IAPs limit activation of RIP kinases by TNF receptor 1 during development
IAPs limit activation of RIP kinases by TNF receptor 1 during development
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DOI：
10.1038/emboj.2012.18
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发表时间：
2012-04-04
期刊：
影响因子：
11.4
通讯作者：
Vaux, David L.
中科院分区：
文献类型：
--
作者：
Moulin, Maryline;Anderton, Holly;Vaux, David L.
凋亡抑制剂（IAP）蛋白cIAP1， cIAP2和XIAP （X-linked IAP）调节细胞凋亡和细胞因子受体信号传导，但它们的重叠功能使其难以区分各自的作用。为此，我们分别和联合删除了iap的基因。虽然缺乏任何一种iap在小鼠中都不会产生明显的表型，但cIap1与cIap2或Xiap的缺失会导致胚胎中期死亡。相比之下，Xiap(-/-) cIap2（-/-）小鼠存活。通过肿瘤坏死因子（TNF）受体1的缺失，而不是TNFR2基因的缺失，cIap2（-/-）和cIap1（-/-）双突变体的死亡被挽救到出生。值得注意的是，受体相互作用蛋白激酶1（Ripk1）的半合子性允许Xiap(-/-) cIap1（-/-）双突变体在出生后存活，并延长了cIap2(-/-) cIap1（-/-）胚胎存活时间。同样，Ripk3的缺失能够挽救cIap2（-/-）和cIap1（-/-）胚胎的妊娠中期缺陷，因为这些胚胎存活到E15.5。因此，在发育过程中需要cIAPs来限制TNF受体1信号通路中RIP激酶的活性。生物医学工程学报（2012）31,1679-1691。doi: 10.1038 / emboj.2012.18;2012年2月10日在线发布
Inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2, and XIAP (X-linked IAP) regulate apoptosis and cytokine receptor signalling, but their overlapping functions make it difficult to distinguish their individual roles. To do so, we deleted the genes for IAPs separately and in combination. While lack of any one of the IAPs produced no overt phenotype in mice, deletion of cIap1 with cIap2 or Xiap resulted in mid-embryonic lethality. In contrast, Xiap(-/-) cIap2(-/-) mice were viable. The death of cIap2(-/-) cIap1(-/-) double mutants was rescued to birth by deletion of tumour necrosis factor (TNF) receptor 1, but not TNFR2 genes. Remarkably, hemizygosity for receptor-interacting protein kinase 1 (Ripk1) allowed Xiap(-/-) cIap1(-/-) double mutants to survive past birth, and prolonged cIap2(-/-) cIap1(-/-) embryonic survival. Similarly, deletion of Ripk3 was able to rescue the mid-gestation defect of cIap2(-/-) cIap1(-/-) embryos, as these embryos survived to E15.5. cIAPs are therefore required during development to limit activity of RIP kinases in the TNF receptor 1 signalling pathway. The EMBO Journal (2012) 31, 1679-1691. doi: 10.1038/emboj.2012.18; Published online 10 February 2012