Browse
Submit Data
Databases
API
Help

Dataset Information

35 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Sec61 translocon limits IRE1? signaling during the unfolded protein response.

ABSTRACT: IRE1? is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1? forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1? complexes in cells with blue native PAGE immunoblotting. We find that IRE1? forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex. In addition, IRE1? oligomerization, activation, and inactivation during ER stress are regulated by Sec61. Loss of the IRE1?-Sec61 translocon interaction as well as severe ER stress conditions causes IRE1? to form higher-order oligomers that exhibit continuous activation and extended cleavage of XBP1u mRNA. Thus, we propose that the Sec61-IRE1? complex defines the extent of IRE1? activity and may determine cell fate decisions during ER stress conditions.

SUBMITTER: Sundaram A

PROVIDER: S-EPMC5449187 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The Sec61 translocon limits IRE1α signaling during the unfolded protein response.

Sundaram Arunkumar A Plumb Rachel R Appathurai Suhila S Mariappan Malaiyalam M

eLife 20170515

IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in th ...[more]

PMID: 28504640

Similar Datasets

IRE1 signaling affects cell fate during the unfolded protein response.

Project description:Endoplasmic reticulum (ER) stress activates a set of signaling pathways, collectively termed the unfolded protein response (UPR). The three UPR branches (IRE1, PERK, and ATF6) promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. How the UPR integrates its cytoprotective and proapoptotic outputs to select between life or death cell fates is unknown. We found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and proapoptotic transcription regulator Chop induction, was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa.

| S-EPMC3670588 | biostudies-literature

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Project description:Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

| S-EPMC9670206 | biostudies-literature

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

Project description:Aging is a major risk factor for neurodegenerative diseases such as dementia and associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the aging mammalian brain. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression is attenuated in conjunction with age-related alterations in synaptic function and pathways linked to neurodegenerative diseases. Similar changes were observed in human brain aging. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

| S-SCDT-EMBOJ-2022-111952 | biostudies-other

IRE1-independent gain control of the unfolded protein response.

Project description:Nonconventional splicing of the gene encoding the Hac1p transcription activator regulates the unfolded protein response (UPR) in Saccharomyces cerevisiae. This simple on/off switch contrasts with a more complex circuitry in higher eukaryotes. Here we show that a heretofore unrecognized pathway operates in yeast to regulate the transcription of HAC1. The resulting increase in Hac1p production, combined with the production or activation of a putative UPR modulatory factor, is necessary to qualitatively modify the cellular response in order to survive the inducing conditions. This parallel endoplasmic reticulum-to-nucleus signaling pathway thereby serves to modify the UPR-driven transcriptional program. The results suggest a surprising conservation among all eukaryotes of the ways by which the elements of the UPR signaling circuit are connected. We show that by adding an additional signaling element to the basic UPR circuit, a simple switch is transformed into a complex response.

| S-EPMC509300 | biostudies-literature

Cytomegalovirus downregulates IRE1 to repress the unfolded protein response.

Project description:During viral infection, a massive demand for viral glycoproteins can overwhelm the capacity of the protein folding and quality control machinery, leading to an accumulation of unfolded proteins in the endoplasmic reticulum (ER). To restore ER homeostasis, cells initiate the unfolded protein response (UPR) by activating three ER-to-nucleus signaling pathways, of which the inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved. To reduce ER stress, the UPR decreases protein synthesis, increases degradation of unfolded proteins, and upregulates chaperone expression to enhance protein folding. Cytomegaloviruses, as other viral pathogens, modulate the UPR to their own advantage. However, the molecular mechanisms and the viral proteins responsible for UPR modulation remained to be identified. In this study, we investigated the modulation of IRE1 signaling by murine cytomegalovirus (MCMV) and found that IRE1-mediated mRNA splicing and expression of the X-box binding protein 1 (XBP1) is repressed in infected cells. By affinity purification, we identified the viral M50 protein as an IRE1-interacting protein. M50 expression in transfected or MCMV-infected cells induced a substantial downregulation of IRE1 protein levels. The N-terminal conserved region of M50 was found to be required for interaction with and downregulation of IRE1. Moreover, UL50, the human cytomegalovirus (HCMV) homolog of M50, affected IRE1 in the same way. Thus we concluded that IRE1 downregulation represents a previously undescribed viral strategy to curb the UPR.

| S-EPMC3738497 | biostudies-literature

Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response.

Project description:The unfolded protein response (UPR) detects the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and adjusts the protein-folding capacity to the needs of the cell. Under conditions of ER stress, the transmembrane protein Ire1 oligomerizes to activate its cytoplasmic kinase and ribonuclease domains. It is unclear what feature of ER stress Ire1 detects. We found that the core ER-lumenal domain (cLD) of yeast Ire1 binds to unfolded proteins in yeast cells and to peptides primarily composed of basic and hydrophobic residues in vitro. Mutation of amino acid side chains exposed in a putative peptide-binding groove of Ire1 cLD impaired peptide binding. Peptide binding caused Ire1 cLD oligomerization in vitro, suggesting that direct binding to unfolded proteins activates the UPR.

| S-EPMC3202989 | biostudies-literature

Unfolded protein response in wildtype, ire1, gcn4, gcn2

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 Keywords: parallel sample

2004-08-19 | GSE1688 | GEO

Unfolded protein response in wildtype, ire1, gcn4, gcn2

2010-06-06 | E-GEOD-1688 | biostudies-arrayexpress

Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1.

Project description:The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. The cellular requirement to synthesize proteins within the ER is matched by its folding capacity. However, the physiological demands or aberrations in folding may result in an imbalance which can lead to the accumulation of misfolded protein, also known as "ER stress." The unfolded protein response (UPR) is a cell-signaling system that readjusts ER folding capacity to restore protein homeostasis. The key UPR signal activator, IRE1, responds to stress by propagating the UPR signal from the ER to the cytosol. Here, we discuss the structural and molecular basis of IRE1 stress signaling, with particular focus on novel mechanistic advances. We draw a comparison between the recently proposed allosteric model for UPR induction and the role of Hsp70 during polypeptide import to the mitochondrial matrix.

| S-EPMC6423427 | biostudies-literature

IRE1?/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis.

Project description:The unfolded protein response (UPR) is a cellular adaptive mechanism that is activated in response to the accumulation of unfolded proteins in the endoplasmic reticulum. The inositol-requiring protein-1?/X-box-binding protein-mediated (IRE1?/XBP1-mediated) branch of the UPR is highly conserved and has also been shown to regulate various cell-fate decisions. Herein, we have demonstrated a crucial role for the IRE?/XBP1-mediated arm of the UPR in osteoclast differentiation. Using murine models, we found that the conditional abrogation of IRE1? in bone marrow cells increases bone mass as the result of defective osteoclastic bone resorption. In osteoclast precursors, IRE1? was transiently activated during osteoclastogenesis, and suppression of the IRE1?/XBP1 pathway in these cells substantially inhibited the formation of multinucleated osteoclasts in vitro. We determined that XBP1 directly binds the promoter and induces transcription of the gene encoding the master regulator of osteoclastogenesis nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, activation of IRE1? was partially dependent on Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate receptors 2 and 3 (ITPR2 and ITPR3) in the endoplasmic reticulum, as pharmacological inhibition or deletion of these receptors markedly decreased Xbp1 mRNA processing. The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1?/XBP1 pathway.

| S-EPMC4563737 | 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