Browse
Submit Data
Databases
API
Help

Dataset Information

29 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A role for the ribosome-associated complex in activation of the IRE1 branch of UPR.

ABSTRACT: 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.

SUBMITTER: Wu IH

PROVIDER: S-EPMC8370116 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A role for the ribosome-associated complex in activation of the IRE1 branch of UPR.

Project description: Not available

| S-EPMC8372851 | biostudies-literature

A role for the ribosome-associated complex in activation of the IRE1 branch of UPR

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

A role for the ribosome-associated complex in activation of the IRE1 branch of UPR

Project description:A role for the ribosome-associated complex in activation of the IRE1 branch of UPR

| PRJNA727298 | ENA

The UPR branch IRE1-bZIP60 in plants plays an essential role in viral infection and is complementary to the only UPR pathway in yeast.

Project description:The unfolded protein response (UPR) signaling network encompasses two pathways in plants, one mediated by inositol-requiring protein-1 (IRE1)-bZIP60 mRNA and the other by site-1/site-2 proteases (S1P/S2P)-bZIP17/bZIP28. As the major sensor of UPR in eukaryotes, IRE1, in response to endoplasmic reticulum (ER) stress, catalyzes the unconventional splicing of HAC1 in yeast, bZIP60 in plants and XBP1 in metazoans. Recent studies suggest that IRE1p and HAC1 mRNA, the only UPR pathway found in yeast, evolves as a cognate system responsible for the robust UPR induction. However, the functional connectivity of IRE1 and its splicing target in multicellular eukaryotes as well as the degree of conservation of IRE1 downstream signaling effectors across eukaryotes remains to be established. Here, we report that IRE1 and its substrate bZIP60 function as a strictly cognate enzyme-substrate pair to control viral pathogenesis in plants. Moreover, we show that the S1P/S2P-bZIP17/bZIP28 pathway, the other known branch of UPR in plants, does not play a detectable role in virus infection, demonstrating the distinct function of the IRE1-bZIP60 pathway in plants. Furthermore, we provide evidence that bZIP60 and HAC1, products of the enzyme-substrate duet, rather than IRE1, are functionally replaceable to cope with ER stress in yeast. Taken together, we conclude that the downstream signaling of the IRE1-mediated splicing is evolutionarily conserved in yeast and plants, and that the IRE1-bZIP60 UPR pathway not only confers overlapping functions with the other UPR branch in fundamental biology but also may exert a unique role in certain biological processes such as virus-plant interactions.

| S-EPMC4398384 | biostudies-literature

Divergence and Conservation of the Major UPR Branch IRE1-bZIP Signaling Pathway across Eukaryotes.

Project description:The unfolded protein response (UPR) is crucial to life by regulating the cellular response to the stress in the endoplasmic reticulum (ER) imposed by abiotic and biotic cues such as heat shock and viral infection. The inositol requiring enzyme 1 (IRE1) signaling pathway activated by the IRE1-mediated unconventional splicing of HAC1 in yeast, bZIP60 in plants and XBP1 in metazoans, is the most ancient branch of the UPR. In this study, we systematically examined yeast IRE1p-HAC1, plant IRE1A/IRE1B-bZIP60 and human hIRE1-XBP1 pairs. We found that, unlike bZIP60, XBP1 is unable to functionally swap HAC1p in yeast, and that the inter-species heterotypic interactions among HAC1p, bZIP60 and XBP1 are not permitted. These data demonstrate evolutionary divergence of the downstream signaling of IRE1-bZIP. We also discovered that the dual cytosolic domains of plant IRE1s act in vivo in a mechanism consistent with IRE1p and hIRE1, and that plant IRE1B not only interacts with IRE1p but also forms typical IRE1 dynamic foci in yeast. Thus, the upstream components of the IRE1 signaling branch including IRE1 activation and action mechanisms are highly conserved. Taken together these data advance the molecular understanding of evolutionary divergence and conservation of the IRE1 signaling pathway across kingdoms.

| S-EPMC4891664 | biostudies-literature

LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 branch of unfolded protein response.

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

The UPR sensor IRE1? promotes dendritic cell responses to control Toxoplasma gondii infection.

