Plasticity of the mammalian integrated stress response

• 成果类型: Article
• 署名作者: Chen, Chien-Wen; Papadopoli, David; Szkop, Krzysztof J.; Guan, Bo-Jhih; Alzahrani, Mohammed; Wu, Jing; Jobava, Raul; Asraf, Mais M.; Krokowski, Dawid; Vourekas, Anastasios; Merrick, William C.; Komar, Anton A.; Koromilas, Antonis E.; Gorospe, Myriam; Payea, Matthew J.; Wang, Fangfang; Clayton, Benjamin L. L.; Tesar, Paul J.; Schaffer, Ashleigh; Miron, Alexander; Bederman, Ilya; Jankowsky, Eckhard; Vogel, Christine; Valasek, Leos Shivaya; Dinman, Jonathan D.; Zhang, Youwei; Tirosh, Boaz; Larsson, Ola; Topisirovic, Ivan; Hatzoglou, Maria
• 署名单位: University System of Ohio; Case Western Reserve University; Lady Davis Institute; Jewish General Hospital - Montreal; McGill University; Karolinska Institutet; University System of Ohio; Case Western Reserve University; King Saud Bin Abdulaziz University for Health Sciences; Yale University; Maria Curie-Sklodowska University; Louisiana State University System; Louisiana State University; University System of Ohio; Cleveland State University; McGill University; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; New York University; Czech Academy of Sciences; Institute of Microbiology of the Czech Academy of Sciences; University System of Maryland; University of Maryland College Park; University System of Maryland; University of Maryland Baltimore; Universities at Shady Grove; McGill University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2267
• DOI: 10.1038/s41586-025-08794-6
• 发表日期: 2025-05-29
• 关键词: messenger-rna translation; vanishing white-matter; eif2 phosphorylation; cell-proliferation; protein-synthesis; gene-expression; adaptation; dephosphorylation; reinitiation

摘要

An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-alpha (eIF2 alpha, encoded by EIF2S1; eIF2 alpha-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 eIF2 alpha-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 eIF2 alpha-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.