Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α.

ABSTRACT: Inositol requiring enzyme 1 (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, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs-degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.

SUBMITTER: Le Thomas A

PROVIDER: S-EPMC8674358 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Endoplasmic reticulum stress sensor IRE1α propels neutrophil hyperactivity in lupus.

Project description:Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 α (IRE1α) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1α has been little studied in relation to neutrophil function or lupus pathogenesis. Here, we found that neutrophils activated by lupus-derived immune complexes demonstrated markedly increased IRE1α ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1α activity that was correlated with global disease activity. Immune complex-stimulated neutrophils produced both mitochondrial ROS (mitoROS) and the activated form of caspase-2 in an IRE1α-dependent fashion, whereas inhibition of IRE1α mitigated immune complex-mediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1α inhibitor to lupus-prone MRL/lpr mice over 8 weeks reduced mitoROS levels in peripheral blood neutrophils, while also restraining plasma cell expansion and autoantibody formation. In summary, these data identify a role for IRE1α in the hyperactivity of lupus neutrophils and show that this pathway is upstream of mitochondrial dysfunction, mitoROS formation, and NETosis. We believe that inhibition of the IRE1α pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions.

| S-EPMC8011900 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-01 | GSE169585 | 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

Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

Project description:Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.

| S-EPMC7246037 | biostudies-literature

Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties.

Project description:The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1α in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1α is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants.

| S-EPMC6023910 | biostudies-literature

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress.

Project description:IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1β have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1β diminishes expression and inhibits signaling by the closely related stress sensor IRE1α. IRE1β can assemble with and inhibit IRE1α to suppress stress-induced XBP1 splicing, a key mediator of the unfolded protein response. In comparison to IRE1α, IRE1β has relatively weak XBP1 splicing activity, largely explained by a nonconserved amino acid in the kinase domain active site that impairs its phosphorylation and restricts oligomerization. This enables IRE1β to act as a dominant-negative suppressor of IRE1α and affect how barrier epithelial cells manage the response to stress at the host-environment interface.

| S-EPMC7041686 | biostudies-literature

Toll-like receptor 2 (TLR2) engages endoplasmic reticulum stress sensor IRE1α to regulate retinal innate responses in Staphylococcus aureus endophthalmitis.

Project description:Endoplasmic reticulum (ER) stress response has been implicated in a variety of pathophysiological conditions, including infectious and inflammatory diseases. However, its contribution in ocular bacterial infections, such as endophthalmitis, which often cause blindness is not known. Here, using a mouse model of Staphylococcus (S.) aureus endophthalmitis, our study demonstrates the induction of inositol-requiring enzyme 1α (IRE1α) and splicing of X-box binding protein-1 (Xbp1) branch of the ER-stress pathway, but not the other classical ER stress sensors. Interestingly, S aureus-induced ER stress response was found to be dependent on Toll-like receptor 2 (TLR2), as evident by reduced expression of IRE1α and Xbp1 mRNA splicing in TLR2 knockout mouse retina. Pharmacological inhibition of IRE1α using 4µ8C or experiments utilizing IRE1α-/- macrophages revealed that IRE1α positively regulates S aureus-induced inflammatory responses. Moreover, IRE1α inhibition attenuated S aureus-triggered NF-κB, p38, and ERK pathways activation and cells treated with these pathway-specific inhibitors reduced Xbp1 splicing, suggesting a positive feedback inhibition. In vivo, inhibition of IRE1α diminished the intraocular inflammation and reduced PMN infiltration in mouse eyes, but, increased the bacterial burden and caused more retinal tissue damage. These results revealed a critical role of the IRE1α/XBP1 pathway as a regulator of TLR2-mediated protective innate immune responses in S aureus-induced endophthalmitis.

| S-EPMC8033405 | biostudies-literature

A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress.

Project description:Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1α endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress, thereby attenuating IRE1α. Although sustained activation of IRE1α is linked to human diseases, it is not clear how IRE1α is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1α/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1α. This leads to inhibition of higher-order oligomerization and attenuation of IRE1α RNase activity during prolonged ER stress. In Sec63-deficient cells, IRE1α remains activated for a long period of time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to regulate the dynamics of IRE1α signaling in cells.

| S-EPMC7809255 | biostudies-literature

Dynamic changes in complexes of IRE1α, PERK, and ATF6α during endoplasmic reticulum stress.

Project description:The endoplasmic reticulum (ER) localized unfolded protein response (UPR) sensors, IRE1α, PERK, and ATF6α, are activated by the accumulation of misfolded proteins in the ER. It is unclear how the endogenous UPR sensors are regulated by both ER stress and the ER luminal chaperone BiP, which is a negative regulator of UPR sensors. Here we simultaneously examined the changes in the endogenous complexes of UPR sensors by blue native PAGE immunoblotting in unstressed and stressed cells. We found that all three UPR sensors exist as preformed complexes even in unstressed cells. While PERK complexes shift to large complexes, ATF6α complexes are reduced to smaller complexes on ER stress. In contrast, IRE1α complexes were not significantly increased in size on ER stress, unless IRE1α is overexpressed. Surprisingly, depletion of BiP had little impact on the endogenous complexes of UPR sensors. In addition, overexpression of BiP did not significantly affect UPR complexes, but suppressed ER stress mediated activation of IRE1α, ATF6α and, to a lesser extent, PERK. Furthermore, we captured the interaction between IRE1α and misfolded secretory proteins in cells, which suggests that the binding of unfolded proteins to preformed complexes of UPR sensors may be crucial for activation.

| S-EPMC5994896 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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