Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism

Elife. 2021 Mar 1:10:e64806. doi: 10.7554/eLife.64806.

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 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.

Keywords: cell biology; cell death; ferroptosis; human; hydrogen peroxide; immunology; inflammation; mouse; tryptophan; venom.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Animals
  • Cell Death
  • Cell Line
  • Cell Line, Tumor
  • Elapid Venoms / enzymology
  • Ferroptosis / drug effects*
  • Gene Expression Regulation
  • Humans
  • Hydrogen Peroxide / metabolism
  • L-Amino Acid Oxidase / metabolism*
  • L-Amino Acid Oxidase / toxicity*
  • Mice
  • Oxidation-Reduction

Substances

  • Amino Acids
  • Elapid Venoms
  • Hydrogen Peroxide
  • Il4i1 protein, mouse
  • L-Amino Acid Oxidase

Associated data

  • GEO/GSE161159
  • GEO/GSE167136

Grants and funding

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