Cellular functions of hub proteins and their deregulation by adenovirus

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Cellular regulatory networks are inherently redundant, representing a multi-node scale-free network that is resistant to disruptions. This type of organization is necessary to avoid critical network failure upon disruption of a single node. The inherent weakness of a cellular regulatory network lies in key regulators of network function, known as "hub proteins". Viruses have evolved exquisite ways in which to target these hubs in order to remodel the network and enable virus propagation and host evasion. Therefore, utilization of viral proteins that remodel the cell provides a useful means of identifying key cellular regulators of important processes. I have identified two novel cellular regulators by their virtue of binding to the adenovirus immediate early gene product E1A: DREF and FUBP1. Both of these proteins are poorly understood and their function within cells is enigmatic. DREF is a transcriptional regulator that is involved in activation of cell cycle and growth control genes. FUBP1 is a protein that appears to play a role in transcriptional regulation by binding to enhancers within gene regulatory regions as well as regulating protein translation. The E1A protein of adenovirus is a small protein composed of 289 amino acids in the largest isoform. E1A can be considered a "hub detector" because of its ability to target key cellular regulators. E1A has been an invaluable tool in the study and understanding of a wide variety of cellular processes. Recent NSERC--funded studies in my laboratory have begun to unravel the mysteries of cellular hub proteins. We have discovered new functions of DREF and FUBP1, in large part thanks to my use of E1A as a molecular probe for dissection of cellular pathways. Work in my lab has identified, for the first time, that DREF is a component of cellular innate immune response and it is deregulated by alteration of its SUMOylation by E1A during virus-driven cellular reprogramming. My lab has also shown that FUBP1 is utilized by E1A to suppress cellular stress response pathway by locking FUBP1 in a complex with the cellular stress regulator p53, preventing p53 from carrying out its functions. These studies only scratch the surface of what the pathways and functions are of DREF and FUBP1, paving the way for further investigations. Study of E1A--binding proteins teaches us not only about E1A but also about the proteins that bind to it. Importantly, discovery of novel E1A-binding proteins identifies key cellular hubs that can be studied using this powerful viral tool. My research program focuses on the identification and characterizaton of cellular hub proteins to better understand their role in cellular processes governing eukaryotic life. In the short term, studies of DREF and FUBP1, and their association with E1A, will clarify their cellular functions and elucidate the reasons behind their targeting by a virus.