Hematopoietic Stem Cells Preferentially Traffic Misfolded Proteins to Aggresomes and Depend on Aggrephagy to Maintain Protein Homeostasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA848853 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19645500_1.fastq.gz | Fastqsanger.gz | |||
| SRR19645500_2.fastq.gz | Fastqsanger.gz | |||
| SRR19645501_1.fastq.gz | Fastqsanger.gz | |||
| SRR19645501_2.fastq.gz | Fastqsanger.gz | |||
| SRR19645502_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 84 |
Similar Datasets
Project description:Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown. Here we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner, and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness, but become dysregulated during aging.
2023-03-21 | GSE206051 | GEO
Project description:Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown. Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.
| S-EPMC10164413 | biostudies-literature
Project description:Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. In Saccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that the FES1 transcript undergoes unique 3' alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally non-stressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus. 4 strains (WT, fes1Î, fes1ÎS, fes1ÎL) were sequenced in triplicates from independent RNA isolations.
2016-02-29 | E-GEOD-78136 | biostudies-arrayexpress
Project description:Cells maintain proteostasis by selectively recognizing and targeting misfolded proteins for degradation. In Saccharomyces cerevisiae, the Hsp70 nucleotide exchange factor Fes1 is essential for the degradation of chaperone-associated misfolded proteins by the ubiquitin-proteasome system. Here we show that the FES1 transcript undergoes unique 3' alternative splicing that results in two equally active isoforms with alternative C-termini, Fes1L and Fes1S. Fes1L is actively targeted to the nucleus and represents the first identified nuclear Hsp70 nucleotide exchange factor. In contrast, Fes1S localizes to the cytosol and is essential to maintain proteostasis. In the absence of Fes1S, the heat-shock response is constitutively induced at normally non-stressful conditions. Moreover, cells display severe growth defects when elevated temperatures, amino acid analogues or the ectopic expression of misfolded proteins, induce protein misfolding. Importantly, misfolded proteins are not targeted for degradation by the ubiquitin-proteasome system. These observations support the notion that cytosolic Fes1S maintains proteostasis by supporting the removal of toxic misfolded proteins by proteasomal degradation. This study provides key findings for the understanding of the organization of protein quality control mechanisms in the cytosol and nucleus.
2016-02-29 | GSE78136 | GEO
Project description:Translational control is a widespread mode of gene regulation in organisms ranging from bacteria to mammals. Computational models posit that translational control of protein expression during elongation is exerted through a traffic jam of multiple ribosomes at ribosome pause sites on mRNAs. Yet neither the in vivo frequency of ribosome traffic jams nor the contribution of such traffic jams to protein expression has been measured in any organism. Here we show that upon starvation for single amino acids in the bacterium Escherichia coli, ribosome traffic jams are pervasive across the transcriptome, but they occur at only a subset of codons cognate to the limiting amino acid, and their severity is determined by the translation efficiency of mRNAs. Surprisingly, a computational model based on the observed traffic jams at ribosome pause sites is quantitatively inconsistent with measured protein synthesis rates. By comparison, a model incorporating abortion of protein synthesis at ribosome pause sites in addition to ribosome traffic jams predicts protein synthesis rate with higher accuracy. Consistent with the latter model, a significant fraction of the nascent polypeptides at ribosome pause sites is degraded through the activity of the transfer-messenger RNA during amino acid starvation in E. coli. Our work provides a minimal, experimentally-constrained model for predicting protein expression from ribosome dynamics, and it suggests the existence of a trade-off between the cellular translational capacity and the processivity of protein synthesis in vivo. 6 samples for ribosome profiling and 5 samples for total mRNA profiling
2014-05-15 | E-GEOD-51052 | biostudies-arrayexpress
Project description:Mutations in the gene encoding surfactant protein C (SFTPC) have been linked to interstitial lung disease in children and adults. Expression of the index mutation, SP-Cdeltaexon4, in transiently transfected cells and type II cells of transgenic mice resulted in misfolding of the proprotein, activation of ER stress pathways and cytotoxicity. In the current study we show that stably transfected cells adapted to chronic ER stress imposed by constitutive expression of SP-Cdeltaexon4 via an NF-kB-dependent pathway. However, infection of cells expressing SP-Cdeltaexon4 with respiratory syncytial virus resulted in significantly enhanced cytotoxicity associated with accumulation of the mutant proprotein, pronounced activation of the unfolded protein response and cell death. Adaptation to chronic ER stress imposed by misfolded SP-C was associated with increased susceptibility to viral-induced cell death. The wide variability in the age of onset of ILD in patients with SFTPC mutations may be related to exposure to an environmental insult that ultimately overwhelms the homeostatic, cytoprotective response. Keywords: transcriptional response to misfolded protein due to genetic modification
2006-03-20 | GSE2980 | GEO
Project description:Seeds in the experimental group were exposed to 48 h of traffic noise recorded in a highly congested area of the city, while the control group was kept under background white noise. While traffic noise exposure made no effects on seed germination, noise treatment significantly increased the growth of seedlings by 39%. By employing RNA-sequencing profiling, we further investigated the noise-induced molecular changes in the A. thaliana seedlings. The aberrant expression of 690 genes was detected in the noise-exposed seedlings.
