RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.
RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.
复制标题
DOI：
10.1038/nature20558
复制
发表时间：
2016-12-01
期刊：
影响因子：
64.8
通讯作者：
Pasparakis M
中科院分区：
文献类型：
--
作者：
Lin J;Kumari S;Kim C;Van TM;Wachsmuth L;Polykratis A;Pasparakis M
受体相互作用蛋白激酶1（RIPK 1）通过激酶依赖性和非依赖性功能调节细胞死亡和炎症。RIPK 1激酶活性诱导caspase-8依赖性细胞凋亡和RIPK 3/混合谱系激酶样（MLKL）依赖性坏死性凋亡。此外，RIPK 1通过激酶非依赖性功能抑制细胞凋亡和坏死性凋亡，这对于晚期胚胎发育和预防上皮屏障中的炎症是重要的。RIPK 1抵消RIPK 3/MLKL介导的坏死性凋亡的机制仍然是个谜。在这里，我们发现RIPK 1通过抑制Z-DNA结合蛋白1（ZBP 1，也称为DAI或DLM 1）介导的RIPK 3/MLKL依赖性坏死性凋亡的激活来预防皮肤炎症。ZBP 1缺陷抑制表皮特异性RIPK 1敲除小鼠的角质形成细胞坏死性凋亡和皮肤炎症此外，内源性小鼠RIPK 1（RIPK 1 mRHIM）的保守RIP同型相互作用基序（RHIM）的突变引起围产期死亡，这是由RIPK 3，MLKL或ZBP 1缺陷预防。此外，角质形成细胞中仅表达RIPK 1 mRHIM的小鼠出现皮肤炎症，但MLKL或ZBP 1缺乏可消除这种炎症。在表达RIPK 1 mRHIM的细胞中，ZBP 1与磷酸化RIPK 3强烈相互作用，表明RIPK 1 RHIM阻止ZBP 1结合和激活RIPK 3。总的来说，这些结果表明，RIPK 1通过抑制ZBP 1诱导的坏死性凋亡来预防成年小鼠的围产期死亡以及皮肤炎症。此外，这些发现将ZBP 1确定为炎症的关键介质，超出了其先前已知的抗病毒防御作用，并表明ZBP 1可能与坏死性凋亡相关炎症性疾病的发病机制有关。
Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammation via kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3/Mixed Lineage Kinase Like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis via kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3/MLKL-mediated necroptosis has remained enigmatic. Here we show that RIPK1 prevents skin inflammation by inhibiting Z-DNA binding protein 1 (ZBP1, also named DAI or DLM1)-mediated activation of RIPK3/MLKL-dependent necroptosis. ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP Homotypic Interaction Motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results showed that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in anti-viral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.
登录
查看更多内容
影响因子：
64.5
作者：
Rickard, James A.;O'Donnell, Joanne A.;Silke, John
通讯作者：
Silke, John
在细胞死亡和炎症的串扰中进行了编程坏死。
影响因子：
29.7
作者：
Chan FK;Luz NF;Moriwaki K
通讯作者：
Moriwaki K
DOI：
10.4049/jimmunol.181.9.6427
发表时间：
2008-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kaiser WJ;Upton JW;Mocarski ES
通讯作者：
Mocarski ES
影响因子：
64.8
作者：
Dannappel M;Vlantis K;Kumari S;Polykratis A;Kim C;Wachsmuth L;Eftychi C;Lin J;Corona T;Hermance N;Zelic M;Kirsch P;Basic M;Bleich A;Kelliher M;Pasparakis M
通讯作者：
Pasparakis M
影响因子：
64.5
作者：
Cho YS;Challa S;Moquin D;Genga R;Ray TD;Guildford M;Chan FK
通讯作者：
Chan FK