Project description:The unfolded protein response (UPR) has emerged as a central regulator of immune cell responses in several pathologic contexts including infections. However, how intracellular residing pathogens modulate the UPR in dendritic cells (DCs) and thereby affect T cell-mediated immunity remains uncharacterized. Here, we demonstrate that infection of DCs with Toxoplasma gondii (T. gondii) triggers a unique UPR signature hallmarked by the MyD88-dependent activation of the IRE1? pathway and the inhibition of the ATF6 pathway. Induction of XBP1s controls pro-inflammatory cytokine secretion in infected DCs while IRE1??promotes MHCI antigen presentation of secreted parasite antigens. In mice, infection leads to a specific activation of the IRE1? pathway, which is restricted to the cDC1 subset. Mice deficient for IRE1? and XBP1 in DCs display a severe susceptibility to T. gondii and succumb during the acute phase of the infection. This early mortality is correlated with increased parasite burden and a defect in splenic T cell responses. Thus, we identify the IRE1?/XBP1s branch of the UPR as a key regulator of host defense upon T. gondii infection.

| S-SCDT-EMBOR-2019-49617V1 | biostudies-other

The UPR Transducer IRE1 Promotes Breast Cancer Malignancy by Degrading Tumor Suppressor microRNAs.

Project description:Dysregulation of inositol-requiring enzyme 1 (IRE1), the primary transducer of Unfolded Protein Response (UPR), has been observed in tumor initiation and progression, but the underlying mechanism remains to be further elucidated. In this study, we identified that the IRE1 gene is frequently amplified and over-expressed in aggressive luminal B breast cancer cells and that IRE1 upregulation is significantly associated with worse overall survival of patients with breast cancer. IRE1 processes and mediates degradation of a subset of tumor suppressor microRNAs (miRNAs), including miR-3607, miR-374a, and miR-96, via a mechanism called Regulated IRE1-Dependent Decay (RIDD). IRE1-dependent degradation of tumor suppressor miR-3607 leads to elevation of RAS oncogene GTPase RAB3B in breast cancer cells. Inhibition of IRE1 endoribonuclease activity with the pharmacological compound 4?8C or genetic approaches effectively suppresses luminal breast cancer cell proliferation and aggressive cancer phenotypes. Our work revealed the IRE1-RIDD-miRNAs pathway that promotes malignancy of luminal breast cancer.

| S-EPMC7490531 | biostudies-literature

UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor.

Project description:BiP is a major endoplasmic reticulum (ER) chaperone and is suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains of UPR proteins IRE1 and PERK switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its co-chaperones, with loss of ATPase stimulation. Furthermore, misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as an Hsp70 chaperone and ER stress sensor.

| S-EPMC6858872 | biostudies-literature

IRE1α/XBP1s branch of UPR links HIF1α activation to mediate ANGII-dependent endothelial dysfunction under particulate matter (PM) 2.5 exposure.

Project description:Short- and long-term exposure to particulate matter (PM) 2.5 instigates adverse health effect upon the cardiovascular (CV) system. Disclosing the molecular events by which PM2.5 evokes CV injuries is essential in developing effective risk-reduction strategy. Here we found that rats after intratracheally instillation with PM2.5 displayed increased circulating level of ANGII, the major bioactive peptide in renin-angiotensin-system (RAS), which resulted from the elevation of ANGII production in the vascular endothelium. Further investigations demonstrated that activation of IRE1α/XBP1s branch of unfolded protein response (UPR) was essential for augmented vascular ANGII signaling in response to PM2.5 exposure, whose effects strictly depends on the assembly of XBP1s/HIF1α transcriptional complex. Moreover, ablation of IRE1/XBP1/HIFα-dependent ACE/ANGII/AT1R axis activation inhibited oxidative stress and proinflammatory response in the vascular endothelial cells induced by PM2.5. Therefore, we conclude that PM2.5 exposure instigates endoplasmic reticulum instability, leading to the induction of IRE1α/XBP1s branch of UPR and links HIF1α transactivation to mediate ANGII-dependent endothelial dysfunction. Identifying novel therapeutic targets to alleviate ER stress and restore local RAS homeostasis in the endothelium may be helpful for the management of PM2.5-induced CV burden.

| S-EPMC5647447 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data