This project is focused on the elucidation of the molecular mechanisms by which the immunologically important NF-kappaB transcription factors can be activated by various signals. This research is important in identification of possible targets for therapeutic intervention in inflammatory diseases marked by undesirable activation of NF-kappaB. In addition, NF-kappaB figures prominently in the expression of the human immunodeficiency virus, as well as several other clinically relevant viruses. The NF-kappaB transcription factors are normally retained in the cytoplasm by association with the inhibitory IkappaB proteins. Signals directly or indirectly related to pathogens or stress lead to first phosphorylation and then proteolytic degradation of the inhibitor, thereby releasing the NF-kappaB factors to translocate to the nucleus and carry out their functions. This project aims to delineate various signaling paths that lead to phosphorylation and subsequent ubiquitination of the IkappaB inhibitors.We have identified the actin-binding protein Filamin as a possible scaffold that aids in the transmission of TNF-generated signals during activation of NF- kappaB. We have cloned via yeast two hybrid analyses several novel proteins that may help link various signaling cascades to the IkappaB kinases. The NIK kinase is one mediator of signals initiated by the TNF, Toll and IL-1 receptors. We have delimited a domain in the NIK required for interaction with the IkappaB kinases and thus for NIK- induced activation of these latter kinases. Finally, we have identified a novel component of a ubiquitin-ligase complex that may help to assemble the complex for ubiquitination of IkappaB proteins. - Signal transduction; NF-kappaB; IkappaB; TNF; IL-1; Toll receptor; NIK; Traf; SCF-ubiquitin ligase complexes.
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