Structure and mechanism of the antiviral E3 ligase ZNFX1

Viral infections are a major cause of disease in humans, livestock and crops. For viruses to replicate and spread, they need to enter inside the cells of their host and hijack the cellular machinery. To counter infection, all organisms, from bacteria to humans, have systems inside their cells which protect them from viruses. These systems act to detect viruses, initiating signaling cascades which lead to the production of factors that directly attack viruses and prevent their replication. During evolution, viruses have also developed systems to neutralise these defence factors. By understanding how cellular defence works at a molecular level, we can learn why genetic diseases lead to immune susceptibility, discover ways to combat viruses with drugs which target anti-defence systems and reveal why some species, like bats, can transmit viruses without suffering disease themselves. This project will focus on an important defence factor called ZNFX1. Patients with inherited mutations in ZNFX1 often die in childhood due to susceptibility to viruses and an overreactive response to them causing the body to attack itself. ZNFX1 is not only found in humans but across animals, plants and fungi, meaning that it is an ancient way that organisms protect themselves from viruses. Despite this importance, the way that ZNFX1 defends cells from viruses is unknown. It has been shown that ZNFX1 binds to the nucleic acids of the virus, which store and transmit its genetic information. Our preliminary data show that when ZNFX1 binds to these nucleic acids it induces an unusual enzymatic reaction that results in labelling of ZNFX1 and the nucleic acids with a small protein called ubiquitin. For other systems, such a ubiquitin label is known to activate various signaling systems which can result in warning the cell there is a virus or to act as a degradation label which marks the virus for destruction. We now aim to work out how this unusual defence system works. Through this, we will determine which nucleic acids activate ZNFX1 and if they come from certain viruses or the host organism. Additionally, we will find out whether the ubiquitin signal acts to sense the virus, to regulate the response to the virus or to directly attack the virus. Overall, we will gain greater understanding into a unique cell defence mechanism with important implications for human and agricultural health.

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