Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism
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 homologs in snake venoms (L-amino acid oxidases [LAAO]), we used comparative approaches to gain insight into the...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/64806 |
| _version_ | 1829096562063572992 |
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| author | Leonie Zeitler Alessandra Fiore Claudia Meyer Marion Russier Gaia Zanella Sabine Suppmann Marco Gargaro Sachdev S Sidhu Somasekar Seshagiri Caspar Ohnmacht Thomas Köcher Francesca Fallarino Andreas Linkermann Peter J Murray |
| author_facet | Leonie Zeitler Alessandra Fiore Claudia Meyer Marion Russier Gaia Zanella Sabine Suppmann Marco Gargaro Sachdev S Sidhu Somasekar Seshagiri Caspar Ohnmacht Thomas Köcher Francesca Fallarino Andreas Linkermann Peter J Murray |
| author_sort | Leonie Zeitler |
| collection | DOAJ |
| description | 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 homologs in snake venoms (L-amino acid oxidases [LAAO]), 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 that venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell protective 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. |
| first_indexed | 2024-04-11T08:59:33Z |
| format | Article |
| id | doaj.art-802abb05636340ee84bfc61d469910e1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T08:59:33Z |
| publishDate | 2021-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-802abb05636340ee84bfc61d469910e12022-12-22T04:32:49ZengeLife Sciences Publications LtdeLife2050-084X2021-03-011010.7554/eLife.64806Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolismLeonie Zeitler0Alessandra Fiore1https://orcid.org/0000-0003-2070-6046Claudia Meyer2Marion Russier3https://orcid.org/0000-0002-9633-9804Gaia Zanella4Sabine Suppmann5Marco Gargaro6Sachdev S Sidhu7https://orcid.org/0000-0001-7755-5918Somasekar Seshagiri8Caspar Ohnmacht9Thomas Köcher10Francesca Fallarino11Andreas Linkermann12Peter J Murray13https://orcid.org/0000-0001-6329-9802Max Planck Institute of Biochemistry, Martinsried, GermanyMax Planck Institute of Biochemistry, Martinsried, GermanyUniversitätsklinikum Carl Gustav Carus Dresden, Dresden, GermanyMax Planck Institute of Biochemistry, Martinsried, GermanyMax Planck Institute of Biochemistry, Martinsried, GermanyMax Planck Institute of Biochemistry, Martinsried, GermanyUniversità degli Studi di Perugia, Perugia, ItalyThe Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, CanadaSciGenom Research Foundation, Bangalore, IndiaHelmholtz Zentrum München Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, GermanyVienna BioCenter Core Facilities GmbH, Vienna, AustriaUniversità degli Studi di Perugia, Perugia, ItalyUniversitätsklinikum Carl Gustav Carus Dresden, Dresden, GermanyMax Planck Institute of Biochemistry, Martinsried, GermanyInterleukin-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 homologs in snake venoms (L-amino acid oxidases [LAAO]), 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 that venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell protective 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.https://elifesciences.org/articles/64806tryptophanvenomferroptosiscell deathhydrogen peroxide |
| spellingShingle | Leonie Zeitler Alessandra Fiore Claudia Meyer Marion Russier Gaia Zanella Sabine Suppmann Marco Gargaro Sachdev S Sidhu Somasekar Seshagiri Caspar Ohnmacht Thomas Köcher Francesca Fallarino Andreas Linkermann Peter J Murray Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism eLife tryptophan venom ferroptosis cell death hydrogen peroxide |
| title | Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism |
| title_full | Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism |
| title_fullStr | Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism |
| title_full_unstemmed | Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism |
| title_short | Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism |
| title_sort | anti ferroptotic mechanism of il4i1 mediated amino acid metabolism |
| topic | tryptophan venom ferroptosis cell death hydrogen peroxide |
| url | https://elifesciences.org/articles/64806 |
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