Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation
Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation
复制标题
葡萄糖传感器 O-GlcNAc 酰化对 Hippo-YAP 通路的调节
DOI：
10.1016/j.molcel.2017.10.010
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发表时间：
2017-11-02
期刊：
影响因子：
16
通讯作者：
Pei, Huadong
中科院分区：
文献类型：
--
作者：
Peng, Changmin;Zhu, Yue;Pei, Huadong
Hippo通路在器官大小控制和组织稳态中至关重要，失调会导致癌症。细胞外营养信号，如葡萄糖，调节Hippo途径的激活。然而，其机制尚不清楚。在这里，我们发现Hippo途径直接受己糖胺生物合成途径（HBP）的调节，以响应代谢营养素。从机制上讲，Hippo途径的核心组分（雅普）是在丝氨酸109处被O-GlcNAc转移酶（OGT）酰化的O-GlcNAc。雅普O-GlcNAc化破坏其与上游激酶LATS 1的相互作用，阻止其磷酸化，并激活其转录活性。这种激活不依赖于AMPK。我们还确定OGT作为YAP调节的基因，形成一个反馈回路。最后，我们证实葡萄糖诱导的雅普O-GlcNAc化和活化促进肿瘤发生。总之，我们的数据建立了HBP在直接连接细胞外葡萄糖信号与Hippo-YAP通路和肿瘤发生中的分子机制和功能意义。
The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.