CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma
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.
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BibTeX
@article{mirabalortega2026crepmediated,
title = {{CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma}},
author = {Liliana Mirabal-Ortega and Sandra Majo and Lucie J Taunay and Magalie Larcher and Dave Yong Xiang Ng and Sara Chabi and Marion Le Grand and Kevin Muller and Jacob Torrejón and Laure Lagaye and Sofia Gaid and Coline Kerbaj and Moustapha Ka and Cristèle Gilbert and Véronique Marsaud and Bertrand Duvillié and Marine Blanchard and Boris Julien and Sophie Leboucher and Florent Dingli and Damarys Loew and Franck Griscelli and Annelise Bennaceur-Griscelli and Franck Bourdeaut and François Doz and Olivier Ayrault and Florence Cavalli and Michael D Taylor and Alain Eychène and Rachid Benhida and Éric Chevet and Eddy Pasquier and Sabine Druillennec and Celio Pouponnot},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77565-2},
url = {https://hal.science/hal-05763127v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma
AU - Liliana Mirabal-Ortega
AU - Sandra Majo
AU - Lucie J Taunay
AU - Magalie Larcher
AU - Dave Yong Xiang Ng
AU - Sara Chabi
AU - Marion Le Grand
AU - Kevin Muller
AU - Jacob Torrejón
AU - Laure Lagaye
AU - Sofia Gaid
AU - Coline Kerbaj
AU - Moustapha Ka
AU - Cristèle Gilbert
AU - Véronique Marsaud
AU - Bertrand Duvillié
AU - Marine Blanchard
AU - Boris Julien
AU - Sophie Leboucher
AU - Florent Dingli
AU - Damarys Loew
AU - Franck Griscelli
AU - Annelise Bennaceur-Griscelli
AU - Franck Bourdeaut
AU - François Doz
AU - Olivier Ayrault
AU - Florence Cavalli
AU - Michael D Taylor
AU - Alain Eychène
AU - Rachid Benhida
AU - Éric Chevet
AU - Eddy Pasquier
AU - Sabine Druillennec
AU - Celio Pouponnot
PY - 2026
DA - 2026/09/24
JO - Nature Communications
DO - 10.1038/s41467-026-77565-2
UR - https://hal.science/hal-05763127v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -