Identification of a Selective Pharmacologic IRE1/XBP1s Activator with Enhanced Tissue Exposure
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ABSTRACT:
PROVIDER: PRJNA1245466 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32957300_1.fastq.gz | Fastqsanger.gz | |||
| SRR32957300_2.fastq.gz | Fastqsanger.gz | |||
| SRR32957301_1.fastq.gz | Fastqsanger.gz | |||
| SRR32957301_2.fastq.gz | Fastqsanger.gz | |||
| SRR32957302_1.fastq.gz | Fastqsanger.gz |
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Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) has emerged as a promising strategy to mitigate etiologically-diverse diseases. Despite this promise, few compounds are available to selectively activate IRE1/XBP1s signaling to probe the biologic and therapeutic implications of this pathway in human disease. Recently, we identified the compound IXA4 as a highly-selective activator of protective IRE1/XBP1s signaling. While IXA4 has proven useful for increasing IRE1/XBP1s signaling in cultured cells and mouse liver, the utility of this compound is restricted by its limited activity in other tissues. To broaden our ability to pharmacologically interrogate the impact of IRE1/XBP1s signaling in vivo, we sought to identify IRE1/XBP1s activators with greater tissue activity than IXA4. We re-analyzed ‘hits’ from the high throughput screen used to identify IXA4, selecting compounds from structural classes not previously pursued. We then performed global RNAseq to confirm that these compounds showed transcriptome-wide selectivity for IRE1/XBP1s activation. Functional profiling revealed compound IXA62 as a selective IRE1/XBP1s activator that reduced A secretion from CHO7PA2 cells and enhanced glucose-stimulated insulin secretion from rat insulinoma cells, mimicking the effects of IXA4 in these assays. IXA62 robustly and selectively activated IRE1/XBP1s signaling in the liver of mice dosed compound intraperitoneally or orally. In treated mice, IXA62 showed broader tissue activity, relative to IXA4, inducing expression of IRE1/XBP1s target genes in additional tissues such as kidney and lung. Collectively, our results designate IXA62 as a selective IRE1/XBP1s signaling activating compound with enhanced tissue activity, which increases our ability to pharmacologically probe the biologic significance and potential therapeutic utility of enhancing adaptive IRE1/XBP1s signaling in vivo.
2025-04-03 | GSE293666 | GEO
Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly-selective IRE1 activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
2020-04-17 | GSE148802 | GEO
Project description:Pharmacologic IRE1/XBP1s Activation Confers Targeted ER Proteostasis Reprogramming
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Project description:Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity
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Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
| S-EPMC7502540 | biostudies-literature
Project description:The unfolded protein response (UPR) sensor IRE1 and its target, the transcription factor XBP1s critically regulate the function of dendritic cell (DC) subtypes. However, the contribution of the IRE1/XBP1s axis in DCs to the antitumor immunity is not entirely understood. Here, using reporter mice we found that DCs, in particular type 1 conventional DCs (cDC1s), are major targets of IRE1 RNase activity in melanoma tumors. Deletion of XBP1s in CD11c+ cells resulted in augmented tumor growth, impaired effector T cell responses and decreased accumulation of TCF-1+CD8+ T cells with a precursor exhausted profile. Transcriptomic studies revealed that XBP1 deletion in tumor cDC1s induced regulated IRE1 dependent decay (RIDD) of mRNAs, which accounted for the dysregulated T cell immunity in melanoma. Thus, a strict regulatory circuit involving IRE1 RNase and XBP1s in DCs ensures optimal antitumor T cell immunity in melanoma models.
2023-05-26 | GSE195439 | GEO
Project description:In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.
| S-EPMC8807832 | biostudies-literature
Project description:The unfolded protein response (UPR) has emerged as important signaling pathway mediating anti-viral defenses to Respiratory Syncytial Virus (RSV) infection. In this study, we examine how Inositol Requiring Enzyme (IREa X-Box Binding Protein spliced (XBP1s) arm of the Unfolded Protein Response (UPR) pathway controls the innate response integrating RNA-seq and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) analyses. XBP1s binds to ~4.2 K high-confidence genomic binding sites. Surprisingly these map to only a small subset of IL10/cytokine genes. We further find that that RSV infection enhances XBP1s occupancy on 786 genomic sites enriched in AP1/Fra-1, RELA and SP1 binding sites controlling a core subset of cytokine regulatory factors genes including IFN response factor 1 (IRF1), CSF2, NFKB1A and DUSP10. Selective IRF1 knockdown experiments demonstrates its requirement in control of type I and -III IFNs and IFN-stimulated genes (ISGs) indicating these genes are indirectly regulated through IRF1 transactivation. We conclude that RSV modulates the XBP1 binding complex to the IRF1 epromoter, providing novel insight into how the IRE1-XBP1s pathway potentiates airway mucosal anti-viral responses.
2023-04-30 | GSE228328 | GEO
Project description:The role of the unfolded protein response (UPR) in the cellular innate response to RSV infection is not fully understood. To better the genomic targets for the IRE1-XBP1 pathway, RNA seq was conducted on RSV-infected small airway cells in the absence or presence of RSV infection and in the absence or presence of a selective IRE1a RNAse inhibitor. We identified expression changes in ~3.2K genes; of these, 279 required IRE1 and were enriched in IL-10 signaling and cytokine signaling pathways. These data indicate that IRE1a-XBP1s regulates genes important in epithelial mesenchymal transition, hexosamine biosynthesis and anti-viral signaling.
2023-04-30 | GSE228327 | GEO
Project description:The IRE1 Rnase domain has been implicated in the pathology of triple negative breast cancer (TNBC), a disease with limited treatment options. The IRE1 Rnase mediates it's effects on the transcriptome via activation of the trancription factor XBP1s and via direct cleavage of mRNA through a process called RIDD. The processes through which the RNase domain contributes to TNBC is not fully understood. We used a novel small molecule inhibitor of the IRE1 Rnase to find novel targets of IRE1 in TNBC, in an effort to elucidate how it contributes to the disease.
2018-08-15 | GSE99766 | GEO