Plasticity of the mammalian integrated stress response PMID: 40140574

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
21. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. [email protected].
22. Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. [email protected].
23. Division of Clinical and Translational Research, Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. [email protected].
24. Department of Biochemistry, McGill University, Montreal, Quebec, Canada. [email protected].
25. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. [email protected].
# Contributed equally.

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.