Zeolitic Imidazolate Frameworks Activate Endosomal Toll-like Receptors and Potentiate Immunogenicity of SARS-CoV-2 Spike Protein Trimer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246178 | GEO | 2024/03/13
REPOSITORIES: GEO
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Project description:Zeolitic Imidazolate Frameworks Activate Endosomal Toll-like Receptors and Potentiate Immunogenicity of SARS-CoV-2 Spike Protein Trimer
| PRJNA1031982 | ENA
Project description:The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer’s disease risk: the APOE4 allele increases risk while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in humans and mice. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.
2024-06-05 | GSE234711 | GEO
Project description:In 12-month-old APOE targeted-replacement mice, we report that overall differences in gene expression were the most prominent when comparing the protective APOE2 to the other two alleles, with fewer differences found when comparing the risk-neutral APOE3 and disease-promoting APOE4 alleles. When compared with either APOE3 or APOE4, differential expression of genes within the endosomal pathways is a prominent feature of APOE2 expression in the brain. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.
2023-07-31 | GSE188267 | GEO
Project description:The NuA4 histone acetyltransferase (HAT) complex is required for gene specific regulation, cell cycle progression, and DNA repair. Dissection of the 13-subunit complex reveals that the Eaf7 subunit bridges Eaf5 with Eaf3, a H3K36me3-binding chromodomain protein, and this Eaf5/7/3 trimer is anchored to NuA4 through Eaf5. This subcomplex represents a functional module as deletions of these genes create similar phenotypes and a large portion of the trimer exists in a native form outside the NuA4 complex. Gene-specific and genome-wide location analyses indicate that the Eaf5/7/3 trimer correlates with transcription activity and is enriched over the coding region. In agreement with a role in transcription elongation, the Eaf5/7/3 trimer interacts with phosphorylated RNA polymerase II and helps its progression. In addition, loss of Eaf5/7/3 partially suppresses intragenic cryptic transcription arising in set2 mutant cells, suggesting a role in nucleosome destabilization. Such a function is supported by genetic interactions with the FACT histone chaperone. On the other hand, loss of the trimer leads to an increase of replication-independent histone exchange over the coding region of transcribed genes. Taken together, these results lead to a model where Eaf5/7/3 associates with elongating polymerase and is involved in the disassembly of nucleosomes in front of the polymerase, but also in their recycling in its wake.
2014-09-25 | E-MTAB-1780 | biostudies-arrayexpress
Project description:The Wnt pathway, which controls crucial steps of the development and differentiation programs, has been proposed to influence lipid storage and homeostasis. In this paper, using an unbiased strategy based on high content genome-wide RNAi screens that monitored lipid distribution and amounts, we find that Wnt3a regulates cellular cholesterol. We show that Wnt3a stimulates the production of lipid droplets, and that this stimulation strictly depends on endocytosed, LDL-derived cholesterol and on functional early and late endosomes. We also show that Wnt signaling itself controls cholesterol endocytosis and flux along the endosomal pathway, which in turn modulates cellular lipid homeostasis. These results underscore the importance of endosome functions for LD formation and reveal a previously unknown cellular program controlling lipid storage and endosome transport under the control of Wnt signaling.
2015-06-20 | E-MTAB-2872 | biostudies-arrayexpress
Project description:Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer’s disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD’s cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell derived neurons (hiPSC-Ns) to test this hypothesis. In SORL1 deficient (SORL1KO) cell lines, we map the trafficking of the glutamate receptor and the BDNF neurotrophic receptor, two kinds of transmembrane proteins that depend on endosomal recycling and that are linked to AD pathophysiology. We find that as with APP, SORL1 is required for efficient endosomal recycling of the glutamate receptor AMPA1 (GLUA1) and the BDNF receptor Tropomyosin-related kinase B (TRKB). Next, we used cell lines engineered to overexpress SORL1 and find that increased SORL1 expression enhances recycling for APP and GLUA1. Finally, we performed an unbiased transcriptomic screen of SORL1KO neurons and the data further support SORL1’s role in endosomal recycling. We observed altered expression networks that regulate cell surface trafficking and neurotrophic signaling. Collectively, and together with other recent observations, these findings suggest that SORL1 is a key and broad regulator of retromer-dependent endosomal recycling in neurons, a conclusion that has both pathogenic and therapeutic implications.
