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PreprintCited by 34RNA and protein synthesis mechanismsPI3K/AKT/mTOR signaling in cancerEndoplasmic Reticulum Stress and Disease

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eIF4E3 Forms an Active eIF4F Complex during Stresses (eIF4F S ) Targeting mTOR and Re-Programs the Translatome

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Weiss, B., Allen, G.E., Kloehn, J., Abid, K., Jaquier-Gubler, P., Curran, J.A.·2021·Nucleic Acids Research
DOI 10.1101/2021.01.22.427788PMC PMC8136781

Preprint — published as 10.1093/nar/gkab267 · Paper page

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Abstract

The eIF4E are a family of initiation factors that bind the mRNA 5’ cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4F S ) is translationally active only during stress and that it selects specific mRNA populations based on 5’ TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have “moon-lighting” functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote “stress resistance” and adaptation.

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Metadata

Authors
Weiss, B., Allen, G. E., Kloehn, J., Abid, K., Jaquier-Gubler, P., & Curran, J. A.
Affiliations
  • University of Geneva (CH)
  • Centre Hospitalier Universitaire Vaudois (CH)
Corresponding author
Curran, J.A.
ORCID
Venue
Nucleic Acids Research
Publisher
openRxiv
Published
2021-01-23
Volume
49
Issue
9
Pages
5159-5176
ISSN
0305-1048 (ISSN-L)
DOI
10.1101/2021.01.22.427788
PMC
PMC8136781
OpenAlex
W3155693148
Cited by
34
References
1
Citations by year
2026: 5 · 2025: 7 · 2024: 7 · 2023: 11 · 2022: 3 · 2021: 1
FWCI
1.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • IRIS (submittedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, other-oa)
Funders
  • European Commission (695596)
  • Ligue Genevoise Contre le Cancer
  • Université de Genève
  • Société Académique de Genève
  • Fondation Ernst et Lucie Schmidheiny
  • H2020 European Research Council (695596)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
EIF4E3, eIF4F, mTOR, integrated stress response, translational regulation, Torin1, 4E-BP1, cellular metabolism, stress tolerance, ribosome profiling, moonlighting proteins
MeSH terms
Animals, Cells, Cultured, Humans, Naphthyridines, RNA Caps, Stress, Physiological, Protein Biosynthesis, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factor-4F, Eukaryotic Initiation Factors, Mice, TOR Serine-Threonine Kinases

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