Same but Different: How Viruses Mimic Human Proteins to Hijack Our Cells' Mechanisms

Viruses are masters of efficiency. With a short genome encoding a small set of proteins, they can infiltrate our much more complex cells and take control of multiple mechanisms inside them. Some of the viral proteins are meant to neutralize the cells' defense systems, but many others are used to interact with the cells' proteins and hijack them for the virus’s purposes - primarily the multiple steps needed for the virus to replicate its genome and multiply. The genetic material encoding these viral proteins was stolen from ancient hosts, and their similarity to the cell's proteins enables them to hack into the protein network and manipulate it.

Dr. Tzachi Hagai from Tel Aviv University's Shmunis School for Biomedicine and Cancer Research studies these interactions between human and viral proteins and how they co-evolve. "This co-evolution is classically presented as an arms race, where one side tries to outmaneuver the other, and the other counters to contradict the change. Kind of like the Queen of Hearts' run in Alice in Wonderland," explains Dr. Hagai. "However, when taking an in-depth look into the known interactions between viral and host proteins, we discover that the interacting host proteins tend to change less than other host proteins not affected by viruses."

To better understand when a protein interaction can evolve and when it cannot, Dr. Hagai's lab is studying how host cells are evolutionarily responding to viruses using proteins crucial for the cell's function in some way. "For example, we are trying to understand why a protein cannot change in the location the viral protein is targeting."

Mapping Viral Proteins

To do that, as part of the newly ERC-funded project, the first step for Dr. Hagai and his colleagues is to map viral proteins "stolen" from hosts to hijack the host networks. "We use recent advancements in predicting protein folding using AI to compare the structures of viral proteins and identify similarities to human proteins, indicating that they can be used to mimic their function in the cell."

The next step is to understand how the identified viral proteins function in a similar manner to that of human proteins. "We want to understand how much the mimicking proteins can serve the same roles as the ‘original’ host proteins in the human cell. Analyzing the similarities and differences allows us to identify points of diversification - when the virus is using the human 'building block' for a new function - and better understand why other viral mimicking proteins remained unchanged."

Dr. Hagai's research is a classic example of basic science: the use of advanced technologies to answer fundamental questions about how biology functions. However, the successful completion of this project could also contribute significantly to our future health. "Identifying conserved viral proteins could help us pinpoint viral weaknesses we can use to design new antiviral therapies," explains Dr. Hagai. "And mapping the viral protein pathways that remain flexible for change can help us better predict which viruses are more or less likely to jump from one species to the next - and through which mechanisms this change could happen."