The c-FLIP–NH(2) terminus (p22-FLIP) induces NF-κB activation

c-FLIP proteins (isoforms: c-FLIP(L), c-FLIP(S), and c-FLIP(R)) play an essential role in the regulation of death receptor–induced apoptosis. Here, we demonstrate that the cytoplasmic NH(2)-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor κB (NF-κB) activity by interacting with the IκB kinase (IKK) complex via the IKKγ subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-κB activation and life/death decisions in lymphocytes and DCs.