IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma

Joanna Obacz, Jerome Archambeau, Elodie Lafont, Manon Nivet, Sophie Martin, Marc Aubry, Konstantinos Voutetakis, Raphael Pineau, Rachel Boniface, Daria Sicari, Diana Pelizzari-Raymundo, Gevorg Ghukasyan, Eoghan McGrath, Efstathios Iason Vlachavas, Matthieu Le Gallo, Pierre Jean Le Reste, Kim Barroso, Tanya Fainsod-Levi, Akram Obiedat, Zvi GranotBoaz Tirosh, Juhi Samal, Abhay Pandit, Luc Negroni, Nicolas Soriano, Annabelle Monnier, Jean Mosser, Aristotelis Chatziioannou, Veronique Quillien, Eric Chevet, Tony Avril*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Intrinsic or environmental stresses trigger the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), leading to ER stress. To cope with this, cells have evolved an adaptive mechanism named the unfolded protein response (UPR) which is hijacked by tumor cells to develop malignant features. Glioblastoma (GB), the most aggressive and lethal primary brain tumor, relies on UPR to sustain growth. We recently showed that IRE1 alpha (referred to IRE1 hereafter), 1 of the UPR transducers, promotes GB invasion, angiogenesis, and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts a worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment toward monocytes/macrophages and neutrophils. Methods: We used human and mouse cellular models in which IRE1 was genetically or pharmacologically invalidated and which were tested in vivo. Publicly available datasets from GB patients were also analyzed to confirm our findings. Results: We showed that IRE1 signaling, through both the transcription factor XBP1s and the regulated IRE1-dependent decay controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, resulting in chemokine production and myeloid infiltration in tumors. Conclusions: Our work identifies a novel IRE1/UBE2D3 proinflammatory axis that plays an instrumental role in GB immune regulation.

Original languageAmerican English
Pages (from-to)858-871
Number of pages14
JournalNeuro-Oncology
Volume26
Issue number5
DOIs
StatePublished - 1 May 2024

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site - for further information please contact journals.permissions@oup.com.

Keywords

  • ER stress
  • IRE1
  • chemokines
  • glioblastoma
  • inflammation

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