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Expression data from IRE1a or XBP1 deficient mouse liver

ABSTRACT: IRE1a and XBP1 are key regulators of the unfolded protein response (UPR). XBP1 ablation causes profound hypolipidemia in mice, and triggers feedback activation of its upstream enzyme IRE1a, instigating regulated IRE1-dependent decay (RIDD), an mRNA degradation mechanism dependent on IRE1a's endoribonuclease activity. Comprehensive microarray analysis of XBP1 and/or IRE1a deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1a.

ORGANISM(S): Mus musculus

PROVIDER: GSE40515 | GEO | 2012/10/17

SECONDARY ACCESSION(S): PRJNA174429

REPOSITORIES: GEO

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Expression data from IRE1a or XBP1 deficient mouse liver

Project description:IRE1a and XBP1 are key regulators of the unfolded protein response (UPR). XBP1 ablation causes profound hypolipidemia in mice, and triggers feedback activation of its upstream enzyme IRE1a, instigating regulated IRE1-dependent decay (RIDD), an mRNA degradation mechanism dependent on IRE1a's endoribonuclease activity. Comprehensive microarray analysis of XBP1 and/or IRE1a deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1a. To identify RIDD substrate mRNAs and direct XBP1 targets in the liver, we performed a comprehensive comparative microarray analysis of three groups of RNA samples: WT and XBP1 deficient mice, WT and IRE1a deficient mice untreated or injected with tunicamycin, and XBP1 deficient mice injected with luciferase or IRE1a siRNA.

2012-10-17 | E-GEOD-40515 | biostudies-arrayexpress

Effect of IRE1a and XBP1 knockdown on gene expression in primary mouse keratinocytes expressing an HRas oncogene

Project description:IRE1a is a critical modulator of the unfolded protein response. Its RNAse activity generates the mature transcript for the XBP1 transcription factor and also degrades other ER associated mRNAs in a process termed Regulated IRE1a Dependent mRNA Decay or RIDD. To determine if IRE1a is critical in the response to oncogenic Ras we used ShRNA to knockdown Ire1a or Xbp1 in primary mouse epidermal keratinocytes transduced with a v-HRAS retrovirus.

2017-06-01 | GSE70899 | GEO

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1-alpha promotes cancer cell survival [RNA-seq]

Project description:Eukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1α oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.

2021-06-01 | GSE169584 | GEO

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1-alpha promotes cancer cell survival [GRO-seq]

2021-06-01 | GSE169583 | GEO

Transcriptional regulation of hematopoietic stem cell progenitors and acute myeloid leukemia by the IRE1a-XBP1 pathway [overexpression]

Project description:The inositol-requiring enzyme-1a (IRE1a), through its key effector transcription factor X-box binding protein-1 (XBP1), regulates cell fate and malignancy in a tissue and cell-specific manner. Here, we define the transcriptional perturbations associated with induction of XBP1 (encoded by the XBP1S gene generated by IRE1a) eficiency in patient derived human AML cells. Beyond its classical role in activating genes involved in restoring cellular proteostasis during the unfolded protein response (UPR), our transcriptome analysis reveal XBP1-dependent regulation of genes involved in diverse biological processes required for HSC homeostasis and acute myeloid leukemia (AML) development.

2023-12-30 | GSE163137 | GEO

Transcriptional regulation of hematopoietic stem cell progenitors and acute myeloid leukemia by the IRE1a-XBP1 pathway [KO]

Project description:The inositol-requiring enzyme-1a (IRE1a), through its key effector transcription factor X-box binding protein-1 (XBP1), regulates cell fate and malignancy in a tissue and cell-specific manner. Here, we define the transcriptional perturbations associated with IRE1a deficiency in normal murine hematopoieitic stem cell (HSC) progenitors and HSC progenitors expressing Flt3 internal tandem duplication (FLT3-ITD) allele, a myeloid leukemia oncogne. Beyond its classical role in activating genes involved in restoring cellular proteostasis during the unfolded protein response (UPR), our transcriptome analysis reveal XBP1-dependent regulation of genes involved in diverse biological processes required for HSC homeostasis and acute myeloid leukemia (AML) development.

2023-12-30 | GSE163136 | GEO

Bulk RNAseq of control, XBP1-deficient or XBP1/IRE1-deficient cDC1s from subcutaneous B16- melanoma bearing mice

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

Effect of the IRE1a-XBP1 pathway inhibition during T helper 2 differentiation

Project description:The purpose of the study was to examine the role of the IRE1a-XBP1 pathway during Th2 lymphocyte activation and differentiation. In vitro Th2 cells were treated with 4μ8c, a drug that specifically inhibits IRE1a endonuclease activity, and transcriptomes were compared.

2018-07-20 | E-MTAB-6894 | biostudies-arrayexpress

Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs.

Project description:Endoplasmic Reticulum (ER) stress is a hallmark of various diseases, which is dealt with through the activation of an adaptive signaling pathway named the Unfolded Protein Response (UPR). This response is mediated by three ER-resident sensors and the most evolutionary conserved, IRE1α signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1α RNase activity can either catalyze the initial step of XBP1 mRNA unconventional splicing or degrade a number of RNAs through Regulated IRE1-Dependent Decay (RIDD). The balance between these two activities plays an instrumental role in cells’ life and death decisions upon ER stress. Until now, the biochemical and biological outputs of IRE1α RNase activity have been well documented, however, the precise mechanisms controlling whether IRE1 signaling is adaptive or pro-death (terminal) remain unclear. This prompted us to further investigate those mechanisms and we hypothesized that XBP1 mRNA splicing and RIDD activity could be co-regulated by the IRE1α RNase regulatory network. We showed that a key nexus in this pathway is the tRNA ligase RtcB which, together with IRE1α, is responsible for XBP1 mRNA splicing. We demonstrated that RtcB is tyrosine phosphorylated by c-Abl and dephosphorylated by PTP1B. Moreover, we identified RtcB Y306 as a key residue which, when phosphorylated, perturbs RtcB interaction with IRE1α, thereby attenuating XBP1 mRNA splicing and favoring RIDD. Our results demonstrate that the IRE1α RNase regulatory network is dynamically fine-tuned by tyrosine kinases and phosphatases upon various stresses and that the nature of the stress determines cell adaptive or death outputs.

2022-02-21 | PXD023433 | Pride

SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1a/XBP1 ER stress pathway in human lung-derived cells

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1a kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1a-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1a as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1a through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1a was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1a, perhaps as a strategy to eliminate detection by the host immune system.

2022-07-20 | GSE193169 | GEO

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