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Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis

Author

Listed:
  • Katherine Labbé

    (Calico Life Sciences LLC)

  • Lauren LeBon

    (Calico Life Sciences LLC)

  • Bryan King

    (Calico Life Sciences LLC)

  • Ngoc Vu

    (Calico Life Sciences LLC)

  • Emily H. Stoops

    (Calico Life Sciences LLC)

  • Nina Ly

    (Calico Life Sciences LLC)

  • Austin E. Y. T. Lefebvre

    (Calico Life Sciences LLC)

  • Phillip Seitzer

    (Calico Life Sciences LLC)

  • Swathi Krishnan

    (Calico Life Sciences LLC)

  • Jin-Mi Heo

    (Calico Life Sciences LLC)

  • Bryson Bennett

    (Calico Life Sciences LLC)

  • Carmela Sidrauski

    (Calico Life Sciences LLC)

Abstract

The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.

Suggested Citation

  • Katherine Labbé & Lauren LeBon & Bryan King & Ngoc Vu & Emily H. Stoops & Nina Ly & Austin E. Y. T. Lefebvre & Phillip Seitzer & Swathi Krishnan & Jin-Mi Heo & Bryson Bennett & Carmela Sidrauski, 2024. "Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52538-5
    DOI: 10.1038/s41467-024-52538-5
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    References listed on IDEAS

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    1. Tomas Adomavicius & Margherita Guaita & Yu Zhou & Martin D. Jennings & Zakia Latif & Alan M. Roseman & Graham D. Pavitt, 2019. "The structural basis of translational control by eIF2 phosphorylation," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Yang Li & Alexis A Jourdain & Sarah E Calvo & Jun S Liu & Vamsi K Mootha, 2017. "CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets," PLOS Computational Biology, Public Library of Science, vol. 13(7), pages 1-29, July.
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