共查询到20条相似文献,搜索用时 15 毫秒
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In yeast the GCN2 kinase mediates translational control ofGCN4 by phosphorylating the subunit of eIF-2 in response to extracellular amino acid limitation. Although phosphorylation of eIF-2 has been shown to inhibit global protein synthesis, amino acid starvation results in a specific activation effect onGCN4 mRNA translation. Under the same conditions, translation of other mRNAs appears only slightly affected. The mechanism responsible for the observed selectivity of the GCN2 kinase is not clear. Here, we present genetic evidence that suggests that locally restricted action of the GCN2 kinase facilitatesGCN4-specific translational regulation. 相似文献
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Brent M. Bijonowski Qin Fu Xuegang Yuan Jerome Irianto Yan Li Samuel C. Grant Teng Ma 《Biotechnology and bioengineering》2020,117(10):3136-3149
Protein homeostasis is critical for cellular function, as loss of homeostasis is attributed to aging and the accumulation of unwanted proteins. Human mesenchymal stem cells (MSCs) have shown promising therapeutic potential due to their impressive abilities to secrete inflammatory modulators, angiogenic, and regenerative cytokines. However, there exists the problem of human MSC expansion with compromised therapeutic quality. Duringin vitro expansion, human MSCs are plated on stiff plastics and undergo culture adaptation, which results in aberrant proliferation, shifts in metabolism, and decreased autophagic activity. It has previously been shown that three-dimensional (3D) aggregation can reverse some of these alterations by heightening autophagy and recovering the metabolic state back to a naïve phenotype. To further understand the proteostasis in human MSC culture, this study investigated the effects of 3D aggregation on the human MSC proteome to determine the specific pathways altered by aggregation. The 3D aggregates and 2D cultures of human MSCs derived from bone marrow (bMSC) and adipose tissue (ASC) were analyzed along with differentiated human dermal fibroblasts (FB). The proteomics analysis showed the elevated eukaryotic initiation factor 2 pathway and the upregulated activity of the integrated stress response (ISR) in 3D aggregates. Specific protein quantification further determined that bMSC and ASC responded to ISR, while FB did not. 3D aggregation significantly increased the ischemic survival of bMSCs and ASCs. Perturbation of ISR with small molecules salubrinal and GSK2606414 resulted in differential responses of bMSC, ASC, and FB. This study indicates that aggregation-based preconditioning culture holds the potential for improving the therapeutic efficacy of expanded human MSCs via the establishment of ISR and homeostasis. 相似文献
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Danni Jin Sheree A. Wek Nathan T. Kudlapur William A. Cantara Marina Bakhtina Ronald C. Wek Karin Musier-Forsyth 《The Journal of biological chemistry》2021,297(4)
Aminoacyl-tRNA synthetases (ARSs) catalyze the charging of specific amino acids onto cognate tRNAs, an essential process for protein synthesis. Mutations in ARSs are frequently associated with a variety of human diseases. The human EPRS1 gene encodes a bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) with two catalytic cores and appended domains that contribute to nontranslational functions. In this study, we report compound heterozygous mutations in EPRS1, which lead to amino acid substitutions P14R and E205G in two patients with diabetes and bone diseases. While neither mutation affects tRNA binding or association of EPRS with the multisynthetase complex, E205G in the glutamyl-tRNA synthetase (ERS) region of EPRS is defective in amino acid activation and tRNAGlu charging. The P14R mutation induces a conformational change and altered tRNA charging kinetics in vitro. We propose that the altered catalytic activity and conformational changes in the EPRS variants sensitize patient cells to stress, triggering an increased integrated stress response (ISR) that diminishes cell viability. Indeed, patient-derived cells expressing the compound heterozygous EPRS show heightened induction of the ISR, suggestive of disruptions in protein homeostasis. These results have important implications for understanding ARS-associated human disease mechanisms and development of new therapeutics. 相似文献
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Recent results have identified a diversity of small RNAs in a wide range of organisms. In this work, we demonstrate that Saccharomyces cerevisiae contains a small RNA population consisting primarily of tRNA halves and rRNA fragments. Both 5′ and 3′ fragments of tRNAs are detectable by Northern blot analysis, suggesting a process of endonucleolytic cleavage. tRNA and rRNA fragment production in yeast is most pronounced during oxidative stress conditions, especially during entry into stationary phase. Similar tRNA fragments are also observed in human cell lines and in plants during oxidative stress. These results demonstrate that tRNA cleavage is a conserved aspect of the response to oxidative stress. 相似文献
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Katarzyna Mnich Izabela Koryga Karolina Pakos-Zebrucka Melissa Thomas Susan E. Logue Leif A. Eriksson Adrienne M. Gorman Afshin Samali 《Journal of cellular and molecular medicine》2021,25(18):8809-8820
Stress-induced apoptosis is mediated primarily through the intrinsic pathway that involves caspase-9. We previously reported that in caspase-9-deficient cells, a protein complex containing ATG5 and Fas-associated death domain (FADD) facilitated caspase-8 activation and cell death in response to endoplasmic reticulum (ER) stress. Here, we investigated whether this complex could be activated by other forms of cell stress. We show that diverse stress stimuli, including etoposide, brefeldin A and paclitaxel, as well as heat stress and gamma-irradiation, caused formation of a complex containing ATG5-ATG12, FADD and caspase-8 leading to activation of downstream caspases in caspase-9-deficient cells. We termed this complex the ‘stressosome’. However, in these cells, only ER stress and heat shock led to stressosome-dependent cell death. Using in silico molecular modelling, we propose the structure of the stressosome complex, with FADD acting as an adaptor protein, interacting with pro-caspase-8 through their respective death effector domains (DEDs) and interacting with ATG5-ATG12 through its death domain (DD). This suggests that the complex could be regulated by cellular FADD-like interleukin-1β-converting enzyme–inhibitory protein (cFLIPL), which was confirmed experimentally. This study provides strong evidence for an alternative mechanism of caspase-8 activation involving the stressosome complex. 相似文献
