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The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis

Author

Listed:
  • Hannah V. Woodcock

    (University College London)

  • Jessica D. Eley

    (University College London)

  • Delphine Guillotin

    (University College London)

  • Manuela Platé

    (University College London)

  • Carmel B. Nanthakumar

    (GlaxoSmithKline R&D)

  • Matteo Martufi

    (GlaxoSmithKline R&D)

  • Simon Peace

    (GlaxoSmithKline R&D)

  • Gerard Joberty

    (Cellzome, a GSK Company)

  • Daniel Poeckel

    (Cellzome, a GSK Company)

  • Robert B. Good

    (GlaxoSmithKline R&D)

  • Adam R. Taylor

    (GlaxoSmithKline R&D)

  • Nico Zinn

    (Cellzome, a GSK Company)

  • Matthew Redding

    (University College London)

  • Ellen J. Forty

    (University College London)

  • Robert E. Hynds

    (University College London
    The Francis Crick Institute)

  • Charles Swanton

    (University College London
    The Francis Crick Institute)

  • Morten Karsdal

    (Nordic Bioscience)

  • Toby M. Maher

    (Imperial College)

  • Andrew Fisher

    (Newcastle University Translational and Clinical Research Institute)

  • Giovanna Bergamini

    (Cellzome, a GSK Company)

  • Richard P. Marshall

    (GlaxoSmithKline R&D)

  • Andy D. Blanchard

    (GlaxoSmithKline R&D)

  • Paul F. Mercer

    (University College London)

  • Rachel C. Chambers

    (University College London)

Abstract

Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-β1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies.

Suggested Citation

  • Hannah V. Woodcock & Jessica D. Eley & Delphine Guillotin & Manuela Platé & Carmel B. Nanthakumar & Matteo Martufi & Simon Peace & Gerard Joberty & Daniel Poeckel & Robert B. Good & Adam R. Taylor & N, 2019. "The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07858-8
    DOI: 10.1038/s41467-018-07858-8
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    Cited by:

    1. Valentina Gandin & Brian P. English & Melanie Freeman & Louis-Philippe Leroux & Stephan Preibisch & Deepika Walpita & Maritza Jaramillo & Robert H. Singer, 2022. "Cap-dependent translation initiation monitored in living cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Jian Huang & Luxin Wang & Yunli Shen & Shengqi Zhang & Yaqun Zhou & Jimin Du & Xiue Ma & Yi Liu & Dandan Liang & Dan Shi & Honghui Ma & Li Li & Qi Zhang & Yi-Han Chen, 2022. "CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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