Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.
cell biology
cell death
ferroptosis
human
hydrogen peroxide
immunology
inflammation
mouse
tryptophan
venom
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
11
11
2020
accepted:
26
02
2021
pubmed:
2
3
2021
medline:
5
2
2022
entrez:
1
3
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33646117
doi: 10.7554/eLife.64806
pii: 64806
pmc: PMC7946422
doi:
pii:
Substances chimiques
Amino Acids
0
Elapid Venoms
0
Hydrogen Peroxide
BBX060AN9V
Il4i1 protein, mouse
EC 1.4.3.2
L-Amino Acid Oxidase
EC 1.4.3.2
Banques de données
GEO
['GSE161159', 'GSE167136']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021, Zeitler et al.
Déclaration de conflit d'intérêts
LZ, AF, CM, MR, GZ, SS, MG, SS, SS, CO, FF, AL, PM No competing interests declared, TK Thomas Köcher is affiliated with Vienna BioCenter Core Facilities GmbH. The author has no financial interests to declare.
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