Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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

DOI

10.1074/jbc.M110.216226

Type

Journal article

Journal

J Biol Chem

Publication Date

15/04/2011

Volume

286

Pages

13282 - 13291

Keywords

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