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Identification of a link between splicing and endoplasmic reticulum proteostasis

ABSTRACT: Identification of a link between splicing and endoplasmic reticulum proteostasis

PROVIDER: PRJNA1068596 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27720239_1.fastq.gz	Fastqsanger.gz
	SRR27720239_2.fastq.gz	Fastqsanger.gz
	SRR27720240_1.fastq.gz	Fastqsanger.gz
	SRR27720240_2.fastq.gz	Fastqsanger.gz
	SRR27720241_1.fastq.gz	Fastqsanger.gz

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Identification of a link between splicing and endoplasmic reticulum proteostasis

Project description:The role of general splicing in endoplasmic reticulum (ER)-proteostasis remains poorly understood. Here, we identify SNRPB, a component of the spliceosome, as a novel regulator of export from the ER. Mechanistically, SNRPB regulates the splicing of components of the ER export machinery, including Sec16A, a regulator of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in intracellular accumulation of type-1 collagen as well as bone defects reminiscent of CCMS. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This indicates that the role of SNRPB in osteogenesis is linked to its effects on ER export. Finally, we show that SNRPB is a target for the unfolded protein response (UPR), which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights SNRPB as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.

2024-10-15 | GSE254122 | GEO

A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways [expression]

Project description:Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

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Phenylhydrazone-based Endoplasmic Reticulum Proteostasis Regulator Compounds with Enhanced Biological Activity

Project description:Phenylhydrazone-based Endoplasmic Reticulum Proteostasis Regulator Compounds with Enhanced Biological Activity

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Phenylhydrazone-based Endoplasmic Reticulum Proteostasis Regulator Compounds with Enhanced Biological Activity

Project description:Pharmacological enhancement of endoplasmic reticulum (ER) proteostasis is an attractive strategy to mitigate pathology linked to etiologically-diverse protein misfolding diseases. However, despite this promise, few compounds have been identified that enhance ER proteostasis through defined mechanisms of action. We previously identified the phenylhydrazone-based compound AA263 as a compound that promotes adaptive ER proteostasis remodeling through mechanisms including activation of the ATF6 signaling arm of the unfolded protein response (UPR). However, the protein target(s) of AA263 and the potential for further development of this class of ER proteostasis regulators had not been previously explored. Here, we employ chemical proteomics to demonstrate that AA263 covalently targets a subset of ER protein disulfide isomerases, revealing a molecular mechanism for the activation of ATF6 afforded by this compound. We then use medicinal chemistry to establish next-generation AA263 analogs showing improved potency and efficacy for ATF6 activation, as compared to the parent compound. Finally, we show that treatment with these AA263 analogs enhances secretory pathway proteostasis to correct the pathologic protein misfolding and trafficking of both a destabilized, disease-associated α1-antitrypsin (A1AT) variant and an epilepsy-associated GABAA receptor variant. These results establish AA263 analogs with enhanced potential for correcting imbalanced ER proteostasis associated with etiologically-diverse protein misfolding disorders

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A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways [ChIP-seq]

2016-12-21 | GSE89344 | GEO

Endoplasmic reticulum proteostasis in senescent cells is a vulnerability to senolytic vanadyl sulfate

Project description:Lifestyles including dietary choices have a major impact on shaping of human physiology and health, including aging. However, the underlying mechanisms remain largely unknown. Here, we use a blood nutrient compound library-based screening approach to demonstrate that vanadyl sulfate (VS), a mineral dietary supplement, selectively induces cell death in senescent cells, thus extends lifespan and ameliorates phenotypes of aging and age-related disorders in vivo. Integrated functional omics strategies including activity-based protein profiling reveal that senescent cells accumulate glutathione disulfide, leading to overall reduced cysteine reactivity of the proteome but elevated cysteine reactivity of proteins that are crucial for endoplasmic reticulum (ER) proteostasis, which licenses VS to effectuate senolysis. VS inactivates reactive cysteines on proteins to form incorrect disulfide bonds, causing aberrant protein misfolding and aggregation that sabotage ER proteostasis, leading to senescent cell death. Our findings uncover a unique vulnerability of senescent cells for therapeutic exploration to treat aging and age-related disorders.

2025-12-15 | GSE284342 | GEO

Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators

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Endoplasmic reticulum proteostasis in senescent cells is a vulnerability to senolytic vanadyl sulfate

Project description:Endoplasmic reticulum proteostasis in senescent cells is a vulnerability to senolytic vanadyl sulfate

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Mutant PDIA3 causes neurodevelopmental impairment by disturbing endoplasmic reticulum proteostasis

Project description:Identification of a disease gene enables the elucidation of the gene function in biological networks. Here we report homozygous c.170G>A (p.Cys57Tyr or C57Y) in protein disulfide isomerase A3 (PDIA3) causing syndromic intellectual disability. PDIA3 catalyzes the formation of disulfide bonds in the endoplasmic reticulum. Experiments in zebrafish embryos showed that PDIA3C57Y is pathogenic, causing developmental problems such as axonal disorganization and skeleton abnormalities. In mammalian models, expression of PDIA3C57Y inhibited axonal growth and impaired synaptic plasticity and memory consolidation. Proteomic and functional analysis revealed that PDIA3C57Y leads to dysregulation of cell adhesion and actin cytoskeleton dynamics associated with altered integrin biogenesis. These alterations were correlated with low catalytic activity of PDIA3C57Y, which also forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. This study shows that the disturbance of the proteostasis network in intellectual disability cases adversely impacts cellular connectivity and neuronal function, constituting a pathogenic pathway to neurodevelopmental impairment.

2021-11-25 | PXD026507 | Pride

XBP1s-Mediated Endoplasmic Reticulum Proteostasis Network Enhancement Can Selectively Improve Folding and Secretion of an Osteogenesis Imperfecta-Causing Collagen-I Variant

Project description:Osteogenesis imperfecta (OI) is most commonly caused by autosomal dominant mutations in genes encoding collagen type-I. Here, we test the hypothesis that modulation of the endoplasmic reticulum (ER) proteostasis network via the unfolded protein response (UPR) can improve the folding and secretion of the lethal osteogenesis imperfecta (OI)-causing G425S a1(I) variant. We show that specific induction of the UPR’s XBP1s transcriptional response enhances G425S a1(I) secretion up to ~300% of basal levels. Notably, the effect is selective – WT a1(I) secretion is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S a1(I). Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S a1(I) patient fibroblasts includes a higher proportion of the mutant a1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions.

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