TY - JOUR
T1 - Plasticity of the mammalian integrated stress response
AU - Chen, Chien Wen
AU - Papadopoli, David
AU - Szkop, Krzysztof J.
AU - Guan, Bo Jhih
AU - Alzahrani, Mohammed
AU - Wu, Jing
AU - Jobava, Raul
AU - Asraf, Mais M.
AU - Krokowski, Dawid
AU - Vourekas, Anastasios
AU - Merrick, William C.
AU - Komar, Anton A.
AU - Koromilas, Antonis E.
AU - Gorospe, Myriam
AU - Payea, Matthew J.
AU - Wang, Fangfang
AU - Clayton, Benjamin L.L.
AU - Tesar, Paul J.
AU - Schaffer, Ashleigh
AU - Miron, Alexander
AU - Bederman, Ilya
AU - Jankowsky, Eckhard
AU - Vogel, Christine
AU - Valášek, Leoš Shivaya
AU - Dinman, Jonathan D.
AU - Zhang, Youwei
AU - Tirosh, Boaz
AU - Larsson, Ola
AU - Topisirovic, Ivan
AU - Hatzoglou, Maria
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/5/29
Y1 - 2025/5/29
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105001482163
U2 - 10.1038/s41586-025-08794-6
DO - 10.1038/s41586-025-08794-6
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C2 - 40140574
AN - SCOPUS:105001482163
SN - 0028-0836
VL - 641
SP - 1319
EP - 1328
JO - Nature
JF - Nature
IS - 8065
M1 - e1900009
ER -