An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

Mónica Román-Trufero; Istvan T. Kleijn; Kevin Blighe; Jinglin Zhou; Paula Saavedra-García; Abigail Gaffar; Marilena Christoforou; Axel Bellotti; Joel Abrahams; Abdelmadjid Atrih; Douglas Lamont; Marek Gierlinski; Pooja Jayaprakash; Audrey M. Michel; Eric O. Aboagye; Mariia Yuneva; Glenn R. Masson; Vahid Shahrezaei; Holger W. Auner

doi:10.26508/lsa.202403014

An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

Mónica Román-Trufero, Istvan T. Kleijn, Kevin Blighe, Jinglin Zhou, Paula Saavedra-García, Abigail Gaffar, Marilena Christoforou, Axel Bellotti, Joel Abrahams, Abdelmadjid Atrih, Douglas Lamont, Marek Gierlinski, Pooja Jayaprakash, Audrey M. Michel, Eric O. Aboagye, Mariia Yuneva, Glenn R. Masson, Vahid Shahrezaei, Holger W. Auner (Lead / Corresponding author)

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Abstract

The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in reg-ulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.

Original language	English
Article number	e202403014
Number of pages	18
Journal	Life Science Alliance
Volume	8
Issue number	5
Early online date	3 Mar 2025
DOIs	https://doi.org/10.26508/lsa.202403014
Publication status	Published - May 2025

ASJC Scopus subject areas

Ecology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Plant Science
Health, Toxicology and Mutagenesis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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License: This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/ licenses/by/4.0/).
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Román-Trufero, M., Kleijn, I. T., Blighe, K., Zhou, J., Saavedra-García, P., Gaffar, A., Christoforou, M., Bellotti, A., Abrahams, J., Atrih, A., Lamont, D., Gierlinski, M., Jayaprakash, P., Michel, A. M., Aboagye, E. O., Yuneva, M., Masson, G. R., Shahrezaei, V., & Auner, H. W. (2025). An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation. Life Science Alliance, 8(5), Article e202403014. https://doi.org/10.26508/lsa.202403014

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title = "An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation",

abstract = "The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in reg-ulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.",

author = "M{\'o}nica Rom{\'a}n-Trufero and Kleijn, \{Istvan T.\} and Kevin Blighe and Jinglin Zhou and Paula Saavedra-Garc{\'i}a and Abigail Gaffar and Marilena Christoforou and Axel Bellotti and Joel Abrahams and Abdelmadjid Atrih and Douglas Lamont and Marek Gierlinski and Pooja Jayaprakash and Michel, \{Audrey M.\} and Aboagye, \{Eric O.\} and Mariia Yuneva and Masson, \{Glenn R.\} and Vahid Shahrezaei and Auner, \{Holger W.\}",

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year = "2025",

month = may,

doi = "10.26508/lsa.202403014",

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Román-Trufero, M, Kleijn, IT, Blighe, K, Zhou, J, Saavedra-García, P, Gaffar, A, Christoforou, M, Bellotti, A, Abrahams, J, Atrih, A, Lamont, D, Gierlinski, M, Jayaprakash, P, Michel, AM, Aboagye, EO, Yuneva, M, Masson, GR, Shahrezaei, V & Auner, HW 2025, 'An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation', Life Science Alliance, vol. 8, no. 5, e202403014. https://doi.org/10.26508/lsa.202403014

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T1 - An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

AU - Román-Trufero, Mónica

AU - Kleijn, Istvan T.

AU - Blighe, Kevin

AU - Zhou, Jinglin

AU - Saavedra-García, Paula

AU - Gaffar, Abigail

AU - Christoforou, Marilena

AU - Bellotti, Axel

AU - Abrahams, Joel

AU - Atrih, Abdelmadjid

AU - Lamont, Douglas

AU - Gierlinski, Marek

AU - Jayaprakash, Pooja

AU - Michel, Audrey M.

AU - Aboagye, Eric O.

AU - Yuneva, Mariia

AU - Masson, Glenn R.

AU - Shahrezaei, Vahid

AU - Auner, Holger W.

PY - 2025/5

Y1 - 2025/5

N2 - The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in reg-ulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.

AB - The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in reg-ulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.

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DO - 10.26508/lsa.202403014

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AN - SCOPUS:86000266103

SN - 2575-1077

VL - 8

JO - Life Science Alliance

JF - Life Science Alliance

IS - 5

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ER -

An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

Abstract

ASJC Scopus subject areas

UN SDGs

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