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Belavgeni, A.* ; Maremonti, F.* ; Tonnus, W.* ; Stadtmüller, M.* ; Gavali, S.* ; Mallais, M.* ; Flade, K.* ; Brucker, A.J.* ; Becker, J.N.* ; Beer, K.* ; Tmava, M.* ; Stumpf, J.* ; Gembardt, F.* ; Hugo, C.* ; Giacca, M.* ; Hale, B.G.* ; Perakakis, N.* ; Sha, W.* ; Pratt, D.A.* ; Schally, A.V.* ; Bornstein, S.R. ; Linkermann, A.*

vPIF-1 is an insulin-like antiferroptotic viral peptide.

Proc. Natl. Acad. Sci. U.S.A. 120:e2300320120 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin–like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone–releasing hormone antagonist–induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords regulated necrosis; ferroptosis; viral defense; necroptosis; apoptosis; Cell-death; Ferroptosis; Metabolism; Mechanism; Apoptosis; Kinase
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 120, Issue: 21, Pages: , Article Number: e2300320120 Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)
Grants transCampus initiative
Natural Sciences and Engineering Research Council of Canada
German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
international research training group
BMBF (Bundesministerium fuer Bildung und Forschung, FERROPath consortium)
Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany