A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response

Amin-Wetzel, Niko; Saunders, Reuben A.; Kamphuis, Maarten J.; Rato, Cláudia; Preißler, Steffen; Harding, Heather P.; Ron, David

doi:10.1016/j.cell.2017.10.040

Cited by 197 publications

(208 citation statements)

References 61 publications

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“…Interestingly, Hu et al (63) observed that newly synthesized BiP is more susceptible to SubAB, raising the possibility that the IRE1a-bound BiP is indeed the newly synthesized protein. Another relevant mechanism maybe the recruitment of a complex of BiP with the cochaperone ERdj4, which was shown to mediate monomerization of IRE1a (64). The availability of this complex may be altered when some BiP is ablated, or perhaps its recruitment to inactive IRE1a is insufficient to limit cluster size.…”

Section: Discussionmentioning

confidence: 99%

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity

et al. 2019

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The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress‐induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase‐inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase‐inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress‐independent cluster, with distinct physical properties and half‐lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.—Ricci, D., Marrocco, I., Blumenthal, D., Dibos, M., Eletto, D., Vargas, J., Boyle, S., Iwamoto, Y., Chomistek, S., Paton, J. C., Paton, A. W., Argon, Y. Clustering of IRE1α depends on sensing ER stress but not on its RNase activity. FASEB J. 33, 9811–9827 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity

et al. 2019

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“…Accumulating misfolded proteins in the ER lumen engage BiP thus releasing the three sensors. A FRET UPR induction assay, developed to quantify the association and dissociation of the IRE1 luminal domain from BiP upon ER stress , demonstrated that the ER luminal co‐chaperone ERdj4/DNAJB9 represses IRE1 by promoting a complex between BiP and the luminal stress‐sensing domain of IRE1α . Moreover, it has recently been reported that another ER luminal chaperone, Hsp47, displaces BiP from the IRE1 UPRosome to promote its oligomerization .…”

Section: Er Stress Consequencesmentioning

confidence: 99%

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

et al. 2018

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The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

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“…IRE1α dimerization can be evaluated by detecting the foci formation of IRE1α-GFP [26] and BiFC assay [27]. Recently, Amin-Wetzel et al also established a new method to measure the endogenous IRE1α dimerization in cells [28]. Newbatt et al reported a DELFIA technology that is specific for detecting IRE1α autotransphosphorylation [29].…”

Section: Discussionmentioning

confidence: 99%

Apocynin protects endothelial cells from endoplasmic reticulum stress-induced apoptosis via IRE1α engagement

Zhang

Liu

et al. 2018

Mol Cell Biochem

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Endoplasmic reticulum (ER) stress-induced endothelial cell (EC) apoptosis has been implicated in a variety of human diseases. In addition to being regarded as an NADPH oxidase (NOX) inhibitor, apocynin (APO) exhibits an anti-apoptotic effect in various cells. The present study aimed to identify the protective role of apocynin in ER stress-mediated EC apoptosis and the underlying mechanisms. We found that ER stress resulted in a significant increase in c-Jun N-terminal kinase phosphorylation, and elicited caspase 3 cleavage and apoptosis. However, apocynin obviously attenuated EC apoptosis and this effect was partly dependent on ER stress sensor inositol-requiring enzyme 1α (IRE1α). Importantly, apocynin upregulated IRE1α expression in both protein and mRNA levels and promoted the pro-survival XBP1 splicing. Our results suggest that apocynin protects ECs against ER stress-induced apoptosis via IRE1α involvement. These findings may provide a novel mechanistic explanation for the anti-apoptotic effect of apocynin in ER stress.

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A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response

Cited by 197 publications

References 61 publications

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

Apocynin protects endothelial cells from endoplasmic reticulum stress-induced apoptosis via IRE1α engagement

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