Plasticity of the mammalian integrated stress response

Chien-Wen Chen, David Papadopoli, Krzysztof J. Szkop, Bo-Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M. Asraf, Dawid Krokowski, Anastasios Vourekas, William C. Merrick, Anton A. Komar, Antonis E. Koromilas, Myriam Gorospe, Matthew J. Payea, Fangfang Wang, Benjamin L. L. Clayton, Paul J. Tesar, Ashleigh Schaffer, Alexander Miron, Ilya Bederman, Eckhard Jankowsky, Christine Vogel, Leoš Shivaya Valášek, Jonathan D. Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson (), Ivan Topisirovic () and Maria Hatzoglou ()
Additional contact information
Chien-Wen Chen: Case Western Reserve University
David Papadopoli: Sir Mortimer B. Davis-Jewish General Hospital
Krzysztof J. Szkop: Science of Life Laboratory
Bo-Jhih Guan: Case Western Reserve University
Mohammed Alzahrani: Case Western Reserve University
Jing Wu: Case Western Reserve University
Raul Jobava: Case Western Reserve University
Mais M. Asraf: Case Western Reserve University
Dawid Krokowski: Maria Curie-Skłodowska University
Anastasios Vourekas: Louisiana State University
William C. Merrick: Case Western Reserve University
Anton A. Komar: Case Western Reserve University
Antonis E. Koromilas: Sir Mortimer B. Davis-Jewish General Hospital
Myriam Gorospe: NIH
Matthew J. Payea: NIH
Fangfang Wang: Case Western Reserve University
Benjamin L. L. Clayton: Case Western Reserve University
Paul J. Tesar: Case Western Reserve University
Ashleigh Schaffer: Case Western Reserve University
Alexander Miron: Case Western Reserve University
Ilya Bederman: Case Western Reserve University
Eckhard Jankowsky: Case Western Reserve University
Christine Vogel: New York University
Leoš Shivaya Valášek: Institute of Microbiology of the Czech Academy of Sciences
Jonathan D. Dinman: University of Maryland
Youwei Zhang: Case Western Reserve University
Boaz Tirosh: Case Western Reserve University
Ola Larsson: Science of Life Laboratory
Ivan Topisirovic: Sir Mortimer B. Davis-Jewish General Hospital
Maria Hatzoglou: Case Western Reserve University

Nature, 2025, vol. 641, issue 8065, 1319-1328

Abstract: Abstract An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-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 eIF2α-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 eIF2α-p induction activates the eIF4E–ATF4–PCK2 axis to maintain energy homeostasis.

Date: 2025
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DOI: 10.1038/s41586-025-08794-6

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