BAG2 Condensates Couple Proteostasis to CD8 + T Cell Surveillance
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE326781 | GEO | 2026/04/08
REPOSITORIES: GEO
Similar Datasets
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 µM Tg, 10 mM TMP (in HEK293DAX), or 10 µM 132, 147 or 263 in biological triplicate at 37 ÌC
2016-07-21 | E-GEOD-84636 | biostudies-arrayexpress
Project description:Yuraszeck2010 - Vulnerabilities in the Tau
Network in Tau Pathophysiology
This model is described in the article:
Vulnerabilities in the tau
network and the role of ultrasensitive points in tau
pathophysiology.
Yuraszeck TM, Neveu P,
Rodriguez-Fernandez M, Robinson A, Kosik KS, Doyle FJ 3rd.
PLoS Comput. Biol. 2010; 6(11):
e1000997
Abstract:
The multifactorial nature of disease motivates the use of
systems-level analyses to understand their pathology. We used a
systems biology approach to study tau aggregation, one of the
hallmark features of Alzheimer's disease. A mathematical model
was constructed to capture the current state of knowledge
concerning tau's behavior and interactions in cells. The model
was implemented in silico in the form of ordinary differential
equations. The identifiability of the model was assessed and
parameters were estimated to generate two cellular states: a
population of solutions that corresponds to normal tau
homeostasis and a population of solutions that displays
aggregation-prone behavior. The model of normal tau homeostasis
was robust to perturbations, and disturbances in multiple
processes were required to achieve an aggregation-prone state.
The aggregation-prone state was ultrasensitive to perturbations
in diverse subsets of networks. Tau aggregation requires that
multiple cellular parameters are set coordinately to a set of
values that drive pathological assembly of tau. This model
provides a foundation on which to build and increase our
understanding of the series of events that lead to tau
aggregation and may ultimately be used to identify critical
intervention points that can direct the cell away from tau
aggregation to aid in the treatment of tau-mediated (or
related) aggregation diseases including Alzheimer's.
This model is hosted on
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and identified by:
BIOMD0000000542.
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To the extent possible under law, all copyright and related or
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2024-09-02 | BIOMD0000000542 | BioModels
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.
2016-07-21 | GSE84636 | GEO
Project description:The pathological aggregation of Tau protein into oligomers and fibrils plays a central role in Alzheimer's disease (AD). Here, we explore the biochemical and cellular properties conferred by a unique 19-amino acid intronic peptide found exclusively in the Tau11i isoform. We demonstrate that this intronic peptide mediates robust formation of high molecular weight (HMW) oligomers that resist denaturing and reducing conditions, distinguishing Tau11i from other Tau isoforms lacking this sequence. Tau11i also uniquely forms stable heterodimers with Tau441, suggesting a role in the propagation of Tau pathology. Additionally, the intronic peptide enhances Tau11i’s liquid-liquid phase separation (LLPS), a critical early event associated with pathological aggregation. In vitro assays showed that Tau11i aggregates into β-sheet-rich fibrils more efficiently than other Tau isoforms, significantly facilitating fibril formation and cellular seeding in Tau biosensor cells. Transcriptomic profiling indicated substantial dysregulation in neuronal pathways involving immune response, synaptic function, and metabolism, with Tau11i-expressing neurons closely mirroring the gene expression patterns of AD neurons, particularly the AT8-negative subtype. Furthermore, Tau11i specifically interacts with stress granule-associated RNA-binding proteins, notably PABPC1, implicating it in stress granule dynamics and RNA homeostasis. Collectively, these findings identify the intronic peptide as a critical factor driving Tau11i-specific oligomerization and early-stage molecular alterations associated with Alzheimer's disease, highlighting its potential as a novel therapeutic target distinct from classic Tau pathology.
2025-12-26 | GSE294848 | GEO
Project description:Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here we investigated how the endoplasmic reticulum (ER) quality control system handles β-sheet proteins that were designed de novo to form amyloid-like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER-β) strongly reduces their toxicity. ER-β is retained within the ER in a soluble polymeric state, despite reaching very high concentrations exceeding those of ER-resident molecular chaperones. ER-β is not removed by ER-associated degradation (ERAD) but interferes with ERAD of other proteins. These findings demonstrate a remarkable capacity of the ER to prevent the formation of insoluble β-aggregates and the secretion of potentially toxic protein species. Our results also suggest a generic mechanism by which proteins with exposed β-sheet structure in the ER interfere with proteostasis.
2017-12-13 | GSE98580 | GEO
Project description:Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer’s disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs fro¬m human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.
2020-08-05 | GSE129308 | GEO
Project description:The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation. The unfolded protein response adapts endoplasmic reticulum (ER) proteostasis via stress-responsive transcription factors including XBP1s and ATF6. Here, R. Luke Wiseman and colleagues implement technology for the orthogonal, ligand-dependent activation of XBP1s and/or ATF6 in a single cell. They characterize how XBP1s and/or ATF6 activation impacts ER proteostasis pathway composition and function. Adapted ER environments influence the proteostasis of destabilized protein variants without affecting the endogenous proteome. The work informs the development of proteostasis environment-adapting therapeutics for protein misfolding-related diseases. In order to activate both XBP1s and ATF6 in the same cell, we incorporated DHFR.ATF6 and tet-inducible XBP1s into a HEK293T-REx cell line stably expressing the tet-repressor. The HEK293DYG control cell line expresses tet-inducible eGFP and DHFR.YFP and is used as a control to demonstrate that the addition of doxycycline (dox) and trimethoprim (TMP) do not induce UPR genes. HEK293DYG cells were treated for 12 h with vehicle or 1 μg/mL dox and 10 μM TMP in biological triplicate. Cells were harvested and RNA was extracted using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column digestion using the RNase-free DNase Set (Qiagen). Data from HEK293DYG cells showed no significant overlap in the ligand-treated transcriptomes obtained from HEK293DAX cells.
2013-04-23 | E-GEOD-44950 | biostudies-arrayexpress
Project description:Aberrant protein aggregation jeopardize cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer’s disease (AD) and Huntington’s disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both, the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable to the development of several disorders including HD, without affecting lifespan. This protection was dependent on the activity of the aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modulates the expression of various genes including these which are known as protein homeostasis (proteostasis) regulators such as txt-13, and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.
2023-12-27 | GSE230640 | GEO
Project description:Alzheimer's disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery forming a 710 kDa client-loading complex. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Tau’s aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative disorders.
2022-08-11 | PXD032037 | Pride