Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism
- Max Planck Institute for Biochemistry, Germany
- Universitätsklinikum Carl Gustav Carus Dresden, Germany
- Max Planck Institute of Biochemistry, Germany
- Università degli Studi di Perugia, Italy
- University of Toronto, Canada
- SciGenom, India
- Helmholtz Zentrum, Germany
- Vienna BioCenter, Austria
- 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.
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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.
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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Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism
eLife 10:e64806.
https://doi.org/10.7554/eLife.64806
