2. Academic Validation
  3. Plasticity of the mammalian integrated stress response

Plasticity of the mammalian integrated stress response

  • Nature. 2025 May;641(8065):1319-1328. doi: 10.1038/s41586-025-08794-6.
Chien-Wen Chen # 1,  David Papadopoli # 2 3,  Krzysztof J Szkop # 4,  Bo-Jhih Guan 1,  Mohammed Alzahrani 5 6 7,  Jing Wu 1,  Raul Jobava 1 8,  Mais M Asraf 1,  Dawid Krokowski 9,  Anastasios Vourekas 10,  William C Merrick 5,  Anton A Komar 5 11,  Antonis E Koromilas 2 3 12,  Myriam Gorospe 13,  Matthew J Payea 13,  Fangfang Wang 14,  Benjamin L L Clayton 1 15,  Paul J Tesar 1 15,  Ashleigh Schaffer 1,  Alexander Miron 1,  Ilya Bederman 1,  Eckhard Jankowsky 5,  Christine Vogel 16,  Leoš Shivaya Valášek 17,  Jonathan D Dinman 18 19,  Youwei Zhang 14,  Boaz Tirosh 5,  Ola Larsson 20,  Ivan Topisirovic 21 22 23 24,  Maria Hatzoglou 25
Affiliations

Affiliations

  • 1 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • 2 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
  • 3 Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
  • 4 Department of Oncology-Pathology, Karolinska Institute, Science of Life Laboratory, Solna, Sweden.
  • 5 Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA.
  • 6 College of Sciences and Health Profession, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
  • 7 King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.
  • 8 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  • 9 Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland.
  • 10 Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, USA.
  • 11 Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, USA.
  • 12 Division of Clinical and Translational Research, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
  • 13 Laboratory of Genetics and Genomics, National Institute of Aging Intramural Research Program, NIH, Baltimore, MD, USA.
  • 14 Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
  • 15 Institute for Glial Sciences, Case Western Reserve University, School of Medicine, Cleveland, OH, USA.
  • 16 Department of Biology, New York University, New York, NY, USA.
  • 17 Laboratory of Regulation of Gene Expression, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.
  • 18 Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA.
  • 19 Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, USA.
  • 20 Department of Oncology-Pathology, Karolinska Institute, Science of Life Laboratory, Solna, Sweden. ola.larsson@ki.se.
  • 21 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. ivan.topisirovic@mcgill.ca.
  • 22 Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. ivan.topisirovic@mcgill.ca.
  • 23 Division of Clinical and Translational Research, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. ivan.topisirovic@mcgill.ca.
  • 24 Department of Biochemistry, McGill University, Montreal, Quebec, Canada. ivan.topisirovic@mcgill.ca.
  • 25 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. mxh8@case.edu.
  • # Contributed equally.
PMID: 40140574 DOI: 10.1038/s41586-025-08794-6
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.

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