Modulation of cell signal transduction pathways by adenovirus E3 and an E3 -14.7K -interacting cell protein
Friedman, Joshua Michael
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The pro-inflammatory cytokine, TNFalpha, is a molecule central to the immune response against various cellular stresses and pathogens such as Adenovirus (Ad). Several products of the Ad genome including E1B-19K, E3-10.4K, E3-14.5K, and E3-14.7K are able to prevent TNFalpha induced cytolysis. In order to understand the mechanism of E3-14.7K prevention of cytolysis induced by TNFalpha, we performed a yeast two-hybrid assay and isolated several 14.7K interacting proteins (FIPs). We have extensively studied one of these FIPs, FIP-3 (also reported as IKKgamma or NEMO) and have demonstrated that it plays an important role in the regulation of the NF-kappaB signal transduction pathway and induces apoptotic cell death after transfection. Furthermore, our studies have also shown that FIP-3/IKKgamma/NEMO is an important modulator of the transcription factor AP-1. FIP3/IKKgamma/NEMO interacts with AP-1 and when overexpressed, significantly induces AP-1 activity through c-Jun. The phosphorylation state of c-Jun is affected both by transient transfections of FIP-3/IKKgamma/NEMO as well as in FIP-3/IKKgamma/NEMO deficient Jurkat cells. Since we isolated FIP-3/IKKgamma/NEMO using an Ad E3 protein, we were interested in determining whether the E3 region could modulate NF-kappaB signaling during viral infection. As a result of these studies, we have shown that the E3 region of group C Ads can inhibit the activation of NF-kappaB by TNFalpha and IL-1. However, by using adenoviruses with selected deletions of individual E3 genes, we demonstrated that the effect of the Ad E3 region on NF-kappaB activity mapped to the E3 10.4/14.5K-protein complex. Through these studies we have demonstrated that Ad E3 products and the cellular proteins they interact with are important molecules on pathways that affect the host immune response.