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.

Center for Gene Regulation in Health and Disease Cleveland State University Cleveland OH USA

College of Sciences and Health Profession King Saud bin Abdulaziz University for Health Sciences Jeddah Saudi Arabia

Department of Biochemistry Case Western Reserve University Cleveland OH USA

Department of Biochemistry McGill University Montreal Quebec Canada

Department of Biological Sciences Louisiana State University Baton Rouge LA USA

Department of Biology New York University New York NY USA

Department of Cell Biology and Molecular Genetics University of Maryland College Park MD USA

Department of Genetics and Genome Sciences Case Western Reserve University Cleveland OH USA

Department of Molecular Biology Institute of Biological Sciences Maria Curie Skłodowska University Lublin Poland

Department of Molecular Biophysics and Biochemistry Yale University New Haven CT USA

Department of Oncology Pathology Karolinska Institute Science of Life Laboratory Solna Sweden

Department of Pharmacology Case Western Reserve University Cleveland OH USA

Division of Clinical and Translational Research Department of Medicine Faculty of Medicine McGill University Montreal Quebec Canada

Gerald Bronfman Department of Oncology Faculty of Medicine McGill University Montreal Quebec Canada

Institute for Bioscience and Biotechnology Research University of Maryland Rockville MD USA

Institute for Glial Sciences Case Western Reserve University School of Medicine Cleveland OH USA

King Abdullah International Medical Research Center Jeddah Saudi Arabia

Laboratory of Genetics and Genomics National Institute of Aging Intramural Research Program NIH Baltimore MD USA

Laboratory of Regulation of Gene Expression Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Lady Davis Institute for Medical Research Sir Mortimer B Davis Jewish General Hospital Montreal Quebec Canada

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