IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma. Obacz, J., Archambeau, J., Lafont, E., Nivet, M., Martin, S., Aubry, M., Voutetakis, K., Pineau, R., Boniface, R., Sicari, D., Pelizzari-Raymundo, D., Ghukasyan, G., McGrath, E., Vlachavas, E., Le Gallo, M., Le Reste, P. J., Barroso, K., Fainsod-Levi, T., Obiedat, A., Granot, Z., Tirosh, B., Samal, J., Pandit, A., Négroni, L., Soriano, N., Monnier, A., Mosser, J., Chatziioannou, A., Quillien, V., Chevet, E., & Avril, T. Neuro Oncol, December, 2023.
doi  abstract   bibtex   
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), one of the UPR transducers, promotes GB invasion, angiogenesis and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment towards 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 (RIDD) controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, ensuing chemokine production and myeloid infiltration in tumors. CONCLUSION: Our work identifies a novel IRE1/UBE2D3 pro-inflammatory axis that plays an instrumental role in GB immune regulation.
@article{obacz_ire1_2023,
	title = {{IRE1} endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma},
	issn = {1523-5866},
	doi = {10.1093/neuonc/noad256},
	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), one of the UPR transducers, promotes GB invasion, angiogenesis and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment towards 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 (RIDD) controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, ensuing chemokine production and myeloid infiltration in tumors.
CONCLUSION: Our work identifies a novel IRE1/UBE2D3 pro-inflammatory axis that plays an instrumental role in GB immune regulation.},
	language = {eng},
	journal = {Neuro Oncol},
	author = {Obacz, Joanna and Archambeau, Jérôme and Lafont, Elodie and Nivet, Manon and Martin, Sophie and Aubry, Marc and Voutetakis, Konstantinos and Pineau, Raphael and Boniface, Rachel and Sicari, Daria and Pelizzari-Raymundo, Diana and Ghukasyan, Gevorg and McGrath, Eoghan and Vlachavas, Efstathios-Iason and Le Gallo, Matthieu and Le Reste, Pierre Jean and Barroso, Kim and Fainsod-Levi, Tanya and Obiedat, Akram and Granot, Zvi and Tirosh, Boaz and Samal, Juhi and Pandit, Abhay and Négroni, Luc and Soriano, Nicolas and Monnier, Annabelle and Mosser, Jean and Chatziioannou, Aristotelis and Quillien, Véronique and Chevet, Eric and Avril, Tony},
	month = dec,
	year = {2023},
	pmid = {38153426},
	keywords = {chemokines, ER stress, glioblastoma, inflammation, IRE1},
	pages = {noad256},
}
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