveal conserved mechanisms of tissue remodeling that rely on the cooperation between autophagy and apoptosis to clear cell corpses, and defects in autophagy and apoptotic cell clearance can contribute to inflammation and autoimmunity. Here we provide an overview of key developmental processes that are mediated by autophagy in multiple animals.
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