HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death
HOIP Deficiency Causes Embryonic Lethality by Aberrant TNFR1-Mediated Endothelial Cell Death
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DOI：
10.1016/j.celrep.2014.08.066
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发表时间：
2014-10-09
期刊：
影响因子：
8.8
通讯作者：
Walczak, Henning
中科院分区：
文献类型：
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作者：
Peltzer, Nieves;Rieser, Eva;Walczak, Henning
线性泛素化对于先天免疫和适应性免疫至关重要。由HOIL-1、HOIP和SHARPIN组成的线性泛素链组装复合物（LUBAC）是唯一已知的产生线性泛素连接的泛素连接酶。HOIP是催化活性LUBAC组分。在这里，我们表明，组成和Tie 2-Cre驱动的HOIP缺失导致异常的内皮细胞死亡，导致缺陷的血管形成和胚胎在妊娠中期死亡。肿瘤坏死因子受体1（TNFR 1）的消融可预防细胞死亡、血管形成缺陷和妊娠中期死亡。HOIP缺陷细胞对肿瘤坏死因子（TNF）和光敏素-α（LT-a）的死亡诱导更敏感，并且异常的复合物-II形成负责在HOIP不存在的情况下对TNFR 1介导的细胞死亡的敏化。最后，我们表明HOIP的催化活性是防止TNF诱导的细胞死亡所必需的。因此，LUBAC及其线性泛素形成活性是通过防止TNFR 1介导的内皮细胞死亡来维持胚胎发生过程中血管完整性所必需的。
Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, and SHARPIN, is the only known ubiquitin ligase that generates linear ubiquitin linkages. HOIP is the catalytically active LUBAC component. Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation. Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation. HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF) and lymphotoxin-a (LT-a), and aberrant complex-II formation is responsible for sensitization to TNFR1-mediated cell death in the absence of HOIP. Finally, we show that HOIP's catalytic activity is necessary for preventing TNF-induced cell death. Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1-mediated endothelial cell death.