Genotoxic stress triggers the selective activation of IRE1α-dependent RNA decay to modulate the DNA damage response
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PROVIDER: PRJNA542101 | ENA |
REPOSITORIES: ENA
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Project description:The molecular connections between homeostatic systems that sustain genome integrity and proteostasis are poorly understood. Here we identified the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to engage repair programs and sustain cell survival. DNA damage engages IRE1 signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) and not its canonical output mediated by the transcription factor XBP1. IRE1α controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The protective role of IRE1α under genotoxic stress is conserved in evolution as demonstreated using fly and mouse models. Altogether, our results uncovered a novel intersection between the molecular pathways that ensure genome stability and proteostasis. Affymetrix gene expression data were pre-processed using ‘affyPLM’ packages of the Bioconductor Software. Genes with the strongest evidence of differential expression were obtained using a linear model fit. Data obtained from untreated wild type or IRE1αcKO after ploy I:C treatment liver tissues were used as reference for tunicamycin (Tm) and etoposide (Eto) treatment respectively. Custom chip definition file version 22 from Brainarray based on Entrez ID’s was used. A false positive rate of a=0.05 with FDR correction and a fold change greater 1.5 was taken as the level of significance.
2019-05-10 | GSE130952 | GEO
Project description:The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.
| S-EPMC7224204 | biostudies-literature
Project description:Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer
| PRJNA736320 | ENA
Project description:Transcriptional profiling of INS1 cells expressing either WT IRE1α, I642G IRE1α, N906A IRE1α, or spliced XBP1 comparing 1μg/mL dox and 5μM 1NMPP1 treated vs control.
2014-12-22 | GSE17148 | GEO
Project description:Ire1α conditional null or control mice of 3-months old were injected intraperitoneally with TM or vehicle. At 8 hours after the injection, total RNA was isolated from murine liver tissue and subjected to Affymetrix microarray analysis. We used microarrays to profile the global programme of gene expression in the livers of Ire1α null and control mice in the absence or presence of ER stress.
2011-02-03 | E-GEOD-27038 | biostudies-arrayexpress
Project description:In this study transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1α revealed changes in lipid metabolism genes associated with an accumulation of triacylglycerols (TAGs). We identified DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Mechanistically, the DGAT2 transcript is cleaved by IRE1 at guanine 260 within a hairpin stem loop structure. Our results highlight the importance of IRE1 RIDD activity in reprograming cellular lipid metabolism
2022-02-28 | GSE176454 | GEO
Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1α-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1α-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1α or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1α-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1α-XBP1 in leukocytes, or treated with pharmacological IRE1α inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1α-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain.
2020-05-16 | GSE131404 | GEO
Project description:Infection by intracellular pathogens can trigger activation of the IRE1α branch of the unfolded protein response (UPR), which then modulates innate immunity and infection outcomes during bacterial or viral infection. However, the mechanisms by which infection activates IRE1α have not been fully elucidated. While recognition of microbe-associated molecular patterns can activate IRE1α, it is unclear whether the canonical role of IRE1α in detecting misfolded proteins is required for its activation. Here, we report that Candida albicans infection of macrophages results in IRE1α activation through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. However, IRE1α activation was not preceded by protein misfolding in response to either C. albicans infection or lipopolysaccharide treatment, implicating a non-canonical mode of IRE1α activation after recognition of microbial patterns. Investigation of the phenotypic consequences of IRE1α activation in macrophage antimicrobial responses revealed that IRE1α activity enhances the fungicidal activity of macrophages. Macrophages lacking IRE1α activity displayed inefficient phagolysosomal fusion, enabling C. albicans to evade fungal killing and escape the phagosome. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.
2023-11-13 | GSE244303 | GEO
Project description:A nuclear export block triggers the decay of newly synthesized polyadenylated RNA
| PRJNA427344 | ENA
Project description:Background/Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Increased intrahepatic bile acid concentrations cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with several adult liver diseases. We evaluated hepatic UPR expression in pediatric patients with end-stage CLD and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD. Methods: We evaluated 34 human liver explants. Cohorts included: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways. Results: Metascape pathway analysis demonstrated that the KEGG ‘protein processing in ER’ pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of p-IRE1α compared to normal controls. These CLD changes were not disease-specific to ALGS or PFIC. IRE1α/XBP1 pathway gene expression was decreased in pediatric CLD compared to AIH disease controls. Conclusion: Pediatric CLD explants have decreased gene and protein expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and could be targeted to treat pediatric CLD.
2022-06-23 | GSE206364 | GEO