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Deny Cell Death: A Viral Doppelgänger’s Plea
To ensure balance in our cellular system, our cells employ diverse mechanisms to attain homeostasis. For instance, when cells suffer damage from agents like chemicals or invading microbes, they will undergo a cellular process termed cell death, which serves to selectively remove these compromised cells. Remarkably, pathogens have also developed a myriad of strategies to escape cell death. A recent study conducted by researchers from University Hospital Carl Gustav Carus at the Technische Universität Dresden sheds light on a new means through which viruses can mimic a human insulin protein to inhibit cell death.
Cell Death Is A Crucial Cellular Defense Mechanism
Cell death plays a pivotal role in the maintenance of tissue homeostasis and the elimination of damaged or infected cells. There are various types of cell death, and each can be triggered by a distinct signal input. One example is apoptosis which enables cells to initiate a self-destruct program to sacrifice themselves when damaged or no longer needed. For instance, during embryonic development in humans each digit is connected with webbed tissues which are later eliminated by apoptosis to form the shape of fingers. Furthermore, apoptosis also acts as a defense mechanism for the clearance of cancerous or infected cells. Notably, evasion of cell death has become a key strategy for pathogens like viruses to continuously replicate within host cells.
So, how do viruses manage to escape cell death?
Viruses Can Mimic Host Proteins to Avoid Cell Death
One way viruses prevent cell death during infection is through viral mimicry. In other words, viruses can encode proteins that closely resemble those found in host cells, allowing them to manipulate cellular function. Viral mimicry is commonly found in DNA viruses, a class of viruses containing DNA as their genetic material. One type of DNA virus named adenovirus can produce a protein called E1B-19K, which serves as a viral counterpart to Bcl-2- a cellular factor that can inhibit apoptosis. As expected, E1B-19K can interfere with the apoptotic pathway to block cell death by mimicking the function of Bcl-2.
Interestingly, viral mimicry can also lead to the acquisition of different functions from its host counterpart.
Viral Mimicry of Human Insulin Acquires a Different Function
Iridoviridae is a family of double-stranded DNA viruses that can infect invertebrates (e.g. fish) and amphibians. A well-known member of the Iridoviridae family is lymphocystis disease virus-1 (LCDV-1), which causes tumor-like lesions in fish. The researchers found these viruses encode a protein called viral insulin–like peptides (VILP) structurally similar to human insulin. Human insulin is a protein critical for the regulation of glucose metabolism in the body. When insulin binds to its receptor on the cell, it will promote the uptake of glucose by cells, and subsequently reduce blood sugar levels in the body. Nevertheless, unlike human insulin VILP has a significantly lower binding affinity for the insulin receptor. Therefore, the researchers speculate that VILP might have a completely different function.
Since VILP is derived from viruses, the study group proposed a potential link between the function of VILP and the host defense. Given that cell death is a primary means for cells to defend against pathogens during infection, the researchers hypothesized that VILP can impede cell death by hijacking its pathways. Using different agents to induce different types of cell death in human cells treated with LCDV-1-encoded VILP, the researchers found cells administered with VILP could only inhibit one form of cell death known as ferroptosis. Ferroptosis is triggered by molecules such as lipid peroxide and characterized by cell membrane rupture. As VILP acts as an inhibitor of ferroptosis, the group subsequently renamed VILP as viral peptide inhibitor of ferroptosis-1 (vPIF-1).
To further understand the antiferroptic properties and function of vPIF-1, the study group identified the functional region of vPIF-1 required to block ferroptosis. The crucial region, which they named the C-peptide of vPIF-1, was found to be shorter than the human counterpart. Moreover, the study also shows that only treatment of vPIF-1, not human insulin or vPIF-1 lacking C-peptide, can inhibit lipid peroxidation when ferroptosis is induced. Together, these findings suggest that vPIF-1 blocks ferroptosis via suppression of lipid peroxidation.
Conclusion
In summary, the study of viral mimicry has offered valuable insights into how viruses manipulate critical cellular processes like cell death. The discovery of VILP in this research not only expands our understanding of how viral proteins can acquire diverse functions from their host, but also reveals a new role of ferroptosis in antiviral defense mechanisms.
Link to the original post: Belavgeni, Alexia, et al. “VPIF-1 Is an Insulin-like Antiferroptotic Viral Peptide.” Proceedings of the National Academy of Sciences, vol. 120, no. 21, 2023, p. e2300320120
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