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RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1(-/-) cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities. To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1(-/-) cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1(-/-) cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIP(L), and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.

Original publication




Journal article


J Biol Chem

Publication Date





13282 - 13291


Animals, Caspase 8, Cell Death, Cell Survival, Cycloheximide, Enzyme Activation, Inhibitor of Apoptosis Proteins, Mice, Mice, Knockout, NF-kappa B, Proteasome Endopeptidase Complex, Protein Stability, Protein Synthesis Inhibitors, Protein-Serine-Threonine Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor-alpha