期刊
MOLECULAR CELL
卷 60, 期 1, 页码 63-76出版社
CELL PRESS
DOI: 10.1016/j.molcel.2015.07.032
关键词
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资金
- IWT
- Marie Curie COFUND initiative
- Ghent University grant (MRP)
- Ghent University grant (GROUP-ID consortium)
- Foundation Against Cancer [F94, 2010-162]
- VIB
- Methusalem grant
- PRIME-XS project - European Union [262067]
- Netherlands Organization for Scientific Research (NWO) [184.032.201]
- Plan Cancer Action 29
- Centre AntiCancereux ULg
- [IAP 7/32]
- [FWO G087511]
- [G097311]
- [G0A4512N]
- [G078713N]
- [G017212N G]
- [G013715N]
- [Methusalem BOF09/01M00709]
- [IAP7/32]
TNF is a master pro-inflammatory cytokine. Activation of TNFR1 by TNF can result in both RIPK1-independent apoptosis and RIPK1 kinase-dependent apoptosis or necroptosis. These cell death outcomes are regulated by two distinct checkpoints during TNFR1 signaling. TNF-mediated NF-kappa B-dependent induction of pro-survival or anti-apoptotic molecules is a well-known late checkpoint in the pathway, protecting cells from RIPK1-independent death. On the other hand, the molecular mechanism regulating the contribution of RIPK1 to cell death is far less understood. We demonstrate here that the IKK complex phosphorylates RIPK1 at TNFR1 complex I and protects cells from RIPK1 kinase-dependent death, independent of its function in NF-kappa B activation. We provide in vitro and in vivo evidence that inhibition of IKK alpha/IKK beta or its upstream activators sensitizes cells to death by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We therefore report on an unexpected, NF-kappa B-independent role for the IKK complex in protecting cells from RIPK1-dependent death downstream of TNFR1.
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