0635913 - MBÚ 2026 RIV GB eng J - Journal Article
Chen, C. - Papadopoli, D. - Szkop, K. J. - Guan, B. - Alzahrani, M. - Wu, J. - Jobava, R. - Asraf, M. M. - Krokowski, D. - Vourekas, A. - Merrick, W. C. - Komar, A. A. - Koromilas, Antonis E. - Gorospe, M. - Payea, M. J. - Wang, F. - Clayton, Benjamin L. L. - Tesar, P. J. - Schaffer, A. - Miron, A. - Bederman, I. - Jankowsky, E. - Vogel, C. - Valášek, Leoš Shivaya - Dinman, J. D. - Zhang, Y. - Tirosh, B. - Larsson, O. - Topisirovic, I. - Hatzoglou, M.
Plasticity of the mammalian integrated stress response.
Nature. Roč. 641, č. 8065 (2025), s. 1319-1328. ISSN 0028-0836. E-ISSN 1476-4687
R&D Projects: GA ČR(CZ) GX19-25821X; GA MŠMT(CZ) EH22_008/0004575
Institutional support: RVO:61388971
Keywords : messenger-rna translation * vanishing white-matter * eif2 phosphorylation * cell-proliferation * protein-synthesis * gene-expression * adaptation * dephosphorylation * reinitiation
OECD category: Cell biology
Impact factor: 50.5, year: 2023 ; AIS: 24.765, rok: 2023
Method of publishing: Open access
Result website:
https://www.nature.com/articles/s41586-025-08794-6DOI: https://doi.org/10.1038/s41586-025-08794-6

An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-alpha (eIF2 alpha, encoded by EIF2S1, eIF2 alpha-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2 alpha-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2 alpha-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.
Permanent Link: https://hdl.handle.net/11104/0366898
Research data: Gene Expression Omnibus repository