Plasticity of the mammalian integrated stress response
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)<sup>1</sup>. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies<sup>2</sup>, 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.
Authors
- Antonis E. Koromilas (ORCID: https://orcid.org/0000-0003-1972-0799)
- Anastassios Vourekas (ORCID: https://orcid.org/0000-0002-1850-5635)
- Ivan Topisirović
- Raul Jobava
- Dawid Krokowski
- Youwei Zhang (ORCID: https://orcid.org/0000-0003-0011-7922)
- Mohammed R. Alzahrani (ORCID: https://orcid.org/0000-0001-7291-5275)
- David Papadopoli
- Anton A. Komar (ORCID: https://orcid.org/0000-0003-4188-0633)
- Ilya Bederman (ORCID: https://orcid.org/0000-0002-1909-5746)
- Leoš Shivaya Valášek (ORCID: https://orcid.org/0000-0001-8123-8667)
- Ashleigh E. Schaffer (ORCID: https://orcid.org/0000-0002-1164-697X)
- Matthew J. Payea (ORCID: https://orcid.org/0000-0002-1960-4563)
- Christine Vogel (ORCID: https://orcid.org/0000-0002-2856-3118)
- Maria Hatzoglou (ORCID: https://orcid.org/0000-0003-2037-1231)
- Paul J. Tesar (ORCID: https://orcid.org/0000-0003-1532-3155)
- Myriam Gorospe (ORCID: https://orcid.org/0000-0001-5439-3434)
- Chien-Wen Chen (ORCID: https://orcid.org/0000-0002-1214-4058)
- Benjamin L.L. Clayton (ORCID: https://orcid.org/0000-0001-9552-404X)
- Boaz Tirosh (ORCID: https://orcid.org/0000-0001-8067-6577)
- William C. Merrick
- Krzysztof J. Szkop (ORCID: https://orcid.org/0000-0001-7845-2945)
- Jonathan D. Dinman (ORCID: https://orcid.org/0000-0002-2402-9698)
- Alexander Miron
- Ola Larsson (ORCID: https://orcid.org/0000-0003-1412-1308)
- Eckhard Jankowsky (ORCID: https://orcid.org/0000-0001-7677-7412)
- Fangfang Wang (ORCID: https://orcid.org/0000-0002-1006-867X)
- Jing Wu
- Bo-Jhih Guan
- Mais M. Asraf
Institutions
- Cleveland State University (US)
- Louisiana State University (US)
- University of Maryland, Baltimore (US)
- National Institute of Standards and Technology (US)
- Maria Curie-Skłodowska University (PL)
- King Saud bin Abdulaziz University for Health Sciences (SA)
- Czech Academy of Sciences (CZ)
- Science for Life Laboratory (SE)
- Jewish General Hospital (CA)
- Karolinska Institutet (SE)
- Yale University (US)
- King Abdullah International Medical Research Center (SA)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- Institute on Aging (US)
- University School (US)
- Institute for Bioscience and Biotechnology Research
- McGill University (CA)
- New York University (US)
- Case Western Reserve University (US)
- University of Maryland, College Park (US)
Publication Details
- Journal
- Nature
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1038/s41586-025-08794-6
- Citations
- 28
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 22.57