Dose-dependent phosphorylation and activation of Hh pathway transcription factors.
Dose-dependent phosphorylation and activation of Hh pathway transcription factors.
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DOI：
10.26508/lsa.202201570
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发表时间：
2022-11
影响因子：
4.4
通讯作者：
Jiang, Jin
中科院分区：
文献类型：
--
作者：
Zhou, Mengmeng;Han, Yuhong;Wang, Bing;Cho, Yong Suk;Jiang, Jin
Hh梯度被翻译成多个Fu/CK1磷酸化位点的Ci/Gli磷酸化梯度，通过逐渐减轻sufu介导的抑制作用，逐渐增加CiA/GliA活性。分级Hedgehog （Hh）信号是由分级Cubitus interruptus (Ci)/Gli转录活性介导的，但Hh梯度如何转化为Ci/Gli活性梯度仍然知之甚少。在这里，我们发现分级Hh诱导多个融合(Fu)/CK1位点的Ci磷酸化逐渐增加，包括位于c端sufu结合域的一个簇。我们证明Fu直接磷酸化了S1382上的Ci，引发了相邻位点上CK1的磷酸化，并且Fu/CK1介导的c端磷酸化干扰了Sufu结合并促进了Ci的激活。n端、中间和c端Fu/CK1位点的磷酸化相互独立地发生，并且随着Hh水平的增加或Hh暴露时间的增加而逐渐增加。增加Fu/CK1位点的磷酸化模拟突变数量，通过减轻sufu介导的抑制作用，导致Ci激活逐渐增加。我们发现c端Fu/CK1磷酸化簇在Gli2中是保守的，并有助于其剂量依赖性激活。我们的研究表明Hh信号梯度被翻译成Ci/Gli磷酸化梯度，通过逐渐释放sufu介导的抑制来激活Ci/Gli。
The Hh gradient is translated into a phosphorylation gradient of Ci/Gli at multiple Fu/CK1 phosphorylation sites, which progressively increases CiA/GliA activity by gradually alleviating Sufu-mediated inhibition. Graded Hedgehog (Hh) signaling is mediated by graded Cubitus interruptus (Ci)/Gli transcriptional activity, but how the Hh gradient is converted into the Ci/Gli activity gradient remains poorly understood. Here, we show that graded Hh induces a progressive increase in Ci phosphorylation at multiple Fused (Fu)/CK1 sites including a cluster located in the C-terminal Sufu-binding domain. We demonstrated that Fu directly phosphorylated Ci on S1382, priming CK1 phosphorylation on adjacent sites, and that Fu/CK1-mediated phosphorylation of the C-terminal sites interfered with Sufu binding and facilitated Ci activation. Phosphorylation at the N-terminal, middle, and C-terminal Fu/CK1 sites occurred independently of one another and each increased progressively in response to increasing levels of Hh or increasing amounts of Hh exposure time. Increasing the number of phospho-mimetic mutations of Fu/CK1 sites resulted in progressively increased Ci activation by alleviating Sufu-mediated inhibition. We found that the C-terminal Fu/CK1 phosphorylation cluster is conserved in Gli2 and contributes to its dose-dependent activation. Our study suggests that the Hh signaling gradient is translated into a Ci/Gli phosphorylation gradient that activates Ci/Gli by gradually releasing Sufu-mediated inhibition.
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影响因子：
9.8
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通讯作者：
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