Ubiquitination and degradation of Tal1/SCL are induced by Notch signaling and depend on Skp2 and CHIP
Ubiquitination and degradation of Tal1/SCL are induced by Notch signaling and depend on Skp2 and CHIP
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DOI：
10.1074/jbc.m704981200
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发表时间：
2008-01-11
影响因子：
4.8
通讯作者：
Sun, Xiao-Hong
中科院分区：
文献类型：
--
作者：
Nie, Lei;Wu, Huaqing;Sun, Xiao-Hong
Notch信号传导控制多种细胞类型中的多种真核分化过程，因此需要Notch触发下游事件的通用工具。泛素介导的蛋白水解以前已被证明是一个这样的工具，其中Notch调节的基本螺旋-环-螺旋转录因子，E47的营业额。在这里，我们发现Notch信号也加速了Tal 1/SCL（T细胞急性白血病1/干细胞白血病）蛋白的降解，这是一种参与造血、血管和神经组织发育的基本螺旋-环-螺旋蛋白。Notch诱导的Tal 1/SCL降解由泛素化和蛋白酶体介导。负责Tal 1降解的序列定位于Tal 1的C末端的区域，其在进化上是保守的，从而表明功能意义。与E47的情况类似，Notch诱导的Tal 1/SCL降解不仅需要SCF泛素连接酶复合物的底物结合亚基Skp 2，而且还依赖于具有泛素连接酶活性的伴侣结合蛋白CHIP。与CHIP的N-末端三肽区（TPR）结构域对于E47泛素化和降解是必需和充分的事实相反，CHIP促进Tal 1降解，同时具有伴侣结合和泛素连接酶活性，这分别由其TPR结构域和U盒介导。虽然TPR结构域不参与Tal 1/SCL结合，但它是增强其降解所必需的。同样地，CHIP的泛素连接酶活性对于Tal 1/SCL结合是不稳定的，但对于降解是必需的。这些发现提供了新的机制的见解cullin为基础的泛素连接酶复合物的操作和潜在的手段，Notch和Tal 1/SCL调节真核生物的发展。
Notch signaling controls diverse eukaryotic differentiation processes in multiple cell types, thus demanding versatile tools with which Notch triggers downstream events. Ubiquitin-mediated proteolysis has previously been shown to be one such tool with which Notch regulates the turnover of the basic helix-loop-helix transcription factor, E47. Here, we show that Notch signaling also accelerated the degradation of Tal1/SCL ( T cell acute leukemia 1/stem cell leukemia) protein, a basic helix-loop-helix protein involved in the development of hematopoietic, vascular, and neuronal tissues. Notch-induced Tal1/SCL degradation was mediated by ubiquitination and proteasomes. The sequence responsible for Tal1 degradation was localized to a region in the C terminus of Tal1, which is evolutionarily conserved, thus suggesting a functional significance. Analogous to the situation for E47, Notch-induced Tal1/SCL degradation not only required Skp2, a substrate-binding subunit of SCF ubiquitin ligase complexes, but also relied on CHIP, a chaperone-binding protein with a ubiquitin ligase activity. In contrast to the fact that the N-terminal tetratricopeptide region (TPR) domain of CHIP is necessary and sufficient for E47 ubiquitination and degradation, CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively. Although the TPR domain was not involved in Tal1/SCL binding, it was required for enhancing its degradation. Likewise, the ubiquitin ligase activity of CHIP was dispensable for Tal1/SCL binding but essential for degradation. These findings provide both novel mechanistic insights into the operation of cullin-based ubiquitin ligase complexes and potential means by which Notch and Tal1/SCL regulate eukaryotic development.