Abstract
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.
Highlights
Ligation-induced recruitment of RIPK1 to TNFR1 was thought to be necessary for activation of the IKK complex that phosphorylates IkB prior to its ubiquitylation by SCFBTrCP
In Response to TNF, TRAF2, and cIAP1 Remain Stable in Wild-type Cells but Are Degraded in RIPK1Ϫ/Ϫ mouse embryonic fibroblasts (MEFs)—Like RIPK1Ϫ/Ϫ MEFs, those derived from TRAF2Ϫ/Ϫ mice have increased sensitivity to induction of apoptosis by TNF [11]
It has been reported that cFLIP levels decline when TRAF2Ϫ/Ϫ MEFs are treated with TNF, whereas they remain stable in wildtype MEFs [3]
Summary
Ligation-induced recruitment of RIPK1 to TNFR1 was thought to be necessary for activation of the IKK complex that phosphorylates IkB prior to its ubiquitylation by SCFBTrCP In this way, RIPK1 was proposed to promote cell survival by allowing activation of the canonical NF-B. Like RIPK1Ϫ/Ϫ cells, those deficient for TRAF2 are more likely to die than wild-type MEFs when treated with low doses of cycloheximide and TNF. This sensitization was shown to be due to loss of function of the RING domain of TRAF2 [9]. The cleaved form of cFLIP, p43cFLIP, remains stable, and is able to protect cells unless transcription or translation are inhibited
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