CD28 costimulatory molecule plays a critical role in the activation of NF-κB. Indeed, while stimulation of T cells with either professional APCs or anti-TCR plus anti-CD28 antibodies efficiently activates NF-κB, TCR alone fails to do that. Moreover, CD28 stimulation by B7 in the absence of TCR may activate IκB kinase α (IKKα) and a non-canonical NF-κB2-like pathway, in human primary CD4(+) T cells. Despite its functional relevance in NF-κB activation, the molecules connecting autonomous CD28-mediated signals to IKKα and NF-κB activation remain still unknown. In searching for specific upstream activators linking CD28 to the IKKα/NF-κB cascade, we identify a novel constitutive association between filamin A (FLNa) and the NF-κB 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 IKKα 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 IKKα.
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