Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, 01307 Dresden, Germany.
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2300320120. doi: 10.1073/pnas.2300320120. Epub 2023 May 15.
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.
虹彩病毒科，如淋巴囊肿病病毒-1 (LCDV-1) 和其他病毒，编码病毒胰岛素样肽 (VILP)，能够触发胰岛素受体 (IR) 和胰岛素样生长因子受体。VILP 的同源性包括高度保守的二硫键。然而，与内源性配体相比，它们与 IR 的结合亲和力低 200-500 倍。因此，我们推测这些肽也具有非胰岛素功能。在这里，我们报告 LCDV-1 VILP 可作为铁死亡的有效和高度特异性抑制剂。铁死亡诱导剂 erastin、RSL3、FIN56 和 FINO2 以及硫氧还蛋白还原酶抑制剂 ferroptocide 产生的非铁死亡坏死导致的细胞死亡被 LCDV-1 强烈阻止，而人胰岛素则没有效果。Fas 诱导的细胞凋亡、坏死、米托坦诱导的细胞死亡和生长激素释放激素拮抗剂诱导的坏死不受影响，表明 LCDV-1 对铁死亡抑制具有特异性。从机制上讲，我们确定病毒 C 肽是抑制脂质过氧化和铁死亡抑制所必需的，而人 C 肽则没有抗铁死亡特性。此外，病毒 C 肽的缺失消除了细胞外系统中的自由基捕获活性。我们得出结论，虹彩病毒科通过表达类胰岛素病毒肽，能够预防铁死亡。与病毒线粒体凋亡抑制剂和病毒 RIP 激活抑制剂 (vIRA) 类似，可防止坏死，我们将 LCDV-1 VILP 重新命名为铁死亡 1 型病毒肽抑制剂。最后，我们的研究结果表明，铁死亡可能在低等生物中作为一种病毒防御机制发挥作用。
