Adenovirus immunoregulatory proteins and control of NF-kappaB
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Adenovirus early region 3 (B) encodes a group of small proteins that regulate host immune responses during virus infection. These proteins are generally referred to by their molecular weight, such as 14.7K, 10.4K and 14.5K. The E3-14.7K protein is an inhibitor of tumor necrosis factor (TNF) alpha-induced cell death. FIP3, isolated as a 14.7K-interacting protein, is an essential component of the multimeric IkappaBalpha kinase (IKK) complex and has been shown to interact with various components (RIP, NIK, IKKbeta) of the NFkappaB activation pathway. FIP3 has also been isolated by other groups and has been given different names, such as IKKgamma and NEMO. FIP3 has been shown to repress basal and TNFalpha-induced NFkappaB activity as well as to induce cell-death when overexpressed. In the current study, we generated a series of deletion mutants and mapped the domains of FIP3 which are responsible for its various functions. Our results suggested that FIP3 might serve as a scaffold protein to organize the various components of the IKK complex. We also found that the carboxyl-terminal half of FIP3 blocked TNFalpha-induced IkappaBalpha phosphorylation and degradation, and in addition we demonstrated that FIP3 inhibited the p65 transactivation activity, suggesting that FIP3 may use multiple strategies to inhibit NFkappaB. We also showed that overexpression of IKKbeta inhibited p65 transactivation activity, suggesting that this feature might be part of a general feedback control mechanism to fine tune NFkappaB activity after stimulation.;E3-10.4K and E3-14.5K proteins act as a complex to inhibit TNFalpha-induced cytolysis. They also cause FAS r&barbelow;eceptor i&barbelow;nternalization and d&barbelow;egradation and thus were renamed as RIDalpha and RIDbeta respectively. TNFalpha treatment also leads to the activation of an NFkappaB stimulation pathway. The activation of NFkappaB is generally regarded as protective against apoptosis since it upregulates the expression of a group of cellular proteins that inhibit cell-death. In our studies we found that RIDalpha/beta complex upregulated NFkappaB activity. This complex did not induce IkappaBalpha phosphorylation and degradation, or NFkappaB nuclear translocation. We found that RIDalpha/beta complex acted synergistically with overexpressed p65 to activate an NFkappaB reporter. Additionally we demonstrated that RIDalpha/beta complex moderately upregulated p65 transactivation activity. Our studies suggested that adenovirus E3-RIDalpha/beta might inhibit or attenuate cell-death by targeting the NFkappaB pathway.
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