Role of Luman/CREB3 and Zhangfei/CREBZF in cellular stress responses and neuronal regeneration

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Cells can be stressed for many reasons: lack of oxygen or nutrients, by-products of neighbouring actively growing cells, by products or structural components of infecting pathogens, products of the immune system, excessive demands to make protein and damage to the cell or surrounding tissue. Cells react by activating specialized responses that allow them to cope with these stressors. While cellular stress responses are meant to benefit the host, they can be detrimental as well. For instance, herpesviruses have evolved to remain latent in their hosts until their host is stressed. They then exploit some of these responses to sense stress and reactivate. In addition, stress responses also allow cancer cells to survive hypoxia, radiation and anti-cancer drugs and to metastasize. In a previous NSERC-Discovery grant funded proposal we discovered two unique cellular proteins which we named Luman and Zhangfei. These proteins are expressed in neurons and may be used by herpes simplex virus to decide whether to replicate, become latent or reactivate. Luman and Zhangfei act at cross-purposes - Luman stimulates viral and host gene expression while Zhangfei suppresses it. Since their discovery, our laboratory and others have determined that the two proteins are involved in a wide variety of important biological processes including modulating stress responses, regulating the synthesis of insulin, allowing dendritic cells (cells that initiate the body's response to pathogens) to mature and initiating the repair of injured sensory neurons. While it is gratifying to see that our initial discovery has generated so much interest, we still do not know how Luman and Zhangfei perform their many functions. Our proposal is an attempt to determine this. Regarding Luman, we will focus on its role in the recovery of the injured neuron. We will use a combination of live-cell microscopy and measurement of gene expression, protein kinases and intracellular signalling pathways to determine how Luman is transported from the site of injury to the cell body and what it does when it gets there. We will also study how Zhangfei is able to suppress the activity of gene activators that mediate stress responses and cancer cell growth.