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A Nucleolar Mechanism Suppresses Organismal Proteostasis by Modulating Signaling of the TGF-β/ERK Axis

ABSTRACT: A Nucleolar Mechanism Suppresses Organismal Proteostasis by Modulating Signaling of the TGF-β/ERK Axis

PROVIDER: PRJNA1040230 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26827508.fastq.gz	Fastqsanger.gz
	SRR26827509.fastq.gz	Fastqsanger.gz
	SRR26827510.fastq.gz	Fastqsanger.gz
	SRR26827511.fastq.gz	Fastqsanger.gz
	SRR26827512.fastq.gz	Fastqsanger.gz

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A Nucleolar Mechanism Suppresses Organismal Proteostasis by Modulating Signaling of the TGF-β/ERK Axis

Project description:The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, aging-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late onset neurodegenerative disorders, such as Alzheimer’s disease (AD). Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet, the identification of proteostasis-regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1-NOL-56 complex, protects model nematodes from proteotoxicity of the AD-causing, Aβ peptide. This mechanism promotes proteostasis across tissues by modulating the activity of TGF-β signaling and by enhancing proteasome activity. Our findings point at new research avenues toward the development of proteostasis-promoting therapies for neurodegenerative maladies.

2024-10-02 | GSE247737 | GEO

Epigenetic regulation of global proteostasis dynamics by RBBP5 ensures mammalian organismal health

Project description:Proteostasis is vital for cellular health, with disruptions leading to pathologies including aging, neurodegeneration and metabolic disorders. Traditionally, proteotoxic stress responses were studied as acute reactions to various noxious factors; however, recent evidence reveals that many stress-response genes exhibit ~12-hour ultradian rhythms under physiological conditions in mammals. These rhythms, driven by an XBP1s-dependent 12h oscillator, are crucial for managing proteostasis. By exploring the chromatin landscape of the murine 12h hepatic oscillator, we identified RBBP5, a key subunit of the COMPASS complex, as an essential epigenetic regulator of proteostasis. RBBP5 is indispensable for regulating both the hepatic 12h oscillator and transcriptional response to acute proteotoxic stress, acting as a co-activator for master proteostasis transcription factor XBP1s. RBBP5 ablation leads to increased sensitivity to proteotoxic stress, chronic inflammation, and hepatic steatosis in mice, along with impaired autophagy and reduced cell survival in vitro. In humans, lower RBBP5 expression is associated with dampened adaptive stress-response gene expression and hepatic steatosis. Our findings establish RBBP5 as a critical regulator of proteostasis, essential for maintaining mammalian organismal health.

2024-10-10 | GSE276159 | GEO

Epigenetic regulation of global proteostasis dynamics by RBBP5 ensures mammalian organismal health

Project description:Epigenetic regulation of global proteostasis dynamics by RBBP5 ensures mammalian organismal health

| PRJNA1155207 | ENA

Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer

Project description:Aberrant activation of the ERK signaling pathway triggers a protective anticancer response characterized by stable growth arrest and activation of tumor suppressors called cellular senescence. Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that activate the ERK pathway. Pancreatic intraepithelial neoplasia of low degree display high levels of phospho-ERK consistent with senescence acting as a barrier for malignant transformation. However, advanced lesions downregulate phospho-ERK levels circumventing the senescence barrier. Restoring ERK hyperactivation in PDAC using an activated allele of the kinase RAF, leads to ERK-dependent growth arrest with senescence biomarkers. Phosphoproteomics analysis of ERK-dependent senescence in PDAC revealed a decrease in several nucleolar phosphoproteins suggesting that high levels of ERK lead to senescence via nucleolar stress. Consistent with this explanation, ERK-dependent senescent cells displayed intranucleolar foci containing RNA polymerase I. Combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response of PDAC cells. The drug cocktail FOLFIRINOX, currently the best treatment for PDAC, also triggered ERK hyperactivation and nucleolar stress characterized by nucleolar foci, solid amyloid aggregates and a decrease in 5.8S and 28S rRNAs. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

2024-06-10 | PXD032257 | Pride

Regulation of germline proteostasis by insulin/IGF-1 signaling

Project description:Gametogenesis involves active protein synthesis and heavily relies on proteostasis. How animals regulate germline proteostasis at the organismal level is poorly understood. Our recent work in C. elegans indicates that germline development requires coordinated activities between insulin/IGF-1 signaling and HSF-1, the transcriptional activator of many molecular chaperones in stress and physiological conditions. In this study, we show that HSF-1 is important for germline proteostasis at ambient temperature. Depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, declines in fecundity and gamete quality. Reduced insulin/IGF-1 signaling confers germ cells' tolerance to limited protein folding capacity and proteotoxic stress by lowering ribosome biogenesis and translation. Interestingly, regulation of germline proteostasis by insulin/IGF-1 signaling occurs non-cell-autonomously. Our data suggest that insulin/IGF-1 signaling controls the expression of the evolutionarily conserved intestinal peptide transporter PEPT-1 via its downstream transcription factor FOXO/DAF-16, therefore allowing dietary proteins to be incorporated into an amino acid pool that fuels ribosomal biogenesis and translation in the germline. We propose that this pathway plays a critical role in regulating germline protein synthesis, which must be at balance with HSF-1-dependent protein folding to achieve proteostasis in gametogenesis.

2024-05-20 | GSE256186 | GEO

FuHsi Maintains Nucleolar Structure and Initiates Nucleolar Biogenesis.

Project description:FuHsi Maintains Nucleolar Structure and Initiates Nucleolar Biogenesis.

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FuHsi Maintains Nucleolar Structure and Initiates Nucleolar Biogenesis.

Project description:We identify a previously uncharacterized human nucleoli-enriched protein FuHsi. FuHsi is an essential nucleolar molecule that regulates nucleolar biogenesis and mouse development.

2024-08-02 | GSE253977 | GEO

organismal metagenomes

Project description:organismal metagenomes Raw sequence reads

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organismal metagenomes

Project description:organismal metagenomes Raw sequence reads

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Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

Project description:Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. Comprehensive transcriptome analysis was employed to validate the capacity of three prioritized compounds to remodel the ER proteostasis environment, and to assess the prefential activation of ATF6 transcriptional targets relative to targets of the IRE1/XBP1s and PERK arms of the UPR. HEK293T-Rex and HEK293-DAX cells were treated for 6 hr with vehicle (DMSO), 1 ÂµM Tg, 10 mM TMP (in HEK293DAX), or 10 ÂµM 132, 147 or 263 in biological triplicate at 37 ÌC

2016-07-21 | E-GEOD-84636 | biostudies-arrayexpress

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