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

详细信息    查看全文

• 作者：Michela Muscolini^a ; Angela Sajeva^a ; Silvana Caristi^a ; Loretta Tuosto ; ^a ; ^{loretta.tuosto@uniroma1.it}
• 关键词：T cells ; CD28 ; Filamin A ; NF-&#x3ba ; B
• 刊名：Immunology Letters
• 出版年：2011
• 出版时间：May 2011
• 年：2011
• 卷：136
• 期：2
• 页码：203-212
• 全文大小：1000 K

文摘

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 (P²⁰⁸YAP²¹¹P²¹²) and tyrosine residues (Y²⁰⁶QPY²⁰⁹APP) 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.