Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions.
Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions.
复制标题
作者：
Werner A;Baur R;Teerikorpi N;Kaya DU;Rape M
后生动物的发育依赖于严格调控的基因表达程序，这些程序指示祖细胞采用特殊的命运。最近的工作发现，翻译后修饰，如单泛素化，也可以决定细胞的命运，而不依赖于对转录的影响，然而，单泛素化是如何在发育过程中实现的还知之甚少。在这里，我们已经确定了一个调控电路，通过E3连接酶CUL3及其底物适配器KBTBD8来控制依赖于单糖基化的神经脊的规范。我们发现，CUL3KBTBD8只有在CK2在多个基序中被磷酸化后，CUL3KBTBD8才会对其重要的靶点进行单泛素化，CK2是一种在胚胎发育过程中其水平逐渐上升的激酶。它对多位点磷酸化的依赖使CUL3KBTBD8能够将胚胎中缓慢上升的CK2转变为对泛素化底物的决定性识别，这反过来对神经脊的指定至关重要。我们的结论是，E3连接酶的多位点依赖性为单糖基化控制的开关样细胞命运转移提供了一个强大的机制。
Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8 to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation.