Stability of HIB-Cul3 E3 ligase adaptor HIB Is Regulated by Self-degradation and Availability of Its Substrates.
Stability of HIB-Cul3 E3 ligase adaptor HIB Is Regulated by Self-degradation and Availability of Its Substrates.
复制标题
HIB-Cul3 E3 连接酶接头 HIB 的稳定性受其底物的自降解和可用性的调节。
DOI：
10.1038/srep12709
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发表时间：
2015-08-12
影响因子：
4.6
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Zhou Z;Xu C;Chen P;Liu C;Pang S;Yao X;Zhang Q
HIB-Cul 3复合物E3连接酶通过调节其底物稳定性来调节生理稳态，并且其活性可以通过改变HIB丰度来调节。然而，HIB的监管仍然难以捉摸。在这里，我们提供的证据表明，HIB是通过蛋白酶体Cul 3介导的多泛素化K48的方式在果蝇。引人注目的是，HIB本身就是降解的目标。我们进一步确定了HIB的三个降解决定子（52 LKSS 56 T、76 LDEE 80 S和117 MESQ 121 R）以及K185和K198对HIB的自降解是必需的。最后，我们证明HIB-Cul 3底物Ci和Puc可以有效保护HIB免受HIB-Cul 3介导的降解。总之，我们的研究表明，有一个精致的平衡之间的衔接和目标，以实现HIB的严格控制，这是必不可少的维持适当的Hh和JNK信号。衔接子自身降解和衔接子与其底物之间丰度相互控制的机制也适用于BTB-Cul 3 E3连接酶衔接子dKeap 1、dDiablo和dKLHL 18。
The HIB-Cul3 complex E3 ligase regulates physiological homeostasis through regulating its substrate stability and its activity can be modulated by changing HIB abundance. However, regulation of HIB remains elusive. Here we provide evidence that HIB is degraded through the proteasome by Cul3-mediated polyubiquitination in K48 manner in Drosophila. Strikingly, HIB is targeted for degradation by itself. We further identify that three degrons (52LKSS56T, 76LDEE80S and 117MESQ121R) and K185 and K198 of HIB are essential for its auto-degradation. Finally, we demonstrate that HIB-Cul3 substrates, Ci and Puc, can effectively protect HIB from HIB-Cul3-mediated degradation. Taken together, our study indicates that there is an exquisite equilibrium between the adaptor and targets to achieve the tight control of the HIB, which is essential for maintaining suitable Hh and JNK signaling. And the mechanism of adaptor self-degradation and reciprocal control of the abundance between adaptor and its substrates is also applied to BTB-Cul3 E3 ligase adaptor dKeap1, dDiablo and dKLHL18.