A role for the ribosome-associated complex in activation of the IRE1 branch of UPR
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ABSTRACT:
PROVIDER: PRJNA727298 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR14421803.fastq.gz | Fastqsanger.gz | |||
| SRR14421804.fastq.gz | Fastqsanger.gz | |||
| SRR14421805.fastq.gz | Fastqsanger.gz | |||
| SRR14421806.fastq.gz | Fastqsanger.gz | |||
| SRR14421807.fastq.gz | Fastqsanger.gz |
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Project description:The ubiquitous ribosome-associated complex (RAC) is a chaperone that spans ribosomes, making contacts near both the polypeptide exit tunnel and the decoding center, a position prime for sensing and coordinating translation and folding. Loss of RAC is known to result in growth defects and sensitization to translational and osmotic stresses. However, the physiological substrates of RAC and the mechanism(s) by which RAC is involved in responding to specific stresses in higher eukaryotes remain obscure. Data presented here uncover an essential function of mammalian RAC in the unfolded protein response (UPR). Knockdown of RAC sensitizes mammalian cells to ER stress and selectively interferes with IRE1 branch activation. Higher-order oligomerization of the IRE1α kinase/endoribonuclease depends upon RAC. These results reveal a surveillance function for RAC in the UPR: modulating IRE1α clustering as required for endonuclease activation and splicing of the substrate Xbp1 mRNA.
2021-06-14 | GSE173852 | GEO
Project description:A role for the ribosome-associated complex in activation of the IRE1 branch of UPR
| PRJNA727298 | ENA
Project description:The ubiquitous ribosome-associated complex (RAC) is a chaperone that spans ribosomes, making contacts near both the polypeptide exit tunnel and the decoding center, a position prime for sensing and coordinating translation and folding. Loss of RAC is known to result in growth defects and sensitization to translational and osmotic stresses. However, the physiological substrates of RAC and the mechanism(s) by which RAC is involved in responding to specific stresses in higher eukaryotes remain obscure. The data presented here uncover an essential function of mammalian RAC in the unfolded protein response (UPR). Knockdown of RAC sensitizes mammalian cells to endoplasmic reticulum (ER) stress and selectively interferes with IRE1 branch activation. Higher-order oligomerization of the inositol-requiring enzyme 1α (IRE1α) kinase/endoribonuclease depends upon RAC. These results reveal a surveillance function for RAC in the UPR, as follows: modulating IRE1α clustering as required for endonuclease activation and splicing of the substrate Xbp1 mRNA.
| S-EPMC8370116 | biostudies-literature
Project description: Not available
| S-EPMC8372851 | biostudies-literature
Project description:Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood. Here, we report that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum where it interacts with HSPA5 leading to activation of the IRE1-XBP1-branch of the Unfolded Protein Response (UPR). LOXL2-dependent UPR activation induces the expression of several EMT-TFs: SNAI1, SNAI2, ZEB2 and TCF3 that are direct transcriptional targets of XBP1. Remarkably, inhibition of IRE1 blocks LOXL2-dependent upregulation of EMT-TFs thus hindering EMT induction. LOXL2 relationship to Endoplasmic Reticulum Stress
2017-05-11 | GSE90605 | GEO
Project description:The unfolded protein response (UPR) allows the endoplasmic reticulum (ER) to recover from the accumulation of misfolded proteins, in part by increasing its folding capacity. IRE1 promotes this remodeling by detecting misfolded ER proteins and activating a transcription factor, XBP-1, through endonucleolytic cleavage of its mRNA. We found that IRE1 independently mediated the rapid degradation of a specific subset of mRNAs. The arrays deposited here show the effects of depletion of IRE1 and XBP-1 on UPR induction in S2 cells. We have characterized the IRE1-dependent repressive branch of this response. Keywords: stress response, RNAi, DTT
2006-05-20 | GSE4867 | GEO
Project description:The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring-enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency (DKO) of IRE1 and its downstream transcription factor XBP1 in NKp46 + NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1 sufficient Ly49H + NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that cell-intrinsic IRE1/XBP1 activation is required for NK cell proliferation early upon viral infection, as part of a canonical UPR response.
2023-10-27 | GSE236819 | GEO
Project description:The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring-enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency (DKO) of IRE1 and its downstream transcription factor XBP1 in NKp46 + NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1 sufficient Ly49H + NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that cell-intrinsic IRE1/XBP1 activation is required for NK cell proliferation early upon viral infection, as part of a canonical UPR response.
2023-10-27 | GSE236820 | GEO
Project description:The unfolded protein response (UPR) continually monitors the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, Ire1, an ER membrane-resident kinase/endoribonuclease, utilizes a mechanism of selective degradation of ER-targeted mRNAs (RIDD) to maintain ER homeostasis. Here, we used a genetic screen to identify factors critical to the Ire1-mediated UPR response in S. pombe and found several proteins, Dom34, Hbs1 and SkiX, previously implicated in ribosome rescue and the no-go-decay (NGD) pathway. Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage on ER-associated mRNAs results in ribosome stalling on the cleaved transcript and, ultimately in full mRNA degradation. The process engages mechanisms of precise, iterated cleavage of the mRNAs and ribosome rescue. This clear signature allowed us to discover hundreds of novel mRNA targets of Ire1. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD surveillance pathway, and establish a critical role for NGD in maintaining ER homeostasis.
2017-09-14 | GSE98934 | GEO
Project description:We measured steady-state mRNA levels by microarray hybridization, comparing WT, (delta)ire1, (delta)gcn4, and (delta)gcn2 cells treated with 2 mM DTT for 30 min (by which time the UPR is qualitatively complete) to untreated samples of the same genotype. WT cells were taken as a positive control for UPR induction, and (delta)ire1 cells as a negative control. Fold change in expression of a given gene was computed as the ratio of mRNA level in the treated sample to the level in an untreated sample of the same genotype. Values reported here are the log2 fold change. Keywords = unfolded protein response Keywords = UPR Keywords = ire1 Keywords = gcn4 Keywords = gcn2
2010-06-06 | E-GEOD-1688 | biostudies-arrayexpress