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Dual IRE1 RNase functions dictate glioblastoma development.

ABSTRACT: Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1? (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.

SUBMITTER: Lhomond S

PROVIDER: S-EPMC5840541 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Dual IRE1 RNase functions dictate glioblastoma development.

Lhomond Stéphanie S Avril Tony T Dejeans Nicolas N Voutetakis Konstantinos K Doultsinos Dimitrios D McMahon Mari M Pineau Raphaël R Obacz Joanna J Papadodima Olga O Jouan Florence F Bourien Heloise H Logotheti Marianthi M Jégou Gwénaële G Pallares-Lupon Néstor N Schmit Kathleen K Le Reste Pierre-Jean PJ Etcheverry Amandine A Mosser Jean J Barroso Kim K Vauléon Elodie E Maurel Marion M Samali Afshin A Patterson John B JB Pluquet Olivier O Hetz Claudio C Quillien Véronique V Chatziioannou Aristotelis A Chevet Eric E

EMBO molecular medicine 20180301 3

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRN ...[more]

PMID: 29311133

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Project description:Ire1 is a signal transduction protein in the endoplasmic reticulum (ER) membrane that serves to adjust the protein-folding capacity of the ER according to the needs of the cell. Ire1 signals, in a transcriptional program, the unfolded protein response (UPR) via the coordinated action of its protein kinase and RNase domains. In this study, we investigated how the binding of cofactors to the kinase domain of Ire1 modulates its RNase activity.Our results suggest that the kinase domain of Ire1 initially binds cofactors without activation of the RNase domain. RNase is activated upon a subsequent conformational rearrangement of Ire1 governed by the chemical properties of bound cofactors. The conformational step can be selectively inhibited by chemical perturbations of cofactors. Substitution of a single oxygen atom in the terminal ?-phosphate group of a potent cofactor ADP by sulfur results in ADP?S, a cofactor that binds to Ire1 as well as to ADP but does not activate RNase. RNase activity can be rescued by thiophilic metal ions such as Mn2+ and Cd2+, revealing a functional metal ion-phosphate interaction which controls the conformation and RNase activity of the Ire1 ADP complex. Mutagenesis of the kinase domain suggests that this rearrangement involves movement of the ?C-helix, which is generally conserved among protein kinases. Using X-ray crystallography, we show that oligomerization of Ire1 is sufficient for placing the ?C-helix in the active, cofactor-bound-like conformation, even in the absence of cofactors.Our structural and biochemical evidence converges on a model that the cofactor-induced conformational change in Ire1 is coupled to oligomerization of the receptor, which, in turn, activates RNase. The data reveal that cofactor-Ire1 interactions occur in two independent steps: binding of a cofactor to Ire1 and subsequent rearrangement of Ire1 resulting in its self-association. The pronounced allosteric effect of cofactors on protein-protein interactions involving Ire1's kinase domain suggests that protein kinases and pseudokinases encoded in metazoan genomes may use ATP pocket-binding ligands similarly to exert signaling roles other than phosphoryl transfer.

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Dual IRE1 RNase functions dictate glioblastoma development.

Publications

Dual IRE1 RNase functions dictate glioblastoma development.

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