title: A novel association between filamin A and NF-κB inducing kinase couples CD28 to inhibitor of NF-κB kinase α and NF-κB activation.
abstract: 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Biology and Biotechnology Charles Darwin, Sapienza University, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Muscolini
authors.forename: Angela
authors.initials: A
authors.lastname: Sajeva
authors.forename: Silvana
authors.initials: S
authors.lastname: Caristi
authors.forename: Loretta
authors.initials: L
authors.lastname: Tuosto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D003285:Contractile Proteins / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D064448:Filamins; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology; D019169:Jurkat Cells; D007739:L Cells; D051379:Mice; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D055232:Proline-Rich Protein Domains / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016415:Sequence Alignment; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D018122:B7-1 Antigen; D018106:CD28 Antigens; D003285:Contractile Proteins; D064448:Filamins; D051550:I-kappa B Kinase; D008840:Microfilament Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011948:Receptors, Antigen, T-Cell; D000097782:NF-kappaB-Inducing Kinase