Grant: Operating Grant

Viruses have many obstacles to overcome in order to infect cells and multiply effectively. All cells possess multiple processes for protection against viral replication, but most viruses have evolved multiple ways to counteract these processes, or merely promote a more efficient infectious process. Human adenoviruses (Ad) cause upper respiratory, eye and gastrointestinal infections. They also induce tumours in rodents and although no evidence yet exists to suggest they cause any human cancer, they have been tremendously valuable as models to better understand the molecular basis of cancer. They are also important vectors used in gene therapy, and replicating forms are in clinical trials for use in treating cancer. We believe that they are excellent models to understand an emerging strategy used by many viruses, that of creating a complex that destroys cellular proteins that block their ability to replicate. An Ad protein, termed E4orf6, has evolved to form a complex, termed a Cullin-based E3 ubiquitin ligase, that degrades cellular proteins. Another Ad protein, termed E1B55K, binds to a range of cellular proteins and then introduces them to the E4orf6 ligase complex so that these bound proteins can be degraded. We already know that several cellular proteins are destroyed by this process, including one that kills cells before the virus can complete replication (p53), two that cause problems for newly-made viral DNA to be assembled into new viruses (Mre11 and DNA ligase IV), and our new discovery, a protein that may limit spread or yield of the newly made viruses (integrin a3). We propose to conduct detailed studies on the Ad E4orf6/E1B55K complex, including the identification of additional cellular protein targets, to gain insight into the nature of substrates that may be targeted by Ad and perhaps other more clinically relevant viruses.