In TNF-stimulated cells, RIPK1 promotes cell survival by stabilizing TRAF2 and cIAP1, which limits induction of non-canonical NF-κB and activation of caspase-8

Ian E Gentle, W. Wei Lynn Wong, Joseph M Evans, Alexandra Bankovacki, Wendy D. Cook, Nufail R. Khan, Ulrich Nachbur, James A Rickard, Holly Anderton, Maryline Moulin, Josep Maria Lluis, Donia M. Moujalled, John Silke, David L. Vaux

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71 Citations (Scopus)


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 (1, 2). 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 wildtype 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 cFLIPL, 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 languageEnglish
Pages (from-to)13282-13291
Number of pages10
JournalJournal of Biological Chemistry
Issue number15
Publication statusPublished - 15 Apr 2011
Externally publishedYes

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