Plasticity of the mammalian integrated stress response

Chien Wen Chen; David Papadopoli; Krzysztof J. Szkop; Bo Jhih Guan; Mohammed Alzahrani; Jing Wu; Raul Jobava; Mais M. Asraf; Dawid Krokowski; Anastasios Vourekas; William C. Merrick; Anton A. Komar; Antonis E. Koromilas; Myriam Gorospe; Matthew J. Payea; Fangfang Wang; Benjamin L.L. Clayton; Paul J. Tesar; Ashleigh Schaffer; Alexander Miron; Ilya Bederman; Eckhard Jankowsky; Christine Vogel; Leoš Shivaya Valášek; Jonathan D. Dinman; Youwei Zhang; Boaz Tirosh; Ola Larsson; Ivan Topisirovic; Maria Hatzoglou

doi:10.1038/s41586-025-08794-6

Plasticity of the mammalian integrated stress response

Chien Wen Chen, David Papadopoli, Krzysztof J. Szkop, Bo Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M. Asraf, Dawid Krokowski, Anastasios Vourekas, William C. Merrick, Anton A. Komar, Antonis E. Koromilas, Myriam Gorospe, Matthew J. Payea, Fangfang Wang, Benjamin L.L. Clayton, Paul J. Tesar, Ashleigh Schaffer, Alexander MironIlya Bederman, Eckhard Jankowsky, Christine Vogel, Leoš Shivaya Valášek, Jonathan D. Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson^*, Ivan Topisirovic^*, Maria Hatzoglou^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e1900009
Journal	Nature
DOIs	https://doi.org/10.1038/s41586-025-08794-6
State	Accepted/In press - 2025
Externally published	Yes

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Access to Document

10.1038/s41586-025-08794-6

Cite this

Chen, C. W., Papadopoli, D., Szkop, K. J., Guan, B. J., Alzahrani, M., Wu, J., Jobava, R., Asraf, M. M., Krokowski, D., Vourekas, A., Merrick, W. C., Komar, A. A., Koromilas, A. E., Gorospe, M., Payea, M. J., Wang, F., Clayton, B. L. L., Tesar, P. J., Schaffer, A., ... Hatzoglou, M. (Accepted/In press). Plasticity of the mammalian integrated stress response. Nature, Article e1900009. https://doi.org/10.1038/s41586-025-08794-6

@article{3ad1fb373ab441f9b771c2e0fa2396d1,

title = "Plasticity of the mammalian integrated stress response",

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 {\textquoteleft}canonical{\textquoteright} 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.",

author = "Chen, {Chien Wen} and David Papadopoli and Szkop, {Krzysztof J.} and Guan, {Bo Jhih} and Mohammed Alzahrani and Jing Wu and Raul Jobava and Asraf, {Mais M.} and Dawid Krokowski and Anastasios Vourekas and Merrick, {William C.} and Komar, {Anton A.} and Koromilas, {Antonis E.} and Myriam Gorospe and Payea, {Matthew J.} and Fangfang Wang and Clayton, {Benjamin L.L.} and Tesar, {Paul J.} and Ashleigh Schaffer and Alexander Miron and Ilya Bederman and Eckhard Jankowsky and Christine Vogel and Val{\'a}{\v s}ek, {Leo{\v s} Shivaya} and Dinman, {Jonathan D.} and Youwei Zhang and Boaz Tirosh and Ola Larsson and Ivan Topisirovic and Maria Hatzoglou",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41586-025-08794-6",

language = "אנגלית",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

}

Chen, CW, Papadopoli, D, Szkop, KJ, Guan, BJ, Alzahrani, M, Wu, J, Jobava, R, Asraf, MM, Krokowski, D, Vourekas, A, Merrick, WC, Komar, AA, Koromilas, AE, Gorospe, M, Payea, MJ, Wang, F, Clayton, BLL, Tesar, PJ, Schaffer, A, Miron, A, Bederman, I, Jankowsky, E, Vogel, C, Valášek, LS, Dinman, JD, Zhang, Y, Tirosh, B, Larsson, O, Topisirovic, I & Hatzoglou, M 2025, 'Plasticity of the mammalian integrated stress response', Nature. https://doi.org/10.1038/s41586-025-08794-6

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

PY - 2025

Y1 - 2025

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 - http://www.scopus.com/inward/record.url?scp=105001482163&partnerID=8YFLogxK

U2 - 10.1038/s41586-025-08794-6

DO - 10.1038/s41586-025-08794-6

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 40140574

AN - SCOPUS:105001482163

SN - 0028-0836

JO - Nature

JF - Nature

M1 - e1900009

ER -

Plasticity of the mammalian integrated stress response

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this