G beta L regulates TNF alpha-induced NF-kappa B signaling by directly inhibiting the activation of I kappa B kinase

초록

The transcriptional activation of NF-kappa B, a critical player in both physiological and pathological cellular responses to diverse cytokines, is dependent on IKK activation. Although molecular mechanisms underlying IKK activation have been well elucidated, the processes that negatively regulate IKK activity are still largely unknown. Using yeast two-hybrid screening, we have identified G beta L as an interacting partner of IKK beta. In this study, we demonstrate that G beta L interacts with IKK alpha and IKK beta in vitro and in vivo. The C-terminal WD domains of G beta L are required for the interaction with both the kinase domain and leucine zipper domain of IKK beta. Overexpression of G beta L inhibits TNF alpha-induced activation of NF-kappa B signaling, while down-regulation of G beta L expression by small interfering RNA enhances NF-kappa B activity. G beta L constitutively interacts with IKK beta, and this interaction is enhanced by TNF alpha treatment. G beta L also inhibits TNF alpha-induced phosphorylation of IKKs. Taken together, these data suggest that G beta L is involved in the negative regulation of TNF alpha-stimulated NF-kappa B signaling through a direct interaction with IKK. (c) 2008 Published by Elsevier Inc.

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