Li Tongchao, Fan Junkai, Blanco-Sánchez Bernardo, Giagtzoglou Nikolaos, Lin Guang, Yamamoto Shinya, Jaiswal Manish, Chen Kuchuan, Zhang Jie, Wei Wei, Lewis Michael T, Groves Andrew K, Westerfield Monte, Jia Jianhang, Bellen Hugo J
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
Markey Cancer Center and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.
PLoS Genet. 2016 May 19;12(5):e1006054. doi: 10.1371/journal.pgen.1006054. eCollection 2016 May.
Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.
刺猬信号通路（Hh）调节后生动物发育和组织稳态的多个方面，并且在众多癌症中呈组成性激活。我们鉴定出E3泛素连接酶Ubr3是果蝇和脊椎动物中Hh信号通路的一种新型正向调节因子。Hh信号通路调节Ubr3介导的Hh信号通路核心组分Cos2的多聚泛素化和降解。在发育中的果蝇眼盘中，ubr3缺失导致光感受器分化延迟以及Hh信号通路减弱。在斑马鱼中，Ubr3缺失导致发育中的眼睛、体节和感觉神经元中Shh信号通路减弱。然而，在斑马鱼中，并非所有需要Hh信号通路的组织都会受到影响。小鼠UBR3使Cos2的哺乳动物同源物Kif7发生多聚泛素化。最后，UBR3缺失上调培养细胞中Kif7蛋白水平并减弱Hh信号通路。总之，我们的研究确定Ubr3是一种新型的、进化上保守的Hh信号通路调节因子，它在某些组织中增强Hh信号。
