vPIF-1 is an insulin-like antiferroptotic viral peptide

by Selleckchem | Jan 28 2024

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.

Comments:

This is quite a fascinating piece of research! It seems like the study delves into the capabilities of viral insulin-like peptides (VILPs), particularly focusing on the LCDV-1 VILP and its function as an inhibitor of ferroptosis. The discovery that this viral peptide can effectively prevent cell death induced by ferroptosis inducers while showing specificity towards ferroptosis inhibition is intriguing.

The identification of the viral C-peptide's necessity for inhibiting lipid peroxidation and preventing ferroptosis, especially in contrast to the human C-peptide lacking antiferroptotic properties, suggests a unique mechanism specific to the viral peptide.

Moreover, drawing parallels between this viral peptide inhibitor of ferroptosis and other viral inhibitors like the mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevent necroptosis adds a layer of understanding to how viruses have evolved to counteract various cell death mechanisms.

The implication that ferroptosis might function as a defense mechanism against viruses in lower organisms is an intriguing concept. It suggests an intricate interplay between viral strategies to counteract cellular defense mechanisms and the cellular responses to combat viral infections.

This research could potentially open up new avenues for understanding the role of ferroptosis in viral infections and could have implications for developing targeted therapies against viral infections or conditions where ferroptosis plays a significant role in pathogenesis.