IRE1: ER stress sensor and cell fate executor

Chen, Yani; Brandizzí, Federica

doi:10.1016/j.tcb.2013.06.005

Cited by 473 publications

(424 citation statements)

References 90 publications

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“…However, little is known concerning the mechanism by which sorafenib induces cell death and the drug resistance gained in response to HCC treatment. Activation of the UPR by the IRE1 signaling pathway is a key component of cell survival decisions in response to ER stress (34). We observed the activation of IRE1 in the sorafenib-treated HCC cells, thereby indicating that sorafenib induces the UPR and ER stress-related apoptosis.…”

Section: Discussionmentioning

confidence: 57%

“…The IRE1 signaling pathway functions as a switch between cytoprotective and proapoptotic outcomes in response to ER stress, and the activation of IRE1 plays a crucial role in the UPR to enhance cell survival (34). Our results indicate that sorafenib treatment triggers the UPR and ER stress-related apoptosis in HCC cells, given the essential role of IRE1 activation in governing the switch from adaptive UPR to ER stress-associated apoptosis in sorafenib-treated HCC cells.…”

Section: Discussionmentioning

confidence: 63%

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RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

Zhou

Guo

et al. 2015

Oncology Reports

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Abstract. Sorafenib is one of the preferred drugs for the treatment of advanced primary hepatocellular carcinoma (HCC). However, its side-effects and acquired resistance limit its use. The unfolded protein response (UPR) induced by chemotherapeutics has been demonstrated to be required for tumor cells to maintain malignancy and therapy resistance. Activation of the IRE1/XBP1 pathway during the UPR is important for tumor survival under pathophysiological conditions. In the present study, we found that the UPR was activated and RACK1 was overexpressed in three human HCC cell lines and in HCC samples. Activation of the IRE1/XBP1 signaling pathway plays a protective role when HCC cells encounter endoplasmic reticulum (ER) stress due to in vitro sorafenib treatment. We then found that the interaction between IRE1 and RACK1 was essential for the activation of IRE1 signaling in sorafenibtreated cells. Exogenous overexpression of RACK1 enhanced the phosphorylation level of IRE1 and increased XBP1 mRNA splicing activity, which protected the HCC cells from sorafenib-induced apoptosis. However, the re-expression of RACK1 led HCC cells to regain susceptibility to sorafenibinduced apoptosis. Taken together, the present study suggests that the RACK1/IRE1 complex may contribute to activation of the UPR in HCC cells. Targeting RACK1 in combination with sorafenib administration is a potential strategy for clinical trials of advanced HCC treatment.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 63%

RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

Zhou

Guo

et al. 2015

Oncology Reports

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“…10,11 Intriguingly, AGB1 is involved in unfolded protein response (UPR), 12,13 a pathway in so-called endoplasmic reticulum (ER) quality control to cope with ER stresses. 14,15 . The molecular mechanism of ER quality control is evolutionarily well conserved among eukaryotic cells.…”

mentioning

confidence: 99%

Heterotrimeric G protein subunits differentially respond to endoplasmic reticulum stress in Arabidopsis

Cho

Iwasa

et al. 2015

Plant Signaling & Behavior

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“…The absence of detectable Ire1a in cells stimulated with LPS for 24 h indicates that misfolded proteins have probably not reached the threshold required for its induction. It is also possible that Ire1a levels are kept in check during early activation because it can decrease protein folding in the ER by promoting mRNA decay, and also induce apoptosis (30). We found that Hrd1 transcript and protein amounts were both higher in WT B cells than in CD40 2/2 B cells and that both were induced when WT B cells…”

Section: Discussionmentioning

confidence: 66%

Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways

Basu

Kaw

D'Souza

et al. 2016

The Journal of Immunology

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CD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T–B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40–CD154 interaction–deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40−/− B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T–B interactions can calibrate B cell differentiation outcomes.

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IRE1: ER stress sensor and cell fate executor

Cited by 473 publications

References 90 publications

RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

RACK1 modulates apoptosis induced by sorafenib in HCC cells by interfering with the IRE1/XBP1 axis

Heterotrimeric G protein subunits differentially respond to endoplasmic reticulum stress in Arabidopsis

Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways

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