The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling.
The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling.
复制标题
泛素 E3 连接酶 TRAF6 通过 TAK1 依赖性信号传导加剧病理性心脏肥大。
DOI：
10.1038/ncomms11267
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发表时间：
2016-06-01
影响因子：
16.6
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Ji YX;Zhang P;Zhang XJ;Zhao YC;Deng KQ;Jiang X;Wang PX;Huang Z;Li H
肿瘤坏死因子受体相关因子6 （TRAF6）是一种调节重要生物过程的泛素E3连接酶。然而，TRAF6在心肌肥厚中的作用尚不清楚。在这里，我们发现TRAF6水平在人类和小鼠肥厚的心脏中升高，这是由活性氧（ROS）的产生调节的。心脏特异性Traf6过表达加剧了压力过载或血管紧张素II （Ang II）挑战时心脏肥大，而Traf6缺乏导致小鼠肥厚表型减轻。在机制上，我们发现在肥厚进展过程中产生的ROS触发TRAF6自泛素化，促进TAB2的募集及其与转化生长因子β活化激酶1 （TAK1）的结合，进而使TRAF6 - TAK1直接相互作用并促进TAK1泛素化。TRAF6与TAK1的结合以及TAK1泛素化和活化的诱导对于TRAF6调控的心脏重构是必不可少的。综上所述，我们将TRAF6定义为以tak1依赖的方式导致心脏肥厚的重要分子开关。TRAF6是一种调节许多生物过程的泛素E3连接酶。本文作者表明，病理性心脏应激过程中产生的ROS诱导TRAF6自身泛素化和活化，促进其与TAK1的相互作用和泛素化，从而促进心脏肥厚的发生。
Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a ubiquitin E3 ligase that regulates important biological processes. However, the role of TRAF6 in cardiac hypertrophy remains unknown. Here, we show that TRAF6 levels are increased in human and murine hypertrophied hearts, which is regulated by reactive oxygen species (ROS) production. Cardiac-specific Traf6 overexpression exacerbates cardiac hypertrophy in response to pressure overload or angiotensin II (Ang II) challenge, whereas Traf6 deficiency causes an alleviated hypertrophic phenotype in mice. Mechanistically, we show that ROS, generated during hypertrophic progression, triggers TRAF6 auto-ubiquitination that facilitates recruitment of TAB2 and its binding to transforming growth factor beta-activated kinase 1 (TAK1), which, in turn, enables the direct TRAF6–TAK1 interaction and promotes TAK1 ubiquitination. The binding of TRAF6 to TAK1 and the induction of TAK1 ubiquitination and activation are indispensable for TRAF6-regulated cardiac remodelling. Taken together, we define TRAF6 as an essential molecular switch leading to cardiac hypertrophy in a TAK1-dependent manner. TRAF6 is a ubiquitin E3 ligase regulating a number of biological processes. Here the authors show that ROS, generated during pathological cardiac stress, induces TRAF6 auto-ubiquitination and activation, promoting its interaction with and ubiquitination of TAK1 that contributes to development of cardiac hypertrophy.