血管生成
生物
泛素
泛素连接酶
细胞生物学
胚胎干细胞
受体
癌症研究
泛素蛋白连接酶类
遗传学
基因
作者
Yesheng Fu,Hongtian Wang,Hongmiao Dai,Qiong Zhu,Chun‐Ping Chu,Xiaoxuan Sun,Yanchang Li,Zhikang Deng,Xuemei Zhou,Yingwei Ge,Zhiqiang Peng,Chao Yuan,Bo Wu,Xi Yang,Rongyu Li,Cui Hua Liu,Fuchu He,Wenyi Wei,Lingqiang Zhang
出处
期刊:Molecular Cell
[Elsevier]
日期:2021-06-21
卷期号:81 (15): 3187-3204.e7
被引量:20
标识
DOI:10.1016/j.molcel.2021.05.031
摘要
Summary
OTULIN coordinates with LUBAC to edit linear polyubiquitin chains in embryonic development, autoimmunity, and inflammatory diseases. However, the mechanism by which angiogenesis, especially that of endothelial cells (ECs), is regulated by linear ubiquitination remains unclear. Here, we reveal that constitutive or EC-specific deletion of Otulin resulted in arteriovenous malformations and embryonic lethality. LUBAC conjugates linear ubiquitin chains onto Activin receptor-like kinase 1 (ALK1), which is responsible for angiogenesis defects, inhibiting ALK1 enzyme activity and Smad1/5 activation. Conversely, OTULIN deubiquitinates ALK1 to promote Smad1/5 activation. Consistently, embryonic survival of Otulin-deficient mice was prolonged by BMP9 pretreatment or EC-specific ALK1Q200D (constitutively active) knockin. Moreover, mutant ALK1 from type 2 hereditary hemorrhagic telangiectasia (HHT2) patients exhibited excessive linear ubiquitination and increased HOIP binding. As such, a HOIP inhibitor restricted the excessive angiogenesis of ECs derived from ALK1G309S-expressing HHT2 patients. These results show that OTULIN and LUBAC govern ALK1 activity to balance EC angiogenesis.
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