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Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

ABSTRACT: Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

PROVIDER: PRJNA542716 | ENA |

REPOSITORIES: ENA

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Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Project description:Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

2020-04-24 | GSE131146 | GEO

Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress.

Project description:Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

| S-EPMC7337508 | biostudies-literature

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB contributing to liver damage and fibrosis

Project description:Collagen is the most abundant protein in the cell and the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive deposition of extracellular matrix (ECM). Here we investigated the possible contribution of the unfolded protein response (UPR), the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum (ER), to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), as a major IRE1-regulated gene, a critical factor involved in collagen maturation. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB in the regulation of collagen production and its role in the pathogenesis of various disease states.

2025-05-17 | PXD041444 | Pride

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

Project description:Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1-alpha promotes cancer cell survival

| PRJNA717050 | ENA

IRE1-dependent transcriptome remodelling upon ER stress in human glioma cells

Project description:We investigate the contribution of IRE1 signaling to the modulation of U87 glioma cells transcriptome upon various stresses. To this end, IRE1 control and IRE1 dominant negative expressing U87 glioma cells were subjected to environmental or chemical challenges and their transcriptome monitored using Affymetrix microarrays. Stress-induced transcriptome modulation in function of IRE1 proficiency/deficiency

2011-12-31 | E-GEOD-27306 | biostudies-arrayexpress

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

Chemically-induced degradation of the endoplasmic-reticulum 1 stress sensor IRE1 2 by a VHL-recruiting chimera

Project description:The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-ribonuclease (KR) and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we designed a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin RING Ligase (CRL) adapter VHL. G6374 induced stable interaction between IRE1 and VHL, driving VHL-dependent IRE1 K48-linked ubiquitination on two principal kinase sites and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutational studies revealed a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocked growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide the first proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.

2025-03-03 | MSV000097222 | MassIVE

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

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

| PRJNA717051 | ENA

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

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

| PRJNA717052 | ENA