Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability
Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability
复制标题
DOI：
10.1073/pnas.1620306114
复制
发表时间：
2017-05-02
影响因子：
11.1
通讯作者：
Jho, Eek-Hoon
中科院分区：
文献类型：
--
作者：
Kim, Youngeun;Kim, Wantae;Jho, Eek-Hoon
Hippo信号控制着调节细胞增殖、存活和器官大小的基因的表达。磷酸化对Hippo通路核心组分的调控已经被广泛研究，但泛素化-去泛素化过程的作用在很大程度上是未知的。为了鉴定调节Hippo信号的去泛素酶，我们进行了无偏siRNA筛选，发现YOD1控制由YAP/TAZ介导的生物反应。在机制上，YOD1去泛素化ITCH （LATS的E3连接酶）并增强ITCH的稳定性，从而导致LATS水平降低和随后的YAP/TAZ水平升高。此外，我们发现mir -21介导的YOD1调控是YAP/TAZ水平细胞密度依赖性变化的原因。通过转基因小鼠模型，我们证明了YOD1的诱导表达增强了肝细胞的增殖，并以YAP/ taz活性依赖的方式导致肝肿大。此外，我们发现YOD1与YAP在肝癌患者中的表达有很强的相关性。总的来说，我们的数据强烈表明YOD1是Hippo通路的调节因子，可能是治疗肝癌的治疗靶点。
Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.