2023-10-15 | GSE240794 | GEO
Project description:Traffic-related air pollution has been a common public health problem, which is associated with central nervous system dysfunction according to large-scale epidemiological studies. Current studies are mostly limited to artificial laboratory exposure environments and specific genetic mechanisms remain unclear. In the spring, we transported the aged mice from the laboratory to the 1-meter-high dry platform in the campus and tunnel at the same time. Aged mice were exposed form 7 am to 7 pm each day for 2, 4 and 12 weeks, respectively. Compared with the control group (in campus), the memory function of mice in the exposure group (in tunnel) was significantly impaired in Morris water maze. Traffic-related air pollution exposure increased the number of activated microglia in the hippocampal DG and CA1, and up-regulated mRNA expression of inflammatory factors IL-18, IL-1β, IL-6 and TNF-α. By screening the risk genes of Alzheimer’s disease, we found the mRNA and protein levels of ABCA7 were down-regulated and those of PYK2 were up-regulated in the dorsolateral prefrontal cortex (dPFC) of aged mice. The DNA methylation ratio increased in four CpG sites of abca7 promoter region and decreased in one CpG site of pyk2 promoter region, which were consistent with the altered expression of ABCA7 and PYK2. In conclusion, exposure to the real traffic environment impaired memory function and enhanced neuroinflammation of aged mice, which could be relevant to the alteration of ABCA7 and PYK2 gene expression. Our work provided a new and promising understanding of the pathological mechanisms of cognitive impairment caused by traffic-related air pollution.
2022-07-16 | GSE208109 | GEO
Project description:Cohesin-mediated loop extrusion is blocked at specific cis-elements, including CTCF sites, producing patterns of loops and domain boundaries along chromosomes. Here, we explore such cis-elements, and their role in gene regulation. We find that transcription termination sites of active genes form cohesin- and RNA polymerase II-dependent domain boundaries that do not accumulate cohesin. At these sites, cohesin is first stalled and then rapidly unloaded. Start sites of transcriptionally active genes form cohesin-bound boundaries, as shown before, but are cohesin-independent. Together with cohesin loading possibly at enhancers, these sites create a pattern of cohesin traffic that guides enhancer-promoter interactions. Disturbing this traffic pattern, by removing CTCF, renders cells sensitive to knock-out of genes involved in transcription initiation, such as the SAGA complexes, and RNA processing such DEAD/H-Box RNA helicases. Without CTCF, these factors are less efficiently recruited to active promoters.
2022-08-15 | GSE180657 | GEO
Project description:Stem cells have long been regarded as a potential origin of cancer. But cancers could also arise from mutated, differentiated cells that reacquire stem cell properties. Here, in mice harboring conditional oncogenic and lineage tracing alleles, we show that cancers develop from Prom1+ (CD133) cells, only in organs where these cells operate as stem cells. Allograft assays demonstrated that these cancers are not necessarily propagated by Prom1+ cancer stem cells, even when initiated in Prom1-lineages that maintain the normal organ. Normal and transformed Prom1+ stem cells in our mice, maintained the gastric mucosa and gastric adenocarcinomas, respectively. Comparison of these cells identified the latent sodium channel gene Nalcn as a novel gastric cancer suppressor that regulates the differentiation of stomach stem cell daughters. Our data provide new evidence that cancers are initiated preferentially within stem cells, and important insights into how these cells are deregulated to initiate and maintain cancers Prom1 conditional mutants in mice that develped tumors and normal from cells various tissues in mice are compared. 117 samples were studied.
2013-09-01 | E-GEOD-40634 | biostudies-arrayexpress