Multisite interaction with Sufu regulates Ci/Gli activity through distinct mechanisms in Hh signal transduction
Multisite interaction with Sufu regulates Ci/Gli activity through distinct mechanisms in Hh signal transduction
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DOI：
10.1073/pnas.1421628112
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发表时间：
2015-05-19
影响因子：
11.1
通讯作者：
Jiang, Jin
中科院分区：
文献类型：
--
作者：
Han, Yuhong;Shi, Qing;Jiang, Jin
肿瘤抑制蛋白suppressor of fused （Sufu）通过抑制Cubitus interruptus (Ci)/ glii（胶质瘤相关癌基因同源物）转录因子在Hedgehog （Hh）信号通路中发挥保守作用，但Sufu抑制Ci/Gli活性的分子机制尚不清楚。本研究表明，除了先前确定的n端位点（SIN）外，苏福还可以通过c端苏福相互作用位点（SIC）结合Ci/Gli，并且苏福对Ci/Gli的最佳抑制需要SIC和SIN。我们发现Sufu可以通过与SIN结合将Ci/Gli隔离在细胞质中，同时依赖于SIC抑制细胞核中Ci/Gli的活性。我们还发现，Sufu与SIC和Ci中间区域的结合可以通过掩盖其在Ci c端区域的结合位点来阻碍转录辅激活子CBP的募集。事实上，将cbp结合位点移动到“暴露”位置可以使Ci抵抗sufu介导的细胞核抑制。因此，我们的研究在Ci/Gli的c端区发现了一个以前未被发现的和保守的Sufu结合基序，并提供了Sufu如何抑制细胞核中Ci/Gli活性的机制见解。
The tumor suppressor protein Suppressor of fused (Sufu) plays a conserved role in the Hedgehog (Hh) signaling pathway by inhibiting Cubitus interruptus (Ci)/Glioma-associated oncogene homolog (Gli) transcription factors, but the molecular mechanism by which Sufu inhibits Ci/Gli activity remains poorly understood. Here we show that Sufu can bind Ci/Gli through a C-terminal Sufu-interacting site (SIC) in addition to a previously identified N-terminal site (SIN), and that both SIC and SIN are required for optimal inhibition of Ci/Gli by Sufu. We show that Sufu can sequester Ci/Gli in the cytoplasm through binding to SIN while inhibiting Ci/Gli activity in the nucleus depending on SIC. We also find that binding of Sufu to SIC and the middle region of Ci can impede recruitment of the transcriptional coactivator CBP by masking its binding site in the C-terminal region of Ci. Indeed, moving the CBP-binding site to an "exposed" location can render Ci resistant to Sufu-mediated inhibition in the nucleus. Hence, our study identifies a previously unidentified and conserved Sufubinding motif in the C-terminal region of Ci/Gli and provides mechanistic insight into how Sufu inhibits Ci/Gli activity in the nucleus.