Ubiquitin Chains in Viral Infections

Viruses such as Influenza A (IAV) and others remain one of the greatest threats to human health and society. Despite their danger and widespread prevalence, the molecular mechanisms of how they infect mammalian hosts and evade the immune system remains poorly understood. Recent studies from our team implicate two common proteins - HDAC6 and unanchored ubiquitin chains - in host cells as key mediators of viral entry via the aggresome processing pathway. This discovery offers a new line of investigation for understanding and preventing viral infections. By identifying the pathways and interactions involved in this infection process, we will provide new molecular targets for the development of broad-spectrum antiviral compounds. Multidisciplinary studies by a team consisting of a molecular biologist, a virologist, and a chemical biologist will use a diverse set of tools to validate these pathways and gain fundamental knowledge about their regulation. To achieve this, detailed studies on the exact nature of the ubiquitin chains needed to activate HDAC6 will allow the development of biochemical and cellular assays of Influenza A infection and enable the determination of the precise mechanism and the downstream cellular pathways necessary for viral infection. The chemical synthesis of labeled ubiquitin chains will support detailed structural studies and a clear understanding of how they are formed and packaged into infectious viral particles. The strong possibility that numerous other virus types also utilize this pathway will be tested with life-threatening agents of current concern including Zika, Dengue, Ebola, and MERS viruses. By demonstrating - with both biological approaches and small molecule compounds - that blocking these cellular processes in cells and animal models reduces viral infection, this project will provide a wealth a novel insights and the basis for the development of a new generation of anti-viral therapies.