2022-03-01 | GSE180793 | GEO
Project description:Through substitution mapping studies, we previously identified that a <330kb region from a rat strain with no renal pathology (the Lewis rat), which when introgressed onto the genetic background of a rat with renal disease (the Dahl Salt-sensitive (S) rat), caused an increase rather than the expected decrease in proteinuria. The purpose of this study was to prioritize a candidate gene and further delineate the mechanism underlying the observed increased in proteinuria. A higher level of proteinuria independent of dietary salt was observed in the congenic rat at a very young age (50-52 day old). The critical congenic segment was further mapped to <42.5kb containing a single candidate gene, rififylin. Rififylin was expressed 1.59 fold higher in the congenic strain compared with S. Overexpression of rififylin is known to delay recycling of endosomes. Renal transcriptome analysis indicated that Atp1a1 one of the most highly differentially expressed genes. Atp1a1 was 5.33 fold higher in the congenic strain compared with S. The protein product of Atp1a1, the alpha subunit of Na+K+ATPase, was also significantly higher in the endosomes of proximal tubules from the congenic strain compared with S. To determine whether the higher amounts of this protein in the endosomes is due to a delay in recycling of endosomes caused by the overexpression of rififylin in the congenic strain, recycling of exogenously labeled-transferrin by single cell cultures of proximal tubules was monitored by confocal microscopy. Recycling of transferrin was significantly delayed in the congenic strain compared with S. These results suggest that impaired endosomal recycling in the proximal tubules from the congenic strain caused by the overexpression of rififylin is a novel molecular mechanism linked to the observed increase in proteinuria of the congenic strain. Three male S control and 3 male congenic S.LEW(10)x12x2x3x5 rats born on the same day were selected, weaned at 30 days of age, and caged with 1 congenic and 1 S rat per cage. They were raised on a low-salt (0.3%) diet (Harlan Teklad diet TD 7034; Harlan–Sprague-Dawley) and sacrificed at 53 days of age and total RNAs were isolated from the kidney. The isolated RNA from each animal was used for the cRNA preparation. cRNA was prepared and fragmented as suggested by Affymetrix technical manual, and simultaneously hybridized (15 µg adjusted cRNA for each chip) to Rat Expression Array 230 2.0 (3' IVT Expression Analysis). Statistical analyses of the microarray data were performed with BH adjustment using R statistical package (version 2.8.1).
2011-12-17 | E-GEOD-30770 | biostudies-arrayexpress
Project description:Through substitution mapping studies, we previously identified that a <330kb region from a rat strain with no renal pathology (the Lewis rat), which when introgressed onto the genetic background of a rat with renal disease (the Dahl Salt-sensitive (S) rat), caused an increase rather than the expected decrease in proteinuria. The purpose of this study was to prioritize a candidate gene and further delineate the mechanism underlying the observed increased in proteinuria. A higher level of proteinuria independent of dietary salt was observed in the congenic rat at a very young age (50-52 day old). The critical congenic segment was further mapped to <42.5kb containing a single candidate gene, rififylin. Rififylin was expressed 1.59 fold higher in the congenic strain compared with S. Overexpression of rififylin is known to delay recycling of endosomes. Renal transcriptome analysis indicated that Atp1a1 one of the most highly differentially expressed genes. Atp1a1 was 5.33 fold higher in the congenic strain compared with S. The protein product of Atp1a1, the alpha subunit of Na+K+ATPase, was also significantly higher in the endosomes of proximal tubules from the congenic strain compared with S. To determine whether the higher amounts of this protein in the endosomes is due to a delay in recycling of endosomes caused by the overexpression of rififylin in the congenic strain, recycling of exogenously labeled-transferrin by single cell cultures of proximal tubules was monitored by confocal microscopy. Recycling of transferrin was significantly delayed in the congenic strain compared with S. These results suggest that impaired endosomal recycling in the proximal tubules from the congenic strain caused by the overexpression of rififylin is a novel molecular mechanism linked to the observed increase in proteinuria of the congenic strain.
2011-12-17 | GSE30770 | GEO
Project description:Autoimmune disease is a systemic inflammatory response of immune blood cells caused by self-tolerance dysfunction, due to genetic or environmental factors or a combination thereof. Studies on autoimmune disease regarding the inhibition of toll-like receptor (TLR)7/9-MyD axis or the regulation of plasmacytoid dendritic cells (pDCs) and Th17 comprising an abundance of respective receptors have shown improvements in phenotypes or molecular markers, providing clues to the practicality of the inhibitors of endosomal TLRs. This study discovered several small-molecule compounds in endosomes exerting specific inhibitory effects on SITE1 shared among TLR 3, 7, 8, and 9, named endosomal TLR inhibitors (ETIs). The drug discovery process involved identifying lead compounds optimized to the receptors using a quantitative structure-activity relationship model and subsequent modification of the compounds to improve their binding affinity to target proteins. To propose a method of verifying the drug effects against side or placebo effect arising from false positives, the drug evaluation process converged from cellular response to signaling process to protein binding. Drug values on the inhibition of endosomal TLRs in autoimmune disease were assessed based on the onset of mild-to-life-threatening autoimmune disease including psoriasis, systemic lupus erythematosus, and multiple sclerosis. Complete healing was achieved for psoriasis through direct or indirect association with TLRs. Therapeutic potential of the novel ETIs for psoriasis was verified and is considered an effective drug for other autoimmune diseases associated with the TLR7/9-MyD axis.
2024-02-29 | GSE255890 | GEO
Project description:Lysosome-related organelles have versatile functions including protein and lipid degradation, signal transduction, and protein secretion. The molecular elucidation of rare congenital diseases affecting endosomal/lysosomal biogenesis has given insights into physiological functions of the innate and adaptive immune system.. Here, we describe a novel human primary immunodeficiency disorder and provide evidence that the endosomal adaptor protein p14, previously characterized as confining mitogen-activated-protein-kinase (MAPK) signaling to late endosomes, is critical for the function of neutrophils, B-cells, cytotoxic T-cells and melanocytes. Combining genetic linkage studies and transcriptional profiling analysis, we identified a homozygous point mutation in the 3â UTR of p14 (also known as MAPBPIP), resulting in decreased protein expression. In p14-deficient cells, the distribution of late endosomes was severely perturbed, suggesting a novel role for p14 in endosomal biogenesis. These findings have implications for understanding endosomal membrane dynamics, compartmentalization of cell signal cascades, and their role in immunity. Experiment Overall Design: EBV-transformed B cell lines from 2 parents and 2 affected children
2008-06-14 | E-GEOD-6322 | biostudies-arrayexpress