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CReP-mediated control of eIF2a 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Vanessa Masson

LAB HEAD: Damarys Loew

PROVIDER: PXD077318 | Pride | 2026-07-21

REPOSITORIES: Pride

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			Action	DRS
	Design_PRIDE_Mirabal_Ortega.xlsx	Xlsx
	H5570FD.msf	Msf
	H5570FD.raw	Raw
	H5571FD.msf	Msf
	H5571FD.raw	Raw

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