Modulation of cell signal transduction pathways by adenovirus E3 and an E3 -14.7K -interacting cell protein
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.
Source: Dissertation Abstracts International, Volume: 63-02, Section: B, page: 6270.;Advisors: Marshall S. Horwitz.