CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The MYC‑amplified group 3 (G3) MB represents a high‑risk disease lacking effective therapies. A genetic screen identified the endoplasmic reticulum chaperone HSPA5 (BiP/GRP78) as a critical dependency in G3 MB. Its silencing induces apoptosis and suppresses tumor growth, with strong activation of the unfolded protein response (UPR). The UPR includes three branches, including the PERK–eIF2α axis, which transiently reduces global protein synthesis while enabling selective translation of stress‑responsive factors such as ATF4. We show that G3 MB requires sustained eIF2α activity for survival. Its inhibition triggers cell death through ATF4‑dependent and ‑independent transcriptional programs and translational reprogramming that deplete essential proteins and promote accumulation of detrimental factors. The eIF2α phosphatase PPP1R15B (CReP) maintains basal eIF2α activity and prevents apoptosis. These findings identify the eIF2α axis and its regulators as a crucial node and a targetable vulnerability in G3 MB. Group 3 (G3) medulloblastoma is an aggressive paediatric brain tumour with limited treatment options. Here, the authors show that CReP phosphatase maintains eIF2α activity, thereby protecting G3 MB cells from apoptosis, and that these cells are sensitive to eIF2α inactivation.

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Publication Details

Journal
Nature Communications
Published
2026-09-11
DOI
https://doi.org/10.1038/s41467-026-77565-2
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
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article

CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma

Franck Bourdeaut, Bertrand Duvillié, Olivier Ayrault, Damarys Loew et al.
Nature Communications
Endoplasmic Reticulum Stress and Disease
article

CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma

Franck Bourdeaut, Bertrand Duvillié, Olivier Ayrault, Damarys Loew, Magalie Larcher, Sara Chabi, Marion Le Grand, Sabine Druillennec, Florence M.G. Cavalli, Dave Yong Xiang Ng, Alain Eychène, Liliana Mirabal-Ortega, Rachid Benhida, Florent Dingli, Cristèle Gilbert, Célio Pouponnot, Éric Chevet, François Doz, Véronique Marsaud, Frank Griscelli, Eddy Pasquier, Sophie Leboucher, Sandra Majo, Marine Blanchard, Jacob Torrejón, Michael D. Taylor, Boris Julien, Ka Moustapha, Annelise Bennaceur-Griscelli, Sofia Gaid, Laure Lagaye, Coline Kerbaj, Kevin Muller, Lucie J Taunay
article en

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The MYC‑amplified group 3 (G3) MB represents a high‑risk disease lacking effective therapies. A genetic screen identified the endoplasmic reticulum chaperone HSPA5 (BiP/GRP78) as a critical dependency in G3 MB. Its silencing induces apoptosis and suppresses tumor growth, with strong activation of the unfolded protein response (UPR). The UPR includes three branches, including the PERK–eIF2α axis, which transiently reduces global protein synthesis while enabling selective translation of stress‑responsive factors such as ATF4. We show that G3 MB requires sustained eIF2α activity for survival. Its inhibition triggers cell death through ATF4‑dependent and ‑independent transcriptional programs and translational reprogramming that deplete essential proteins and promote accumulation of detrimental factors. The eIF2α phosphatase PPP1R15B (CReP) maintains basal eIF2α activity and prevents apoptosis. These findings identify the eIF2α axis and its regulators as a crucial node and a targetable vulnerability in G3 MB. Group 3 (G3) medulloblastoma is an aggressive paediatric brain tumour with limited treatment options. Here, the authors show that CReP phosphatase maintains eIF2α activity, thereby protecting G3 MB cells from apoptosis, and that these cells are sensitive to eIF2α inactivation.

Nature Communications
Centre National de la Recherche Scientifique (FR), Inserm (FR), Baylor College of Medicine (US), Université Côte d'Azur (FR), Université Paris Cité (FR), Université Paris Sciences et Lettres (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Institut de Chimie de Nice (FR), Oncogenesis Stress Signaling (FR), Centre Eugène Marquis (FR), Centre de Recherche en Cancérologie de Marseille (FR), Children's Cancer Center (US), Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (FR), Université de Rennes (FR), École Nationale Supérieure des Mines de Paris (FR), Institut Curie (FR)
Institut National Du Cancer
Good health and well-being
Openalex Percentile: Top 14%
Endoplasmic Reticulum Stress and Disease
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