β-Arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα

Abstract

In addition to their roles in desensitization and signaling of seven-membrane-spanning receptors, β-arrestins have been more recently implicated in regulating non-seven-membrane-spanning receptor pathways. By using a yeast two-hybrid screen, we identified the inhibitor of NF-κB, IκBα, as a binding partner of β-arrestin 1. Both β-arrestin 1 and 2 interact with IκBα in transfected cells as assessed by immunoprecipitation experiments. Additionally, upstream kinases known to regulate the function of IκBα, such as IκB kinase α and β and NF-κB-inducing kinase, were also shown to interact with β-arrestin. Overexpression of either β-arrestin 1 or β-arrestin 2 led to marked inhibition of NF-κB activity, as measured by reporter gene activity. Inhibition of NF-κB activity was independent of the type of stimulus used for NF-κB activation. Conversely, suppression of β-arrestin 1, but not β-arrestin 2, expression by using RNA interference led to a 3-fold increase in tumor necrosis factor-stimulated NF-κB activity as measured by NF-κB mobility-shift analysis. These data uncover a role of β-arrestins in the regulation of NF-κB-mediated gene regulation.