Dual IRE1 RNase functions dictate glioblastoma development

Lhomond, Stéphanie; Avril, Tony; Dejeans, Nicolas; Voutetakis, Konstantinos; Doultsinos, Dimitrios; McMahon, Mari; Pineau, Raphaël; Obacz, Joanna; Papadodima, Olga; Jouan, Florence; Bourien, Héloïse; Logotheti, Marianthi; Jégou, Gwénaële; Pallares‐Lupon, Néstor; Schmit, Kathleen; Reste, Pierre‐Jean Le; Etcheverry, Amandine; Mosser, Jean; Barroso, Kim; Vauléon, Élodie; Maurel, M.; Samali, Afshin; Patterson, John B.; Pluquet, Olivier; Hetz, Claudio; Quillien, Véronique; Chatziioannou, Aristotelis; Chevet, Éric

doi:10.15252/emmm.202115622

Cited by 34 publications

(72 citation statements)

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“…We have recently identified CD95 mRNA as being cleaved by IRE1 in an in vitro RNA cleavage assay 11 . To evaluate if the level of CD95 mRNA is controlled by IRE1 in a cellular context, we used the U87 GB cell line, which displays a constitutive activation of IRE1 11 . Expression of a dominant-negative (DN) form of IRE1, which represses the activation of endogenous IRE1, and thus its RNase activity 30, 31 , led to a significant increase in the basal level of CD95 mRNA ( Fig 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Next, we explored whether the activation of the RIDD and XBP1s branches of IRE1 RNase activity might correlate with CD95 mRNA expression levels in human tumours. Thus, we analysed the expression of this DR mRNA in tumours classified according to their RIDD and XBP1s gene expression signature, as defined previously 11 . This analysis revealed that XBP1s-high tumours present a significantly heightened expression of CD95, as compared to XBP1s-low tumours ( Fig 5C ).…”

Section: Resultsmentioning

confidence: 99%

Section: Basal and Er-stress Induced Ire1 Activation Limits Cd95 Expr...mentioning

confidence: 99%

“…This constitutive activation does not result in cell death, as would be the case in normal cells, but rather allows cancer cells to thrive through activation of pro-tumoral outcomes 4,5 . Thus, both UPR and DR signalling contribute to tumour progression and relapse in various cancer models including glioblastoma (GB) [6][7][8][9][10][11] and Triple Negative Breast Cancer (TNBC) [12][13][14][15][16] . The UPR consists of three core signalling branches initiated by the activation of three sensors upon ER stress.…”

Section: Introductionmentioning

confidence: 99%

“…Although the relationships between ER stress and TRAIL-R have been relatively well explored, whether and how IRE1 and CD95 signalling are also linked remains however, unclear. We have recently identified CD95 mRNA as being cleaved by IRE1 RNase in an in vitro RNA cleavage assay 11 . Herein, we investigate the impact of IRE1 RNase activity in CD95 signalling, revealing a previously unrecognised dual functional link between these pathways.…”

Section: Introductionmentioning

confidence: 99%

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IRE1 RNase controls CD95-mediated cell death

Pelizzari-Raymundo

Gallo

Pineau

et al. 2022

Preprint

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Unfolded Protein Response (UPR) and Death Receptor (DR) signalling are cellular stress pathways frequently activated towards pro-tumoral cellular outputs in cancer. Experimental evidence has highlighted functional links between the UPR and signalling by the DR TRAIL-R1/2. Herein, we demonstrate that the UPR sensor IRE1 controls the expression of the DR CD95/Fas, and its cell death-inducing capacity. Whereas CD95 is not a general determinant of ER stress-induced cell death, IRE1 RNase activity inhibition increased CD95 expression and exacerbated CD95L-induced cell death in glioblastoma (GB) and Triple-Negative Breast Cancer (TNBC) cell lines. In accordance, CD95 mRNA was identified as a target of the Regulated IRE1-Dependent Decay of RNA (RIDD). Moreover, CD95 expression is elevated in TNBC and GB human tumours exhibiting low RIDD activity. Surprisingly, CD95 expression is also reduced in XBP1s-low human tumour samples. We show that IRE1 RNase inhibition led to CD95 expression attenuation and reduced CD95-mediated hepatic toxicity in mice. In addition, overexpression of XBP1s sensitized GB and TNBC cells to CD95L-induced cell death. Overall, these results demonstrate the tight IRE1-mediated control of CD95-dependent cell death signals in a dual manner through both RIDD and XBP1s, and they identify a pharmacologically actionable link between IRE1 and CD95 signalling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Basal and Er-stress Induced Ire1 Activation Limits Cd95 Expr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IRE1 RNase controls CD95-mediated cell death

Pelizzari-Raymundo

Gallo

Pineau

et al. 2022

Preprint

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TGFβ1 regulates HRas‐mediated activation of IRE1α through the PERK‐RPAP2 axis in keratinocytes

Mogre

Blazanin

Walsh

et al. 2022

Molecular Carcinogenesis

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Transforming Growth Factor β1 (TGFβ1) is a critical regulator of tumor progression in response to HRas. Recently, TGFβ1 has been shown to trigger ER stress in many disease models; however, its role in oncogene‐induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol‐requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)‐like endoplasmic reticulum kinase (PERK) to mediate the tumor‐suppressive roles of TGFβ1 in mouse keratinocytes expressing mutant forms of HRas. TGFβ1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1α activation by TGFβ1. Pharmacological and genetic approaches demonstrated that TGFβ1‐dependent dephosphorylation of IRE1α was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK‐dependent IRE1α phosphatase. In addition, TGFβ1‐mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK‐induced IRE1α dephosphorylation and inactivation. Together, these results demonstrate a critical cross‐talk between UPR proteins that is important for TGFβ1‐mediated tumor suppressive responses.

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Dual RNase activity of IRE1 as a target for anticancer therapies

Bartoszewska,

Sławski,

Collawn

et al. 2023

J. Cell Commun. Signal.

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The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic. Graphical abstract

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Dual IRE1 RNase functions dictate glioblastoma development

Abstract: The journal is waiting on the results of institutional proceedings regarding inconsistencies in Figure 8A and will update the scientific record appropriately in due course.

Cited by 34 publications

References 5 publications

IRE1 RNase controls CD95-mediated cell death

IRE1 RNase controls CD95-mediated cell death

TGFβ1 regulates HRas‐mediated activation of IRE1α through the PERK‐RPAP2 axis in keratinocytes

Dual RNase activity of IRE1 as a target for anticancer therapies

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