Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude

Bakunts, Anush; Orsi, Andrea; Vitale, Milena; Cattaneo, Angela; Lari, Federica; Tadè, Laura; Sitia, Roberto; Raimondi, Andrea; Bachi, Ángela; Anken, Eelco van

doi:10.7554/elife.27518

Cited by 77 publications

(124 citation statements)

References 54 publications

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“…1A, B). We conclude that IRE1a clustering in HAP1 cells is qualitatively and quantitatively similar to the clustering described before in 293T-Rx cells (13,33,41). IRE1a clustering is dynamic, with a time course that parallels the transient nature of XBP1 splicing (42,43).…”

Section: Reconstitution Of Ire1gfp In Hap1 Ire1ko Cells Allows Studyisupporting

confidence: 84%

“…IRE1a clustering is a response to many forms of ER stress because it is induced by chemical stressors as well as by the presence of misfolded, nonsecreted protein, as has also been shown by Bakunts et al (41). Importantly, IRE1a clusters in response to mild, not only severe stress, so it is likely a physiologically relevant response.…”

Section: Discussionmentioning

confidence: 58%

“…Furthermore, the RNase activity seems to restrict the clustering and to promote their dissociation with time. The dissociation of clusters under continuous Tm treatment is likely dependent on increased concentration of BiP in the ER as a result of a transcriptional response, as suggested by Bakunts et al (41).…”

Section: Bip Cleavage Induces Massive Persistent Ire1a Clusteringmentioning

confidence: 78%

“…These data show that ablation of even a fraction of cellular BiP is sufficient to induce massive IRE1a clustering, whereas deliberate expression of exogenous BiP has the reverse effect ( Fig. 3D), reflecting either the presumed ratio of active BiP to total misfolded protein (41) or the sensitivity of a special pool of BiP that binds IRE1a. The SubAB-induced clustering differed from that induced by the more physiologic ER stress in 2 important ways: first, the clusters were much longer lived and did not disperse over 8 h ( Fig.…”

Section: Bip Cleavage Induces Massive Persistent Ire1a Clusteringmentioning

confidence: 87%

“…Another form of milder, more physiologic ER stress is expression of a misfolded protein. Bakunts et al (41) showed that accumulation of unassembled Ig m chain induced IRE1a clustering and we quantified the clustering behavior in response to a permanently misfolded enzyme, the NHK variant of a1AT (8,9). We coexpressed mCherry-tagged NHK or WT a1AT in 293T cells, that stably expressed the dox-inducible IRE1GFP.…”

Section: Clustering Of Ire1a Under Mild Er Stressmentioning

confidence: 99%

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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: Reconstitution Of Ire1gfp In Hap1 Ire1ko Cells Allows Studyisupporting

confidence: 84%

Section: Discussionmentioning

confidence: 58%

Section: Bip Cleavage Induces Massive Persistent Ire1a Clusteringmentioning

confidence: 78%

Section: Bip Cleavage Induces Massive Persistent Ire1a Clusteringmentioning

confidence: 87%

Section: Clustering Of Ire1a Under Mild Er Stressmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2019

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A mutation in the Na‐K‐2Cl cotransporter‐1 leads to changes in cellular metabolism

Omer

Koumangoye

Delpire

2020

Journal Cellular Physiology

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The Na-K-Cl cotransporter-1 (NKCC1), by mediating the electroneutral transport of Na + , K + , and Cl − plays an important role in cell volume regulation, epithelial transport, and the control of neuronal excitability. Recently, we reported the first known human mutation in SLC12A2, the gene encoding NKCC1. The 17-year old patient suffers from multiorgan failure. Laboratory tests conducted on muscle and liver biopsies of the patient showed abnormal increase in mitochondrial DNA copy number and increased glycogen levels, indicating the possibility that the transporter may play a role in energy metabolism. Here, we show that fibroblasts isolated from the patient demonstrate a significant increase in mitochondrial respiration, compared to fibroblasts isolated from healthy individuals. Similarly, Madin Darby canine kidney (MDCK) cells transfected with enhanced green fluorescent protein (EGFP)tagged mutant NKCC1 DNA demonstrated increased mitochondrial respiration when compared to MDCK cells expressing EGFP-tagged wild-type (WT) cotransporter. Direct inhibition of the cotransporter through addition of bumetanide did not change the rate of basal respiration, but led to increased maximal mitochondrial respiration. Fibroblasts extracted from NKCC1 WT/DFX and NKCC1 DFX/DFX mice also demonstrated a significant elevation in mitochondrial respiration, compared to fibroblasts isolated from their WT littermates. Expression of the mutant protein was associated with an increase in hydrogen peroxide and peroxidase activity and a decrease in messenger RNA transcript levels for protein involved in the unfolded protein response. These data reveal that cells expressing the mutant cotransporter demonstrate increased mitochondrial respiration and behave like they are experiencing a state of starvation.

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IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis

Huang

Zhang

Sun

et al. 2021

Journal Cellular Physiology

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IRE1 is an important central regulator of unfolded protein response (UPR) in the endoplasmic reticulum (ER) because of its ability to regulate cell fate as a function of stress sensing. When misfolded proteins accumulated in chondrocytes ER, IRE1 disintegrates with BIP/GRP78 and undergoes dimer/oligomerization and transautophosphorylation. These two processes are mediated through an enzyme activity of IRE1 to activate endoribonuclease and generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis. The deficiency of inositol‐requiring enzyme 1α (IRE1α) in chondrocytes downregulates prosurvival factors XBP1S and Bcl‐2, which enhances the apoptosis of chondrocytes through increasing proapoptotic factors caspase‐3, p‐JNK, and CHOP. Meanwhile, the activation of IRE1α increases chondrocyte viability and reduces cell apoptosis. However, the understanding of IRE1 responses and cell death fate remains controversial. This review provides updated data about the role IRE1 plays in chondrocytes and new insights about the potential efficacy of IRE1 regulation in cartilage repair and osteoarthritis treatment.

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Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude

Cited by 77 publications

References 54 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

A mutation in the Na‐K‐2Cl cotransporter‐1 leads to changes in cellular metabolism

IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis

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