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J. Schultner A. S. Kitaysky G. W. Gabrielsen S. A. Hatch C. Bech 《Proceedings. Biological sciences / The Royal Society》2013,280(1771)
Life-history strategies describe that ‘slow’- in contrast to ‘fast’-living species allocate resources cautiously towards reproduction to enhance survival. Recent evidence suggests that variation in strategies exists not only among species but also among populations of the same species. Here, we examined the effect of experimentally induced stress on resource allocation of breeding seabirds in two populations with contrasting life-history strategies: slow-living Pacific and fast-living Atlantic black-legged kittiwakes. We tested the hypothesis that reproductive responses in kittiwakes under stress reflect their life-history strategies. We predicted that in response to stress, Pacific kittiwakes reduce investment in reproduction compared with Atlantic kittiwakes. We exposed chick-rearing kittiwakes to a short-term (3-day) period of increased exogenous corticosterone (CORT), a hormone that is released during food shortages. We examined changes in baseline CORT levels, parental care and effects on offspring. We found that kittiwakes from the two populations invested differently in offspring when facing stress. In response to elevated CORT, Pacific kittiwakes reduced nest attendance and deserted offspring more readily than Atlantic kittiwakes. We observed lower chick growth, a higher stress response in offspring and lower reproductive success in response to CORT implantation in Pacific kittiwakes, whereas the opposite occurred in the Atlantic. Our findings support the hypothesis that life-history strategies predict short-term responses of individuals to stress within a species. We conclude that behaviour and physiology under stress are consistent with trade-off priorities as predicted by life-history theory. We encourage future studies to consider the pivotal role of life-history strategies when interpreting inter-population differences of animal responses to stressful environmental events. 相似文献
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Mei Zheng Xingbei Liu Jingchen Lin Xinye Liu Zhouying Wang Mingming Xin Yingyin Yao Huiru Peng Dao‐Xiu Zhou Zhongfu Ni Qixin Sun Zhaorong Hu 《The Plant journal : for cell and molecular biology》2019,97(3):587-602
Excess soluble salts in soil are harmful to the growth and development of most plants. Evidence is emerging that the plant cell wall is involved in sensing and responding to salt stress, but the underlying mechanisms are not well understood. We reveal that the histone acetyltransferase General control non‐repressed protein 5 (GCN5) is required for the maintenance of cell wall integrity and salt stress tolerance. The levels of GCN5 mRNA are increased in response to salt stress. The gcn5 mutants exhibited severe growth inhibition and defects in cell wall integrity under salt stress conditions. Combining RNA sequencing and chromatin immunoprecipitation assays, we identified the chitinase‐like gene CTL1, polygalacturonase involved in expansion‐3 (PGX3) and MYB domain protein‐54 (MYB54) as direct targets of GCN5. Acetylation of H3K9 and H3K14 mediated by GCN5 is associated with activation of CTL1, PGX3 and MYB54 under salt stress. Moreover, constitutive expression of CTL1 in the gcn5 mutant restores salt tolerance and cell wall integrity. In addition, the expression of the wheat TaGCN5 gene in Arabidopsis gcn5 mutant plants complemented the salt tolerance and cell wall integrity phenotypes, suggesting that GCN5‐mediated salt tolerance is conserved between Arabidopsis and wheat. Taken together, our data indicate that GCN5 plays a key role in the preservation of salt tolerance via versatile regulation in plants. 相似文献
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Arabidopsis nonresponding to oxylipins locus NOXY7 encodes a yeast GCN1 homolog that mediates noncanonical translation regulation and stress adaptation 下载免费PDF全文
Yovanny Izquierdo Pablo Benito Bran López Ruth Marcos Tomás Cascón Mats Hamberg Carmen Castresana 《Plant, cell & environment》2018,41(6):1438-1452
Stress adaptation and translational regulation was studied using noxy7 (nonresponding to oxylipins7) from a series of Arabidopsis thaliana mutants. We identified the noxy7 mutation in At1g64790, which encodes a homolog of the yeast translational regulator General Control Nonderepressible1 (GCN1) that activates the GCN2 kinase; GCN2 in turn phosphorylates the α subunit of the translation initiation factor eIF2. This regulatory circuit is conserved in yeast and mammals, in which phosphorylated eIF2α (P‐eIF2α) facilitates stress adaptation by inhibiting protein synthesis. In phenotypic and de novo protein synthesis studies with Arabidopsis mutants, we found that NOXY7/GCN1 and GCN2 mediate P‐eIF2α formation and adaptation to amino acid deprivation; however, P‐eIF2α formation is not linked to general protein synthesis arrest. Additional evidence suggested that NOXY7/GCN1 but not GCN2 regulates adaptation to mitochondrial dysfunction, high boron concentration, and activation of plant immunity to infection by Pseudomonas syringae pv tomato (Pst). In these responses, NOXY7/GCN1 acts with GCN20 to regulate translation in a noncanonical pathway independently of GCN2 and P‐eIF2α. These results show the lesser functional relevance of GCN2 and P‐eIF2α in plants relative to other eukaryotes and highlight the prominent role of NOXY7/GCN1 and GCN20 in regulation of translation and stress adaptation in plants. 相似文献