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Nature:RIPK1 既激发又抑制细胞死亡

摘要 : 发表于2014年9月4日出版的《Nature》杂志上的两项研究中,两个独立研究小组发现,“受体相互作用蛋白-1激酶”(RIPK1),细胞死亡途径的一个组成蛋白,也能够支撑机体的上皮细胞存活。这些发现颠覆了关于细胞死亡和存活是由不同的因素所调控的观点。
图示:旧的Ripk1IEC-KO小鼠的表征。

图示:旧的Ripk1IEC-KO小鼠的表征。

“受体相互作用蛋白-1激酶”(RIPK1)参与各种细胞死亡通道的激发和炎症信号传导的控制。

在本期Nature上发表文章的两个单独的研究小组采用对比方法发现,除了促进细胞死亡外,RIPK1在支持小鼠上皮细胞存活中还发挥一个矛盾的功能,该功能是独立于其激酶功能的。

RIPK1通过阻止由FADD/caspase-8介导的凋亡和依赖于RIPK3的坏死性凋亡来抑制上皮细胞凋亡和坏死性凋亡。这些发现连同遗传数据表明,RIPK1是小肠和皮肤中上皮细胞存活、动态平衡和炎症的一个主调控因子。

原文摘要:

RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis

Nozomi Takahashi, Lars Vereecke, Mathieu J. M. Bertrand, Linde Duprez, Scott B. Berger,Tatyana Divert, Amanda Gonçalves, Mozes Sze, Barbara Gilbert, Stephanie Kourula, Vera Goossens, Sylvie Lefebvre, Claudia Günther, Christoph Becker, John Bertin, Peter J. Gough, Wim Declercq, Geert van Loo & Peter Vandenabeele

Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-κB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-κB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-κB activation.

RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis

Marius Dannappel, Katerina Vlantis, Snehlata Kumari, Apostolos Polykratis, Chun Kim,Laurens Wachsmuth, Christina Eftychi, Juan Lin, Teresa Corona, Nicole Hermance, Matija Zelic, Petra Kirsch, Marijana Basic, Andre Bleich, Michelle Kelliher & Manolis Pasparakis

Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.

 

对应Nature杂志: 2014年9月4日Nature杂志精选

来源: Nature 浏览次数:421

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