NF-κB-Independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-Dependent Apoptotic and Necroptotic Cell Death during TNF Signaling

被引：429

作者：

Dondelinger, Yves ^{[1
,2
]}

Jouan-Lanhouet, Sandrine ^{[1
,2
]}

Divert, Tatyana ^{[1
,2
]}

Theatre, Emilie ^{[3
]}

Bertin, John ^{[4
]}

Gough, Peter J. ^{[4
]}

Giansanti, Piero ^{[5
,6
,7
]}

Heck, Albert J. R. ^{[5
,6
,7
]}

Dejardin, Emmanuel ^{[3
]}

Vandenabeele, Peter ^{[1
,2
,8
]}

Bertrand, Mathieu J. M. ^{[1
,2
]}

机构：

[1] VIB, Inflammat Res Ctr, B-9052 Zwijnaarde Ghent, Belgium

[2] Univ Ghent, Dept Biomed Mol Biol, B-9052 Zwijnaarde Ghent, Belgium

[3] Univ Liege, GIGA Research, Lab Mol Immunol & Signal Transduct, B-4000 Liege, Belgium

[4] GlaxoSmithKline, Immunoinflammat Therapeut Area, Pattern Recognit Receptor Discovery Performance, Collegeville, PA 19426 USA

[5] Univ Utrecht, Biomol Mass Spectrometry & Prote, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands

[6] Univ Utrecht, Utrecht Inst Pharmaceut Sci, NL-3584 CH Utrecht, Netherlands

[7] Netherlands Prote Ctr, NL-3584 CH Utrecht, Netherlands

[8] Univ Ghent, Methusalem Program, B-9052 Zwijnaarde Ghent, Belgium

来源：

MOLECULAR CELL | 2015年 / 60卷 / 01期

关键词：

SEVERE LIVER DEGENERATION; SMALL-MOLECULE INHIBITOR; MIXED LINEAGE KINASE; MICE LACKING; NEMO/IKK-GAMMA; DOMAIN-LIKE; RECEPTOR; ACTIVATION; UBIQUITINATION; NECROSIS;

D O I：

10.1016/j.molcel.2015.07.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：63 / 76

页数：14

共 57 条

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Regulation of cell death and autophagy by IKK and NF-κB: critical mechanisms in immune function and cancer [J].