A novel association between filamin A and NF-κB inducing kinase couples CD28 to inhibitor of NF-κB kinase α and NF-κB activation

CD28 costimulatory molecule plays a critical role in the activation of NF-kappa B. Indeed, while stimulation of T cells with either professional APCs or anti-TCR plus anti-CD28 antibodies efficiently activates NF-kappa B. TCR alone fails to do that. Moreover, CD28 stimulation by B7 in the absence of TCR may activate I kappa B kinase a (1KK alpha) and a non-canonical NF-kappa B2-like pathway, in human primary CD4(+) T cells. Despite its functional relevance in NF-kappa B activation, the molecules connecting autonomous CD28-mediated signals to IKK alpha and NF-kappa B activation remain still unknown. In searching for specific upstream activators linking CD28 to the IKK alpha/NF-kappa B cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-kappa B inducing kinase (NIK), in both Jurkat and human primary T cells. Following CD28 engagement by B7, in the absence of TCR, FLNa-associated NIK is activated and induces IKK alpha kinase activity. Both proline (p(208)YAp(211)p(212)) and tyrosine residues (Y(206)QPY(209)APP) within the C-terminal proline-rich motif of CD28 are involved in the recruitment of FLNa/NIK complexes to the membrane as well as in the activation of NIK and IKK alpha. (C) 2011 Elsevier B.V. All rights reserved.