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Zeitler, L.* ; Fiore, A.* ; Meyer, C.* ; Russier, M.* ; Zanella, G.* ; Suppmann, S.* ; Gagaro, M.* ; Sidhu, S.S.* ; Seshagiri, S.* ; Ohnmacht, C. ; Köcher, T.* ; Fallarino, F.* ; Linkermann, A.* ; Murray, P.J.*

Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.

eLife 10:e64806 (2021)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cell Biology ; Human ; Immunology ; Inflammation ; Mouse; Immunosuppressive Enzyme Il4i1; Substrate; Cells; Venom
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Journal eLife
Quellenangaben Volume: 10, Issue: , Pages: , Article Number: e64806 Supplement: ,
Publisher eLife Sciences Publications
Publishing Place Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Grants City of Vienna
Vienna Business Agency
EC | European Research Council (ERC)
Max-Planck-Gesellschaft (MPG)