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.
Highlights
Most cells of the immune system depend on external supplies of all essential and most non-essential amino acids for proliferation in active immune responses, and for diverse effector functions, such as nitric oxide generation from arginine (Murray, 2016)
The membranes of L-amino acid oxidases (LAAOs)-treated HeLa cells began to bleb after ~5 hr, and all cells were dead within 12 hr (Figure 1E,F; Video 1)
Our results indicate that snake venom LAAOs and mammalian IL4i1 diverged in their functions to kill or protect cells, respectively
Summary
Most cells of the immune system depend on external supplies of all essential and most non-essential amino acids for proliferation in active immune responses, and for diverse effector functions, such as nitric oxide generation from arginine (Murray, 2016). Amino acid auxotrophy of immune cells forms checkpoints whereby distinct amino acid metabolizing enzymes expressed in different cell types control cell proliferation, fate, and function (Murray, 2016) These regulated enzymes metabolize arginine (Arginases 1 and 2 and nitric oxide synthase two or iNOS) and tryptophan (indole-2,3dioxygenases, IDO1 and IDO2). Numerous elements of IL4i1 and LAAO biology remain unresolved These include the mechanistic basis of the association between IL4i1 and different cancers (Carbonnelle-Puscian et al, 2009; Cousin et al, 2015; Sadik et al, 2020), the mode of action of LAAOs in snake venoms, and how this compares to mammalian IL4i1, the cell types that express IL4i1 and relative role of IL4i1mediated microenvironmental amino acid depletion versus product generation. We propose that components of the pro-tumor effects of IL4i1 are linked to local anti-ferroptotic effects on transformed cells
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