Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway.
Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway.
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DOI：
10.1038/nchembio.2036
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发表时间：
2016-04
影响因子：
14.8
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Chan P;Han X;Zheng B;DeRan M;Yu J;Jarugumilli GK;Deng H;Pan D;Luo X;Wu X
TEA结构域（TEAD）转录因子与共激活因子雅普/TAZ结合，调节Hippo通路的转录输出，在器官大小控制和肿瘤发生中起重要作用。蛋白质S-棕榈酰化将脂肪酸（棕榈酸）连接到半胱氨酸残基上，并调节蛋白质运输、膜定位和信号传导活动。使用基于活性的化学探针，我们发现人TEAD具有内在的棕榈酰化酶样活性，并在生理条件下在进化上保守的半胱氨酸残基处进行自棕榈酰化。我们确定了脂质结合的TEAD的晶体结构，并发现棕榈酸酯的脂质链插入到一个保守的深疏水口袋。值得注意的是，棕榈酰化是TEAD与雅普/TAZ结合所必需的，但与Vgll 4肿瘤抑制因子结合则是必需的。此外，棕榈酰化不改变TEAD的定位。此外，TEAD棕榈酰化缺陷突变体损害TAZ介导的肌肉分化在体外，和约克介导的组织过度生长在果蝇体内。我们的研究直接将自棕榈酰化与Hippo通路的转录调控联系起来。
TEA domain (TEAD) transcription factors bind to the co-activator YAP/TAZ, and regulate the transcriptional output of Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches fatty acid (palmitate) to cysteine residues, and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme-like activities, and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs, and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation is required for TEAD’s binding to YAP/TAZ, but dispensable for the binding to Vgll4 tumor suppressor. In addition, palmitoylation does not alter TEAD’s localization. Moreover, TEAD palmitoylation-deficient mutants impaired TAZ-mediated muscle differentiation in vitro, and Yorkie-mediated tissue overgrowth in Drosophila in vivo. Our study directly linked autopalmitoylation to the transcriptional regulation of Hippo pathway.