YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]. YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

The Hippo pathway downstream effectors YAP and TAZ display oncogenic potential via their transcriptional co-activator function, mediated primarily by binding to TEAD transcription factors. Many studies have focused on identifying YAP/TAZ-TEAD target genes, but their role in the regulation of protein synthesis has remained largely unexplored. Here we show that YAP activation is sufficient to overcome the global translation restriction of 5TOP-containing mRNAs, which is induced by serum deprivation and dependent on the inactivation of mTORC1. We found that YAP/TAZ repressed the expression of DDIT4, a negative regulator of mTORC1 whose expression is otherwise upregulated by serum deprivation. Forced expression of DDIT4 was sufficient to suppress translation and transformative potential of serum-unresponsive uveal melanoma cells, which harbor G protein mutations. Our findings highlight crosstalk between Hippo-YAP/TAZ and mTORC1 pathways in the regulation of translation and offer a new perspective towards understanding YAP/TAZ-driven malignancies. Overall design: Ribo-seq data of 293AD cells expressing vector control or FLAG-YAP 5SA, subjected to (or not) overnight (14 h) serum deprivation

Hippo信号通路（Hippo pathway）的下游效应因子YAP与TAZ主要通过结合TEAD转录因子（TEAD transcription factors）发挥转录共激活因子功能，进而展现致癌潜能。既往诸多研究聚焦于鉴定YAP/TAZ-TEAD的靶基因，但二者在蛋白质合成调控中的作用仍未得到充分探索。本研究发现，YAP激活足以克服由血清饥饿诱导、依赖mTOR复合物1（mTORC1）失活的5'端寡聚嘧啶修饰信使RNA（5'TOP-containing mRNAs）的全局翻译阻滞。我们观察到，YAP/TAZ可抑制DNA损伤诱导转录因子4（DDIT4）的表达；DDIT4是mTORC1的负调控因子，正常情况下其表达会因血清饥饿而上调。强制表达DDIT4即可抑制携带G蛋白突变的血清无响应型葡萄膜黑色素瘤（uveal melanoma）细胞的翻译能力与致瘤潜能。本研究结果揭示了Hippo-YAP/TAZ与mTORC1通路在翻译调控中的串扰效应，为理解YAP/TAZ驱动的恶性肿瘤提供了全新视角。实验设计：对表达空载体对照或FLAG-YAP 5SA的293AD细胞进行核糖体测序（Ribo-seq），样本分别经过（或未经过）14小时的血清饥饿处理。