Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism

  1. Leonie Zeitler
  2. Alessandra Fiore
  3. Claudia Meyer
  4. Marion Russier
  5. Gaia Zanella
  6. Sabine Suppmann
  7. Marco Gagaro
  8. Sachdev S Sidhu
  9. Somasekar Seshagiri
  10. Caspar Ohnmacht
  11. Thomas Köcher
  12. Francesca Fallarino
  13. Andreas Linkermann
  14. Peter J Murray  Is a corresponding author
  1. Max Planck Institute for Biochemistry, Germany
  2. Universitätsklinikum Carl Gustav Carus Dresden, Germany
  3. Max Planck Institute of Biochemistry, Germany
  4. Università degli Studi di Perugia, Italy
  5. University of Toronto, Canada
  6. SciGenom, India
  7. Helmholtz Zentrum, Germany
  8. Vienna BioCenter, Austria
  9. Technical University of Dresden, Germany

Abstract

Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologues in snake venoms (LAAO, L-amino acid oxidases), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell productive gene expression program inhibiting ferroptotic redox death by generating indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and through the activation of an anti-oxidative gene expression program. Thus, the pro-tumor effects of IL4i1 are likely mediated by local anti-ferroptotic pathways via aromatic amino acid metabolism, arguing that an IL4i1 inhibitor may modulate tumor cell death pathways.

Data availability

RNAseq data have been deposited in GEO under accession code GSE161159, GSE167136.

Article and author information

Author details

  1. Leonie Zeitler

    Immunoregulation, Max Planck Institute for Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  2. Alessandra Fiore

    Immunoregulation, Max Planck Institute for Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  3. Claudia Meyer

    Sektion Nephrologie, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
    Competing interests
    No competing interests declared.
  4. Marion Russier

    Immunoregulation, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9633-9804
  5. Gaia Zanella

    Immunoregulation, Max Planck Institute for Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  6. Sabine Suppmann

    Immunoregulation, Max Planck Institute for Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  7. Marco Gagaro

    Dipartimento di medicina e chirurgia, Università degli Studi di Perugia, Perugia, Italy
    Competing interests
    No competing interests declared.
  8. Sachdev S Sidhu

    Donnelly Centre, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7755-5918
  9. Somasekar Seshagiri

    Research Foundation, SciGenom, Bangalore, India
    Competing interests
    No competing interests declared.
  10. Caspar Ohnmacht

    Center of Allergy and Environment, Helmholtz Zentrum, Munich, Germany
    Competing interests
    No competing interests declared.
  11. Thomas Köcher

    Core Facilities GmbH, Vienna BioCenter, Vienna, Austria
    Competing interests
    Thomas Köcher, Thomas Köcher is affiliated with Vienna BioCenter Core Facilities GmbH. The author has no financial interests to declare..
  12. Francesca Fallarino

    Dipartimento di medicina e chirurgia, Università degli Studi di Perugia, Perugia, Italy
    Competing interests
    No competing interests declared.
  13. Andreas Linkermann

    Technical University of Dresden, Dresden, Germany
    Competing interests
    No competing interests declared.
  14. Peter J Murray

    Immunoregulation, Max Planck Institute for Biochemistry, Martinsried, Germany
    For correspondence
    murray@biochem.mpg.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6329-9802

Funding

Deutsche Forschungsgemeinschaft (SFB-TRR 127)

  • Andreas Linkermann
  • Peter J Murray

Deutsche Forschungsgemeinschaft (FOR 2599)

  • Caspar Ohnmacht
  • Peter J Murray

Deutsche Forschungsgemeinschaft (SFB-TRR 205)

  • Andreas Linkermann

Max-Planck-Gesellschaft

  • Peter J Murray

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Tiffany Horng, ShanghaiTech University, China

Publication history

  1. Received: November 11, 2020
  2. Accepted: February 26, 2021
  3. Accepted Manuscript published: March 1, 2021 (version 1)
  4. Version of Record published: March 10, 2021 (version 2)

Copyright

© 2021, Zeitler et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Leonie Zeitler
  2. Alessandra Fiore
  3. Claudia Meyer
  4. Marion Russier
  5. Gaia Zanella
  6. Sabine Suppmann
  7. Marco Gagaro
  8. Sachdev S Sidhu
  9. Somasekar Seshagiri
  10. Caspar Ohnmacht
  11. Thomas Köcher
  12. Francesca Fallarino
  13. Andreas Linkermann
  14. Peter J Murray
(2021)
Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism
eLife 10:e64806.
https://doi.org/10.7554/eLife.64806

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