IRE1α Cleaves Select microRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2

Upton, John-Paul; Wang, Likun; Han, Dan; Wang, Eric S.; Huskey, Noelle E.; Lim, Lionel; Truitt, Morgan; McManus, Michael T.; Ruggero, Davide; Goga, Andrei; Papa, Feroz R.; Oakes, Scott A.

doi:10.1126/science.1226191

Cited by 559 publications

(560 citation statements)

References 25 publications

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“…4,5,7 Pro-survival as well as pro-apoptotic roles have been suggested for IRE1-dependent decay of mRNAs (RIDD). 5,6,18 Our system does not allow direct monitoring of RIDD, however, the data available to date would indicate that RIDD cannot occur independent of XBP1 splicing. 5,7,18 Thus, we assume that the observed attenuation of XBP1-YFP splicing is indicative of a decrease in all IRE1 endonuclease activities including mRNA decay.…”

Section: Discussionmentioning

confidence: 99%

“…However, IRE1 endonuclease activity has been shown to splice additional mRNAs and microRNAs, which has been interpreted both as a pro-survival mechanism when occurring early during ER stress and as contributing to apoptosis when occurring late during ER stress. [4][5][6][7] Additionally, it has been shown that IRE1-mediated splicing is eventually attenuated despite continuous ER stress. This has been proposed to be a switch into cell death facilitated by the pro-apoptotic outputs of the PERK signalling pathway.…”

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confidence: 99%

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Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

et al. 2015

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An accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) mediated via the activation of three transmembrane proteins IRE1, PERK and ATF6. Signalling through these proteins is aimed at enhancing the ER folding capacity and reducing the folding load. If these processes fail to re-establish protein homeostasis within the ER, then cell death prevails via apoptosis. How the shift from pro-survival to pro-apoptotic signalling is regulated remains unclear with both IRE1 and PERK signalling associated with pro-survival as well as pro-apoptotic signalling. To investigate the temporal activation of IRE1 and PERK in live cells and their relationship to cellular fate, we devised single cell reporters for both ER stress signalling branches. SH-SY5Y neural cells stably expressing these fluorescent protein reporter constructs to monitor IRE1-splicing activity and PERK-mediated ATF4-translation were imaged using single cell and high content time lapse live cell microscopy. We could correlate an early onset and attenuation of XBP1 splicing in the IRE1-reporter cells as cytoprotective. Indeed, silencing of IRE1 expression using shRNA inhibited splicing of XBP1 resulting in an early onset of cell death. In contrast, in the PERK-reporter cells, we observed that a slow rate of ATF4-translation and late re-initiation of general translation coincided with cells which were resistant to ER stress-induced cell death. Interestingly, whereas silencing of PERK did not affect overall levels of cell death in response to ER stress, it did increase sensitivity to ER stressors at early time points following treatment. Our results suggest that apoptosis activation in response to ER stress is not caused by a preferential activation of a single UPR branch, or by a switch from one branch to the other. Rather, our data indicated that the relative timing of IRE1 and PERK signalling determines the shift from cell survival to apoptosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

et al. 2015

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“…33 miRNA precursors have also been identified as RIDD substrates in vitro. 34 Disruption of miRNA maturation by RIDD cleavage may further affect multiple biological processes by modulating miRNA-mRNA interactions throughout the cell.…”

Section: Upr In Disease Pathogenesismentioning

confidence: 99%

Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

Hiramatsu

Chiang

Kurt

et al. 2015

The American Journal of Pathology

157

147

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“…Another arm of the UPR transiently attenuates global protein translation to decrease the nascent protein burden and prevent aberrant accumulation of unfolded proteins [3]. Unresolved ER stress and constitutive UPR activation in metazoans can both lead to cell death via caspase activation and apoptosis [4-6]. Apoptotic induction appears to be a consequence of prolonged UPR activation [6, 7].…”

Section: Introductionmentioning

confidence: 99%

“…Unresolved ER stress and constitutive UPR activation in metazoans can both lead to cell death via caspase activation and apoptosis [4-6]. Apoptotic induction appears to be a consequence of prolonged UPR activation [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Approaches to imaging unfolded secretory protein stress in living cells

Lajoie

Fazio

Snapp

2014

Endoplasmic Reticulum Stress in Diseases

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The endoplasmic reticulum (ER) is the point of entry of proteins into the secretory pathway. Nascent peptides interact with the ER quality control machinery that ensures correct folding of the nascent proteins. Failure to properly fold proteins can lead to loss of protein function and cytotoxic aggregation of misfolded proteins that can lead to cell death. To cope with increases in the ER unfolded secretory protein burden, cells have evolved the Unfolded Protein Response (UPR). The UPR is the primary signaling pathway that monitors the state of the ER folding environment. When the unfolded protein burden overwhelms the capacity of the ER quality control machinery, a state termed ER stress, sensor proteins detect accumulation of misfolded peptides and trigger the UPR transcriptional response. The UPR, which is conserved from yeast to mammals, consists of an ensemble of complex signaling pathways that aims at adapting the ER to the new misfolded protein load. To determine how different factors impact the ER folding environment, various tools and assays have been developed. In this review, we discuss recent advances in live cell imaging reporters and model systems that enable researchers to monitor changes in the unfolded secretory protein burden and activation of the UPR and its associated signaling pathways.

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IRE1α Cleaves Select microRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2

Cited by 559 publications

References 25 publications

Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

Multiple Mechanisms of Unfolded Protein Response–Induced Cell Death

Approaches to imaging unfolded secretory protein stress in living cells

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