The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways

• Published in: Current biology Vol. 10; no. 11; pp. 640 - 648
• Main Authors: Kataoka, T., Budd, R.C., Holler, N., Thome, M., Martinon, F., Irmler, M., Burns, K., Hahne, M., Kennedy, N., Kovacsovics, M., Tschopp, J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.06.2000
• Subjects: caspase-8; CD3 antigen; Erk protein; FADD protein; FasL protein; FLIP protein; NF-^KB protein
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/S0960-9822(00)00512-1

Background: Activation of Fas (CD95) by its ligand (FasL) rapidly induces cell death through recruitment and activation of caspase-8 via the adaptor protein Fas-associated death domain protein (FADD). However, Fas signals do not always result in apoptosis but can also trigger a pathway that leads to proliferation. We investigated the level at which the two conflicting Fas signals diverge and the protein(s) that are implicated in switching the response. Results: Under conditions in which proliferation of CD3-activated human T lymphocytes is increased by recombinant FasL, there was activation of the transcription factors NF-κB and AP-1 and recruitment of the caspase-8 inhibitor and FADD-interacting protein FLIP (FLICE-like inhibitory protein). Fas-recruited FLIP interacts with TNF-receptor associated factors 1 and 2, as well as with the kinases RIP and Raf-1, resulting in the activation of the NF-κB and extracellular signal regulated kinase (Erk) signaling pathways. In T cells these two signal pathways are critical for interleukin-2 production. Increased expression of FLIP in T cells resulted in increased production of interleukin-2. Conclusions: We provide evidence that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-κB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.